Structural Heart Disease

Chapter 1: Hypertension: Causes, investigations, complications & treatment

Hypertension is the leading cause of morbidity and mortality worldwide. The individual and public health effects of hypertension are devastating. Due to the simplicity of diagnosing hypertension and the effectiveness of antihypertensive treatments, targeting hypertension is the single most effective public health measure available (Ezzati et al, Lim et al). Approximately 90–95% of individuals with hypertension have essential hypertension, also referred to as primary hypertension. Essential hypertension is defined as hypertension without an identifiable underlying cause. Researchers previously believed that this form of hypertension was a physiological reaction that was necessary to maintain normal hemodynamics, hence the term essential. However, a growing body of science suggests that essential hypertension is a multifactorial disease caused by a complex interplay between genes and environment. Industrialization and a Western lifestyle are strongly related to the development of hypertension. Developing and non-Western countries rarely display the blood pressure trajectories and high prevalence of hypertension that is ubiquitous in high-income Western countries. Fortunately, modern antihypertensive therapy enables most patients to return to normal blood pressure (normotension). Combination therapy with multiple antihypertensives is often necessary to normalize blood pressure. Management of hypertension requires careful consideration of other cardiovascular risk factors and coexisting conditions. Therapy must be tailored to each patient.

Optimal blood pressure

Optimal blood pressure is 115 mm Hg systolic and 75 mm Hg diastolic (115/75 mm Hg). Thus, optimal blood pressure is significantly lower than the current threshold for hypertension, and the current treatment target levels for patients with and without diabetes. The threshold for hypertension is currently 140 mm Hg systolic or 90 mm Hg diastolic (140/90 mm Hg). The discordance between optimal blood pressure and the definition of hypertension is explained by a cost-benefit equation. The benefits of interventions for hypertension exceeds the risks and costs at 140/90 mm Hg. However, it may be argued that this cutoff is somewhat arbitrary and there may be individual benefits of initiating treatment at lower blood pressure levels.

KEY POINTS• The risk of cardiovascular disease increases gradually at blood pressure levels above 115/75 mm Hg.• A rise in blood pressure of 20 mm Hg systolic or 10 mm Hg diastolic leads to a doubling of the risk of stroke and acute myocardial infarction.• The threshold for diagnosing hypertension is systolic blood pressure 140 mm Hg or diastolic blood pressure 80 mm Hg or higher.• Approximately 50% of all cardiovascular events attributable to hypertension occur in individual with blood pressure below the cutoff for hypertension (Lewington et al, Lawes et al, Pulter et al).

Epidemiology of hypertension

Blood pressure is normally distributed in the population. Individual blood pressure increases gradually during the life course (Balijepalli et al).Blood pressure is positively correlated with societal economic development, age, alcohol intake, body weight, male sex and salt intake. Population blood pressure increases in parallel with economic development and industrialization.The increasing prevalence of obesity, diabetes, sedentary lifestyle, the rapid economic development and ageing of most populations is driving the rapid increase in the global prevalence of hypertension.It is estimated that between 15% and 37% of the global population have hypertension and the prevalence is increasing rapidly (Pulter et al, Lim et al). Thus, the current and impending burden of disease caused by hypertension is inapprehensible.

KEY POINT: >1 billion individuals worldwide have hypertension.

Symptoms of hypertension

Hypertension is most often asymptomatic. The high prevalence and asymptomatic nature of the disease motivates liberal screening among adults, in order to detect disease before complications arise.

Non-specific symptoms of hypertension include the following:

HeadacheReduced exercise capacityTiredness, fatigueDyspneaNosebleedsFlushingVertigo (dizziness)Chest discomfort (chest pain)Hematuria (blood in urine)

These symptoms are non-specific and (among individuals with hypertension) it is difficult to determine whether these symptoms are due to elevated blood pressure or other causes.

Other signs of hypertension are related to complications, e.g coronary artery disease (angina pectoris) acute myocardial infarction (acute chest pain), stroke, heart failure (dyspnea, edema, tachycardia), renal failure.

Physiological regulation of blood pressure

Blood pressure is the pressure in larger arteries. Systolic blood pressure is the pressure in the arteries during systole (i.e the highest pressure during the cardiac cycle). Diastolic blood pressure is the pressure in the arteries during diastole (i.e the lowest pressure during the cardiac cycle). The average (mean) blood pressure in the arteries (MAP, mean arterial pressure) is the product of cardiac output and total peripheral resistance:

MAP = TPR × CO

Systolic and diastolic blood pressure are easier to measure than total peripheral resistance and cardiac output. Moreover, MAP can be estimated using systolic and diastolic pressure, according to the following formula:

MAP = [SBP + (DBP×2)] / 3SBP = systolic blood pressure; DBP = diastolic blood pressure.

Neurohormonal mechanisms

Multiple physiological mechanisms interact to control blood pressure by influencing cardiac output and and total peripheral resistance. The renin–angiotensin–aldosterone system (RAAS) has a fundamental role in regulating blood pressure. RAAS includes several effector molecules that control vascular tone and fluid balance. Activation of RAAS leads to fluid retention, increased vascular tone (vasoconstriction) and unfavorable changes in the myocardium, kidneys and blood vessels. Inhibition of RAAS results in fluid excretion and reduced vascular tone (vasodilation); it also alleviates the unfavorable cellular changes in the myocardium, kidneys and endothelium.

Left ventricular function

Left ventricular function is crucial for the ability to generate systolic pressure and maintain diastolic pressure. Impaired systolic function or diastolic function leads to heart failure, reduced cardiac output, and ultimately a reduction in blood pressure. Heart failure is always associated with increased atrial and ventricular filling pressure, which results in secretion of natriuretic peptides (BNP and NT-proBNP). These peptides increase diuresis and exert vasodilating effects.

Blood vessels and the autonomous nervous system

Blood vessels have a fundamental role in regulating blood pressure. An array of hormones (including RAAS effectors), neurotransmitters (autonomic nervous system) and local signal substances (e.g nitric oxide [NO]) interact to continuously regulate vascular tone. The autonomic nervous system also regulates blood pressure via stretch receptors (baroreceptors) in the carotid body (carotid sinus in the common carotid artery). High systolic blood pressure leads to distention of the carotid sinus, which stimulates baroreceptors to increase signaling to the hypothalamus. This prompts the hypothalamus to decrease sympathetic output in order to lower blood pressure. People with high blood pressure typically have higher activity in the sympathetic nervous system, as compared to normotensive individuals.

Intake of salt (sodium) and potassium

Salt balance is strongly correlated with fluid balance and, consequently, blood pressure. Reducing the intake of salt (sodium) can lower blood pressure. In contrast, increased intake of potassium results in lowering of blood pressure (refer to Treatment of hypertension below).

Fluid intake

Fluid intake is likewise an important factor. High fluid intake elevates blood pressure, at least transiently. Dehydration results in lower blood pressure, at least transiently. The transient effect is explained by the activation of several neurohormonal (e.g RAAS) systems that counteract the effect of excess fluid intake or dehydration.

Renal function

Kidney function is also important for blood pressure regulation. Renal failure results in fluid retention, disturbance of RAAS, and electrolyte disturbances. Aldosterone exerts its effects in the kidneys by increasing fluid retention, in addition to its vasoconstricting effects.

Definition of hypertension

The threshold for diagnosing hypertension is systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg. The relation between blood pressure and risk of cardiovascular disease is continuous, such that the risk of cardiovascular events and complications increases gradually as blood pressure rises above the optimal level, i.e 115/75 mm Hg.

Although optimal blood pressure is considered to be 115/75 mm Hg, the threshold for hypertension is ≥140 mm Hg systolic and ≥90 mm Hg diastolic. There is consensus that the level 140/90 mm Hg represents the threshold where the benefit of interventions outweighs the risks and costs.

Degrees of hypertension

Hypertension is graded from I to III (Table 1). Most studies indicate that systolic blood pressure is a stronger predictor (i.e risk factor) of cardiovascular events and long-term complications, as compared with diastolic blood pressure. Whether this difference reflects a true causal differences remains elusive. (It is mathematically difficult to disentangle variables that are strongly correlated, regardless of whether regression methods or machine learning methods are used).

The risk of cardiovascular disease increases when systolic blood pressure exceeds 115 mm Hg or when diastolic blood pressure exceeds 75 mm Hg. That means the risk of cardiovascular complications increases already below the threshold for hypertension.

TABLE 1. CLASSIFICATION OF HYPERTENSION.

Classification	Systolic pressure (mm Hg)		Diastolic pressure(mm Hg)
Optimal	115 (<120)	and	75 (<80)
Normal	120–129	and/or	80–84
High normal	130–139	and/or	85–89
Grade Ihypertension	140–159	and/or	90–99
Grade IIhypertension	160–179	and/or	100–109
Grade IIIhypertension	≥180	and/or	≥110
Isolated systolic hypertension	≥140	and	<90

Blood pressure variability

The cumulative (total) risk conferred by a cardiovascular risk factor can be assessed in terms of area under the curve, where the x-axis represents time and y-axis represents the value for that specific risk factor. The area under the curve represents the overall burden that the risk factor brings over time. For LDL cholesterol the area under the curve is simply the total amount of LDL cholesterol that the vascular tree is exposed to over time. Individuals with high LDL cholesterol are exposed to more LDL cholesterol over time, as compared with individuals with lower LDL levels during the same time period. Temporary fluctuations in LDL cholesterol have no significant effect on cardiovascular risk; it is the total amount that determines risk. The same concept can be applied to blood pressure. However, with regards to blood pressure, the following must be noted:

Blood pressure variability is defined as episodic and pronounced increases in blood pressure. Such variations are associated with increased risk of cardiovascular events, notably stroke (Pulter et al).A very large increase in blood pressure (hypertensive crisis) may immediately cause hemorrhagic stroke or aortic dissection.

Hence, with regards to blood pressure, early diagnosis and continuous monitoring is important to reduce cardiovascular risk.

Measuring blood pressure

Routine office measurement of blood pressure:

The patient should sit relaxed for 5 minutes before measuring blood pressure.Measurement is done with the cuff placed at the level of the heart.The cuff is inflated until the palpable pulse in the radial artery cannot be felt.The cuff is deflated slowly, while listening in the stethoscope.The first sound (Korotkoff sound 1) is heard when blood pressure is equivalent to systolic blood pressure.When the pulsating sound disappears, the pressure is equivalent to diastolic pressure.Repeat the measurement 2 or 3 times and calculate the mean of the measurements. The documented blood pressure is the mean value.

If the pressure is above the threshold for hypertension (140/90 mm Hg), then a second measurement should be performed after a few days. If the pressure remains elevated on the second measurement, a diagnosis of hypertension is made. Occasionally, three measurements are needed.

When hypertension is confirmed, the pressure in both arms should be compared. A pressure difference greater than 15 mm Hg should prompt careful investigation for atherosclerotic disease and, in young individuals, aortic coarctation. A pressure difference larger than 15 mm Hg is common in individuals with severe atherosclerosis.

Measuring blood pressure with automatic blood pressure monitor yields a few units (mercury) lower blood pressure, as compared with manual measurement. Table 2 presents thresholds for hypertension with different methods for measurement.

TABLE 2. THRESHOLDS FOR HYPERTENSION WITH DIFFERENT METHODS

Method	Time	Systolic pressure (mm Hg)	Diastolic pressure (mm Hg)
Office / clinic blood pressure		≥140	≥90
Ambulatory blood pressure	Daytime	≥135	≥85
	Night-time	≥120	≥70
	24 h mean	≥130	≥80
Home blood pressure		≥135	≥85

When investigating suspected hypertension, two to three measurements are usually made at the primary care or outpatient clinic. However, 24-hour ambulatory blood pressure has the highest sensitivity and specificity for hypertension. Cost analysis suggests that ambulatory blood pressure measurement is cost-effective and excludes 25% of all cases of white coat hypertension (UK NICE Guidelines).

Masked hypertension

Masked hypertension means that office measurements of blood pressure are normal, but ambulatory measurements confirms that the patient is hypertensive. Masked hypertension is a topic under intensive research. Given that masked hypertension may be common, it is justifiable to encourage patients to monitor their blood pressure at home using blood pressure monitors available to consumers.

White coat hypertension

Up to 25% of people with hypertension on office measurements have normal blood pressure when repeating measurements at home. This condition, in which blood pressure is temporarily elevated while in the clinic, is referred to as white coat hypertension. In case of suspicion of white coat hypertension, a 24-hour ambulatory measurement should be performed.

Risk factors for hypertension

HeredityHigh ageHigh alcohol intakeMetabolic syndromePhysical inactivitySmokingDiabetesObesityHigh calorie intakeHigh salt intakePsychosocial stressSleep apneaAtherosclerotic vascular disease.

Complications of hypertension

Heart failure, left ventricular dysfunctionMyocardial infarction (acute coronary syndromes)Coronary heart disease (ischemic heart disease)Stroke (ischemic stroke, intracerebral hemorrhage)Kidney failureAtrial fibrillationPeripheral vascular disease (PAD)DementiaVisual impairment

Essential hypertension

Constitutes 90–95% of all cases of hypertension.Typically middle-aged and elderly individuals.Pathophysiology unknown. Strong association with industrialization, sedentary lifestyle, increasing age, alcohol, salt intake and genetic predisposition (heredity). It is believed that 30% of the risk is attributable to genetics. Over 100 genetic loci have been identified. The individual effect of each locus is very small.

Secondary hypertension

Secondary hypertension is defined as hypertension caused by an identifiable disease, e.g endocrine disorder, kidney disease, drug side effect. Common causes of secondary hypertension are as follows:

Conn’s diseaseCushing syndrome: overweight, polyuria, polydipsia, diabetes, Cushing phenotype, moon face, buffalo-hump, striae, hirsutism.Renal artery stenosis: renal impairment (declining eGFR, increasing creatinine), abdominal murmur on auscultation.Pheochromocytoma: headache, sudden sweating and pallor (flush), palpitations, sudden increases in blood pressure.Chronic kidney disease (CKD): CKD causes hypertension.Liddle syndrome: genetic (monogenic) disease that causes hypertension.

Secondary hypertension tends to debut earlier in life. Secondary hypertension should be suspected if antihypertensive has insufficient effect, despite combination therapy and adequate dose titration.

Routine examinations in patients with hypertension

Medical history, with emphasis on cardiovascular disease.Physical examination, with emphasis on cardiovascular disease.Heredity for hypertension?Specific questions: Tobacco habits, dietary habits, licorice consumption, physical activity, salt intake, potassium intake, medications.Blood tests: glucose (HbA1c), sodium, potassium, TSH, T3, T4, ALT, AST, gamma-GT, lipids (total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol), creatinine, eGFR.Specific blood tests if suspicion of secondary hypertension.Consider referral to echocardiography in case of cardiac murmur.Consider analysing natriuretic peptides (BNP, NT-proBNP) if signs or symptoms of heart failure.Consider referral for CTCA*, myocardial perfusion scintigraphy or stress echocardiography if signs or symptoms of coronary artery disease.Consider primary prevention with statins if high 10-year risk of vascular events.

*CTCA = Computerized tomography or coronary arteries

Treatment of hypertension

Diet and lifestyle treatments

Reduce intake of salt to <5 g/ day. This is recommended despite the fact that there is data questioning the effect of this. Presumably, the effect of reducing intake of salt is greater among people with hypertension, compared to people with normal blood pressure. In high-income countries, the average daily salt intake is about 10 g.Increase intake of potassium. Low intake of potassium can raise blood pressure and vice versa. Recommended intake is 3.5-5.0 g/day. Do not recommend increased intake of potassium in patients with renal failure.Increase physical activity. All forms of exercise lower blood pressure. It is recommended that all patients exercise 30 to 60 minutes three times per week. This can lower systolic blood pressure by 11 mm Hg and diastolic blood pressure by 5 mm Hg (Borjesson et al).Weight loss. Losing weight results in lowering of both systolic and diastolic blood pressure.Limit intake of alcohol to 1 standard glass for women and 2 standard glasses for men (daily). This can be expected to lower blood pressure by approximately 3 mm Hg.Recommend the DASH (Dietary Approaches to Stop Hypertension) diet. DASH diet can lower systolic blood pressure by 8–14 mm Hg.

Antihypertensive medications

Although monotherapy (one drug) may be sufficient for grade I hypertension, combination therapy (2 or 3 drugs) is more effective and may cause fewer side effects (combination therapy allows for lower doses of individual drugs).Avoid combining ACE inhibitors and ARBs as these act on the same system (RAAS) and the risk of side effects, as well as the need to repeatedly measure electrolytes and kidney function, increases significantly.The treatment strategy is equal for men and women.The higher the blood pressure, the more important to lower blood pressure rapidly and substantially.

TABLE 3. ANTIHYPERTENSIVE DRUGS

Diuretics	First-line option
Calcium channel inhibitors (antagonists)	First-line option
ACE inhibitors	First-line option
Angiotensin receptor blockers (ARB)	First-line option
Beta blockers	– Secondary option in individuals without cardiovascular disease.– First-line option in individuals with heart failure, ischemic heart disease, ventricular tachyarrhythmias, atrial tachyarrythmias or left ventricular dysfunction
Alfa blockers	Secondary option.Typically used in resistant hypertension.
Aldosterone blockers	Secondary option.Typically used in resistant hypertension or in patients with heart failure.

Proposed treatment algorithm

Initiate treatment with one of the following:ACE inhibitors: enalapril 10–20 mg × 1 or ramipril 5–10 mg × 1.ARB: losartan 50–100 mg × 1 or candesartan 8–32 mg × 1.Calcium antagonist: amlodipine 5–10 mg × 1 or felodipine 2.5–5 mg × 1.Thiazide: hydrochlorothiazide 12.5–25 mg × 1 or bendroflumethiazide 2.5–5 mg × 1.If treatment effect is insufficient, add another drug from the list above and increase doses.If treatment effect remains insufficient, add a third drug.Consider adding beta-blockers (metoprolol depot 50–100 mg × 1 or bisoprolol 2.5–10 mg × 1).Alpha-blockers and aldosterone antagonists are used in resistant hypertension.

Beta blockers for hypertension

Beta-blockers are no longer a first-line option for patients with hypertension. Beta-blockers, however, should be preferred in patients with coronary heart disease (ischemic heart disease), previous myocardial infarction, heart failure, atrial fibrillation (supraventricular tachyarrhythmias), ventricular tachyarrhythmias or left ventricular dysfunction. Beta-blockers generally have a smaller effect on blood pressure than other antihypertensives.

Diuretics for hypertension

First-line option.Can be considered to anyone with hypertension.Especially suitable for patients with heart failure.Electrolytes should be assessed after initiation of therapy.Thiazide diuretics (thiazides) are well documented and well-tolerated by elderly. Potassium-sparing diuretics (amiloride) can be used in patients with hypokalemia.Loop diuretics (furosemide) represent an alternative.

Calcium antagonists for hypertension

First-line option.Amlodipine and felodipine are effective and can be considered to anyone with hypertension.Verapamil and diltiazem have negative inotropic and chronotropic effects, and are therefore contraindicated in heart failure, AV Block II and AV Block III.

ACE inhibitors for hypertension

First-line option.Preferred in cases with heart failure.Monitor electrolytes, creatinine, eGFR before and after initiation.Side effects: angioedema (rare), dry cough (10–20%), impaired renal function.Contraindicated in pregnant women.Full effect emerge after 3 to 4 weeks.

ARB (angiotensin receptor blockers) for hypertension

First-line option.Preferred in cases with heart failure.Not combined with ACE inhibitors.ARBs can replace ACE inhibitors if the latter causes unbearable cough.Contraindicated in pregnant women.Caution in renal impairment.Full effect emerge after 3 to 4 weeks.

Alpha blockers for hypertension

Doxazosin may be considered if blood pressure target level is not achieved despite the use of 2 or 3 blood pressure medications.

Aldosterone antagonists for hypertension

Preferred in cases with heart failure.For other patients, spironolactone may be given if hypertension is treatment resistant.Side effects: hyperkalemia, gynecomastia.

Special Patient Groups

Ischemic heart disease (coronary heart disease): Beta blockers are preferred, although the evidence for beta-blockers is weak in patients with normal left ventricular function. Beta blockers reduce angina pectoris.

Ventricular or supraventricular arrhythmias: Beta blockers should be preferred in patients with tachyarrhythmias. Early data shows that beta-blockers reduce the risk of ventricular tachyarrhythmias (reduction of ventricular extrasystoles and ventricular tachycardia). Beta blockers do not have anti-arrhythmic effects, but reduces ventricular rate in atrial fibrillation, atrial flutter and atrial tachycardia.

Type 1 diabetes, type 2 diabetes: ACE inhibitors and ARBs preserve renal function in diabetics and are therefore preferred.

Chronic kidney disease (renal failure): ACE inhibitors and ARBs can preserve renal function and should be preferred. Consult a nephrologist if creatinine rises >30% or eGFR drops rapidly after initiation of therapy with ACE or ARBs.

Renal denervation

The sympathetic fibers to the kidneys can be disrupted by means of radiofrequency ablation. This procedure is referred to as renal denervation. Several studies showed that renal denervation may cure resistant hypertension. However, these studies were flawed (lacking a sham control group) and subsequent studies, with rigorous methodology, showed that renal denervation had no significant effect (Bhatt et al).

References

Balijepalli et al: Percentile distribution of blood pressure readings in 35683 men and women aged 18 to 99 years. Journal of Human Hypertension volume 28, pages193–200(2014).

Lawes et al: Blood pressure and the global burden of disease 2000. Part II: estimates of attributable burden. J Hypertens 2006; 24: 423–30.

Oparil et al: Hypertension. Nature Reviews. doi:10.1038/nrdp.2018.14

Pulter et al: Hypertension. Lancet 2015; 386: 801–12.

Lim et al: A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2224–60.

Williams et al: 2018 ESC/ESH Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH). European Heart Journal, (2018).

Lewington et al: Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 360, 1903–1913 (2002).

NICE. 2011 Guidelines for Hypertension: Clinical Management of Primary Hypertension in Adults. http://publications.nice.org.uk/ hypertension-cg127 (accessed Jan 8, 2015).

Luft et al. Twins in cardiovascular genetic research. Hypertension 37, 350–356 (2001).

Fagard et al. Heritability of conventional and ambulatory blood pressures: a study in twins. Hypertension 26, 919–924 (1995).

Borjesson et al: Physical activity and exercise lower blood pressure in individuals with hypertension: narrative review of 27 RCTs. Br. J. Sports Med. 50, 356–361 (2016).

Kristina Bengtsson Bostrom et al. Hypertoni. Lakemedelsboken (2016).

Bhatt et al: A Controlled Trial of Renal Denervation for Resistant Hypertension. New England Journal of Medicine (2014).

(none)

---

Chapter 2: Heart failure: Introduction

Heart failure

Heart failure is a major public health problem worldwide. While the incidence of coronary heart disease and acute myocardial infarction has been reduced by approximately 50% during the past few decades, the incidence of heart failure has remained stable. New data suggest that the incidence of heart failure among young adults has increased in recent years (Nabel et al, Savarese et al). This is a paradoxical and worrisome trend, particularly in light of the improvements in the management of hypertension (coronary heart disease and hypertension are traditionally viewed as the main drivers of heart failure). It is believed that the aging population, and increased prevalence of obesity, diabetes, and dysglycemia are propelling the heart failure pandemic. Indeed, a growing body of evidence suggests that heart failure is now the most frequent complication of diabetes (Shah et al, McMurray et al).

Management of heart failure progressed rapidly during the 1970s and 1980s. Beta-blockers, ACE (angiotensin-converting enzyme) inhibitors, and angiotensin receptor blockers (ARB) were introduced and improved survival dramatically. When the pioneers Waagstein, Hjalmarsson, and Swedberg proposed using beta-blockers – which have negative inotropic and negative chronotropic effects – to treat heart failure, they were met with skepticism. Their landmark studies proved that beta blockers prolong life, alleviate symptoms and reduce the risk of hospitalization for patients with heart failure. Several landmark studies followed and proved that beta blockers, ACE inhibitors, and ARBs were effective for treating heart failure. The rapid advances in the 1970s and 1980s were followed by almost two decades without any major breakthrough in the management of heart failure. In 2014 the PARADIGM-HF study introduced a new drug class, the ARNI (Angiotensin–Neprilysin Inhibitors), a long-awaited breakthrough.

Heart failure is a serious condition with a poor long-term prognosis. The 5-year survival rate after hospitalization for heart failure is 60%, which is comparable to common cancers (Stewart et al). In addition, heart failure is a disabling condition with a very negative impact on quality of life. Approximately half of all patients with heart failure die suddenly, as a result of ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation). Early diagnosis and aggressive management can prolong survival, improve quality of life, reduce hospitalizations, and reduce the risk of sudden death.

According to the American Heart Association (ACA) and the European Society for Cardiology (ESC), there are three types of heart failure: HFPEF, HFmrEF and HFREF. This classification is based primarily on the measurement of left ventricular ejection fraction (LVEF). The majority of all clinical trials, epidemiological studies and mechanistic studies have been carried out in HFREF (heart failure with reduced ejection fraction). Thus, our current knowledge of heart failure is virtually synonymous with knowledge of HFREF. HFPEF (heart failure with preserved ejection fraction) and HFmrEF (heart failure with mid-range ejection fraction) are relatively new entities and there are currently no effective treatments that modify the natural course in these conditions. Yet, long-term survival is slightly better among patients with HFPEF, as compared with patients with HFREF.

Table 1. Types of heart failure.

Type	Description	Ejection fraction (%)
HFREF	Heart Failure with Reduced Ejection Fraction	<40%
HFmrEF	Heart Failure with midrange Ejection Fraction	40–49%
HFPEF	Heart Failure with Preserved Ejection Fraction	≥50%

In HEREF, left ventricular systolic function (ejection fraction) is impaired (defined as ejection fraction <40%). In HFPEF, there are clinical signs of heart failure despite normal ejection fraction (EF ≥50%). In HFMRef, there are signs of heart failure with ejection fraction in the range 40–49%.

The mechanisms causing HFPEF are unknown. Virtually all patients with HFPEF display diastolic dysfunction.

The majority of all patients with heart failure have extensive comorbidity. Ischemic heart disease, myocardial infarction, hypertension, arrhythmias, pulmonary disease, chronic kidney disease, diabetes (type 1 diabetes, type 2 diabetes), are common coexisting conditions. This complicates the treatment of heart failure due to the risk of drug interactions and complicates the titration of medications (e.g. ACE inhibitors in patients with renal failure). Cardiorenal syndrome is a particularly lethal combination, in which the patient has heart failure and kidney failure.

Epidemiology of heart failure

Heart failure is more common among men.

6.5 million adults in the United States have heart failure (Benjamin et al)

Heart failure is a contributing cause of 1 in 8 deaths in 2017 (CDC).

Among individuals aged 65 years or older, 5–10% have heart failure.

The lifetime risk of developing heart failure is 20% for a 40-year-old.

The incidence of heart failure has been stable for the past two decades, despite dramatic reductions in the incidence of acute myocardial infarction and improved management of hypertension.

Diabetes is probably one of the most common causes of heart failure (diabetic cardiomyopathy; Packer et al).

Prognosis

Table 2. Long-term survival after hospitalization for heart failure.

Time since hospitalization	Survival (%)
1 year	70%
5 year	60%

Mortality in heart failure is equal to that observed in common cancers. Half of all deaths are explained by sudden cardiac arrest due to ventricular tachycardia and ventricular fibrillation. The remaining deaths are caused by a gradual deterioration of left ventricular function and thromboembolic complications.

Causes of heart failure

Mechanisms of heart failure

Myocardial disease: pathological change in the myocardium.

Structural heart disease: e.g. valvular disease, congenital heart disease.

Arrhythmias

Conduction disturbances

Hemodynamic conditions

The underlying cause determines whether heart failure is transient or chronic. For example, heart failure due to myocardial infarction is chronic, whereas heart failure due to tachycardia (e.g atrial fibrillation) can be cured with restoration of sinus rhythm.

Related chapter: Tachycardia-induced cardiomyopathy.

Coronary artery disease and myocardial infarction

Myocardial infarction (STEMI, Non-STEMI) is the most common cause of heart failure. With regard to coronary heart disease, experts still debate whether chronic ischemia can cause heart failure in the absence of myocardial infarction (Camici et al, McMurray et al).

Hypertension

Hypertension is the most common cause of morbidity and mortality worldwide (Ezzati et al). Hypertension is also the second most common cause of heart failure. Hypertension causes heart failure by increasing afterload, which the left ventricle counteracts by developing hypertrophy. However, hypertrophy causes cardiac remodeling (see below), ultimately leading to impaired systolic function and chamber dilatation.

Diabetes

Diabetes is a common cause of heart failure and heart failure is viewed as a diabetes complication (diabetic cardiomyopathy; Packer et al). Diabetic cardiomyopathy is presumably caused by chronic hyperglycemia, which induces microvascular dysfunction and promotes the development of fibrosis in the myocardium.

Arrhythmias causing heart failure

Bradycardia (bradyarrhythmia) can cause heart failure when cardiac output (CO) drops below demand.

Prolonged tachycardia (tachyarrhythmia) can cause heart failure (tachycardia-induced heart failure). A common cause of tachycardia-induced heart failure is atrial fibrillation. However, any prolonged tachyarrhythmia can cause heart failure.

Atrial fibrillation and heart failure are strongly correlated. However, it is unclear whether heart failure causes atrial fibrillation, although it appears plausible; heart failure leads to ventricular dilation and elevated ventricular and atrial pressure. The latter may subsequently lead to left atrial enlargement and atrial fibrillation.

Structural heart disease

Structural heart disease refers to structural abnormalities in the myocardium, valves or greater vessels. Myocardial infarction, which results in structural changes (necrosis) in the myocardium, is also considered in this category. Other conditions include congenital heart disease and valvular heart disease (congenital or acquired). The most common valvular diseases that cause heart failure are as follows:

Aortic stenosis (AS)

Aortic regurgitation (AR)

Mitral stenosis (MS)

Mitral regurgitation (MR)

Pericardial disease (restrictive pericarditis, constrictive pericarditis) can also cause heart failure by impairing ventricular relaxation (diastole).

Cardiac toxicity

Substance abuse

Alcohol is the most common substance causing heart failure. Alcoholic cardiomyopathy is a common cause of heart failure worldwide. Alcohol causes dilated cardiomyopathy.

Cancer drugs and radiation therapy

Cancer drugs are an increasingly common cause of heart failure. The most common cancer drugs with known cardiotoxicity are as follows (Suter et al):

Doxorubicin

Daunorubicin (daunomycin)

Epirubicin

Mitoxantrone

Fluorouracil (5-FU)

Capecitabine

Cyclophosphamide

Cisplatin

Paclitaxel

Trastuzumab

Lapatinib

Bevacizumab

Sunitinib

Imatinib

Dasatinib

Nilotinib

Radiotherapy can cause myocarditis and pericarditis (constrictive pericarditis), resulting in heart failure.

Cardiac tumors and metastases

Cardiac tumors can cause heart failure, as can cardiac metastases.

Genetic causes of heart failure

In addition to mutations causing storage diseases (see below), heart failure may be the result of genetic mutations affecting cardiac myocytes. These mutations typically cause abnormalities in structural proteins, particularly actin, myosin, and proteins in the desmosome (intercalated discs). Such mutations lead to characteristic cardiomyopathies:

Dilated cardiomyopathy (DCM)

Hypertrophic obstructive cardiomyopathy (HOCM, HCM)

Arrhythmogenic right ventricular cardiomyopathy (ARVD, ARVC)

Other causes of heart failure

Heavy metals – Accumulation of heavy metals may cause heart failure. The following metals are known to cause heart failure:

Iron (hemochromatosis)

Copper

Lead

Cadmium

Cobolt

Storage diseases

Amyloidosis

Sarcoidosis

Pompe’s disease

Fabry’s disease

Hemochromatosis (accumulation of iron)

Immunological conditions

Rheumatoid arthritis (RA)

Systemic Lupus Erythematosus (SLE)

Giant cell myocarditis

Eosinophilic myocarditis

Endocrine causes

Hypothyreosis

Hyperthyreosis (thyrotoxicosis)

Hyperparathyroidism

Cushing’s syndrome

Acromegaly

Conn’s disease

Addison’s disease

Pregnancy

Postpartum cardiomyopathy (peripartum cardiomyopathy) is defined as new onset of heart failure between the last month of pregnancy and 5 months post-delivery, provided that no other causes of heart failure can be established.

Nutritional causes

Anorexia nervosa

Thiamin deficiency (cardiac beriberi)

Hemodynamic changes

Hypotension

Sepsis

Severe anemia

Volume overload (e.g renal failure)

Cardiac remodeling

Cardiac remodeling is observed in the majority of patients with heart failure, regardless of etiology. Cardiac remodeling affects the natural course of heart failure. It ultimately leads to gradual dilatation (enlargement) of the left ventricle and thus worsening heart failure.

Cardiac remodeling results from changes in the genome expression of cardiac myocytes. These changes result in molecular, cellular and interstitial changes which gradually affect the size, shape and function of the heart. Cell death, interstitial fibrosis and reduced contractility are the hallmarks of cardiac remodeling.

The goal of heart failure therapy is to slow or reverse the progression of cardiac remodeling. ACE inhibitors, ARBs, ARNI and beta blockers all affect the remodeling process.

Symptoms of heart failure

Symptoms of heart failure are often nonspecific, especially in the early phase. Distinguishing heart failure from other common cardiopulmonary conditions may be challenging, particularly in the following patients:

Patients with pulmonary disease (e.g., chronic obstructive pulmonary disease [COPD]), as dyspnea and poor exercise capacity are common in chronic pulmonary disease.

Overweight, obese or diabetic patients (type 2 diabetes): these patients frequently experience dyspnea and poor exercise capacity due to body weight and abdominal obesity.

Elderly individuals: dyspnea and poor exercise capacity are common in the elderly.

Ankle and lower limb edema are common side effects of calcium channel blockers and glitazones.

Ankle and lower limb edema may be caused by venous insufficiency.

Typical symptoms of heart failure

Dyspnea (shortness of breath)

Orthopnea (shortness of breath in the supine position)

Paroxysmal nocturnal dyspnea (sudden attacks of dyspnea occurring at night, typically a few hours after falling asleep)

Poor exercise capacity (exercise intolerance)

Fatigue

Ankle edema, lower limb edema

Less typical symptoms of heart failure (non-specific)

Palpitations

Weight gain

Weight loss (advanced heart failure)

Dizziness

Syncope

Cough

Loss of appetite

Confusion

Depression

Weight gain due to fluid retention is common in the early phase. However, in advanced heart failure, weight loss is also common, which is explained by the development of cachexia.

Symptoms of decompensated (acute) heart failure

Heart failure is a chronic condition characterized by gradual deterioration of cardiac function. Clinically stable periods may be interrupted by sudden worsening of heart failure (i.e decompensation), with increased fluid retention, worsening dyspnea and need for hospitalization. Figure 1 presents typical symptoms in patients with decompensated heart failure (Goldberg et al).

Figure 1. Frequency of symptoms in patients with acute decompensated heart failure (Goldberg et al).

New York Heart Association (NYHA) functional classification of heart failure

Heart failure patients are classified according to the severity of the symptoms. The New York Heart Association (NYHA) Functional Classification is the most commonly used classification system (Table 3).

Table 3. New York Heart Association (NYHA) functional classification of heart failure

NYHA Class	Patient Symptoms
I	No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea.
II	Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea.
III	Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea.
IV	Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases.

Clinical signs of heart failure

Physical examination may reveal any of the following in patients with heart failure:

Hepatojugular reflux: With the patient sitting at an angle of 45°, pressing on the liver leads to dilation of the jugular vein. The jugular vein is distended because blood flow through the right ventricle is impaired in patients with heart failure.

Wide jugular vein, due to distension of the vein (increased jugular venous pressure). This implies right heart failure.

Presence of a third heart sound (S3), also known as the “ventricular gallop”.

Lateral displacement and enlargement of the apical (apex) impulse.

Pulmonary auscultation: Fine or coarse crackles, depending on the severity of pulmonary edema.

Pulmonary percussion: dull percussion note.

Tachycardia: cardiac output is maintained by increasing the heart rate.

Irregular pulse: extrasystoles (supraventricular extrasystole, ventricular extrasystole), and supraventricular arrhythmias (atrial fibrillation, atrial flutter, atrial tachycardia, etc) are common in heart failure. Ventricular arrhythmias (ventricular tachycardia) are less common but occur in most patients with heart failure.

Tachypnea

Hepatomegaly

Ascites

Cold extremities

Oliguria

Narrow pulse pressure

Diagnosing heart failure: criteria & guidelines

Diagnosis of chronic heart failure

Patients with symptoms or signs of heart failure may be evaluated in primary care or the outpatient clinic. The initial evaluation should determine the probability of heart failure by assessing the following components:

Medical history

Physical examination

12-lead resting ECG

A detailed medical history is fundamental to assessing the risk of heart failure. The presence of coronary artery disease, previous myocardial infarction, hypertension, and other risk factors and causes of heart failure should be carefully reviewed. Physical examination should focus on the signs noted above. Resting ECG must be obtained in all patients.

Figure 2. Evaluation of patients with symptoms or signs of heart failure.

Figure 2. Overview of diagnosis, classification and management of heart failure

If medical history, physical examination and ECG are all normal, then heart failure is unlikely and other diagnoses should be considered. If any component is abnormal, plasma natriuretic peptides should be measured. The upper normal limit for natriuretic peptides (NT-proBNP and BNP) is the threshold for excluding heart failure.

NT-proBNP and BNP in heart failure

Plasma natriuretic peptides are assessed in patients with abnormal medical history, physical examination or resting ECG. The American Heart Association and European Society for Cardiology recommend measurement of BNP (Brain Natriuretic Peptide) or NT-proBNP (N-Terminal proBNP). If NT-proBNP or BNP is higher than the threshold (for excluding heart failure), echocardiography should be performed. Echocardiography should also be performed if NT-proBNP and BNP are not available.

NT-proBNP or BNP levels above the threshold strongly suggest heart failure and require further investigation with echocardiography.

Table 4. Thresholds for NT-proBNP and BNP

Biomarker	Threshold for exclusion of heart failure
Chronic heart failure
NT-proBNP	125 pg/mL
BNP	35 pg/mL
Acute (decompensated) heart failure
NT-proBNP	300 pg/mL
BNP	100 pg/mL

High levels of NT-proBNP or BNP strongly suggests heart failure. However, there are numerous other causes of elevated levels of natriuretic peptides (Table 5). The value of measuring NT-proBNP and BNP is greatest when the probability of heart failure is low to moderate. Note that the threshold for natriuretic peptides is higher in the acute setting (Table 5). The same thresholds are applied to HFREF and HFPEF. Generally, patients with HFREF have higher levels of NT-proBNP and BNP.

According to current (2024) guidelines from the ESC, AHA and ACC, heart failure is excluded if NT-proBNP or BNP levels are below the threshold.

Note that obesity results in lower levels of NT-proBNP and BNP. Furthermore, patients with heart failure who are well-treated may exhibit normal, or near-normal, levels of natriuretic peptides.

Table 5. Causes of increased levels of natriuretic peptides (NT-proBNP, BNP)

CARDIAC CAUSES
Heart failure
Atrial fibrillation
Acute coronary syndromes
Pulmonary embolism
Left ventricular hypertrophy (LVH)
Hypertrophic Cardiomyopathy (HCM, HOCM)
Myocarditis, Perimyocarditis
Electrical conversion, defibrillation
Congenital heart disease
Heart surgery
Pulmonary hypertension
Tachyarrhythmias
NON-CARDIAC CAUSES
Kidney failure
Aging
Stroke
Subarachnoid bleeding
Liver cirrhosis
COPD (chronic obstructive pulmonary disease)
Anemia
Severe infection (sepsis, pneumonia)
Ketoacidosis
Thyreotoxicosis
Paraneoplastic syndrome

ECG in heart failure

A completely normal ECG strongly speaks against heart failure (Mant et al). It is often difficult to determine whether the ECG is completely normal. There are numerous normal variants and non-significant abnormalities that may be ambiguous.

The ECG can not confirm nor exclude heart failure, but a completely normal ECG strongly speaks against heart failure.

Echocardiography in heart failure

Echocardiography is the preferred modality to investigate cardiac function. Traditionally, ejection fraction (EF) has been the predominant parameter for assessing cardiac function. Nowadays, diastolic function, systolic ventricular function, ventricular size, atrial size, etc are all investigated with numerous methods. Although a diagnosis of HFREF is based solely on ejection fraction, multiple other parameters for chamber size and diastolic function are needed to establish a diagnosis of HFPEF (heart failure with preserved ejection fraction).

Echocardiography can determine the type of heart failure (HFREF, HFPEF, HFmrEF) and assess structural and functional parameters with regard to the myocardium, valves, pericardium and chamber dimensions.

Cardiac MRI (Cardiac Magnetic Resonance Imaging)

Cardiac MRI is considered the gold standard for the majority of parameters of cardiac function. Although the use of cardiac MRI is increasing, it is still not widely available and therefore not recommended as part of routine evaluation of patients with suspected heart failure.

Diagnostic criteria for heart failure

Heart Failure with Reduced Ejection Fraction (HFREF)

Criteria for heart failure with reduced ejection fraction (HFREF):

Symptoms of heart failure, with or without objective signs of heart failure.

Ejection fraction <40%.

Heart Failure with mid-range Ejection Fraction (HFmrEF)

Criteria for HFmrEF:

Symptoms of heart failure, with or without objective signs of heart failure.

Ejection fraction 40–49%

Elevated levels of NT-proBNP or BNP.

One or two of the following:

Structural Heart Disease (left ventricular hypertrophy and/or left atrial enlargement)

Diastolic dysfunction

Heart Failure with Preserved Ejection Fraction (HFPEF)

It is relatively difficult to diagnose heart failure with preserved ejection fraction. This is partly because there is no clear consensus regarding how diastolic function should be determined. A range of echocardiographic techniques exists to assess diastolic dysfunction. The vast majority of patients with HFPEF exhibit structural abnormalities, most notably left ventricular hypertrophy (LVH) or left atrial enlargement (LAE).

A diagnosis of HFPEF is difficult to establish.

Symptoms are less pronounced in patients with HFPEF, as compared with patients with HFREF.

HFPEF is more common among women, elderly, diabetics, people with sleep apnea, obesity, overweight, COPD, pulmonary hypertension, metabolic syndrome, atrial fibrillation, hypertension and chronic kidney disease.

Criteria for heart failure with preserved ejection fraction (HEFPEF):

Symptoms of heart failure, with or without objective signs of heart failure.

Ejection fraction ≥50% (normal).*

Elevated levels of NT-proBNP or BNP.

One or two of the following:

Structural abnormalities (LVH and/or LAE)

Diastolic dysfunction

*In some clinical studies, the cut-off for ejection fraction is ≥40%, which is classed as HFmrEF according to ESC.

Structural changes consistent with heart failure, according to ESC:

Left atrial volume index (LAVI) >34 ml/m²

Left ventricular mass index (LVMI) ≥ 115 g/m² for males and ≥ 95 g/m² for females.

E/E′ ≥13

Mean e’ septal and lateral wall <9 cm/s.

Treatment of heart failure

Treatment goals

The ideal treatment for heart failure should have a beneficial effect on all four following elements:

Alleviate symptoms, reduce suffering and increase quality of life.

Reduce the rate of hospitalizations.

Improve functional capacity.

Prolong survival.

Generally, treatments that prolong survival (e.g beta blockers) will also alleviate symptoms, reduce the risk of hospitalization and improve functional capacity. Diuretics, on the other hand, have a marked effect on symptoms but no effect on survival.

Current evidence-based therapy for heart failure is based almost solely on patients with HFREF. There are no evidence-based treatment available for HFPEF.

Treatment of heart failure with reduced ejection fraction (HFREF)

Figure 3. Algorithm for treatment of heart failure with reduced ejection fraction. Click to enlarge.

Diuretics

All patients with heart failure require diuretics to alleviate dyspnea and eliminate excess fluid.

It is recommended that the lowest possible dose be used to avoid hypokalemia and hyponatremia. Higher doses are necessary in advanced heart failure.

Consider the increased risk of gouty arthritis.

Table 6. Diuretics

	Intial dose (mg)	Regular daily dose (mg)
LOOP DIURETICS
Furosemide	20–40	40–240
Bumetanide	0.5–1.0	1–5
Torasemide	5–10	10–20
TIAZIDES
Hydrochlorothiazide	25	12.5–100
Metolazone	2.5	2.5–10
lndapamidec	2.5	2.5–5

Table 7. Potassium sparing diuretics

	Initial dose if using ACEi/ARB (mg)	Initial dose if not using ACEi/ARB (mg)	Regular dose if using ACEi/ARB (mg)	Regular dose if not using ACEi/ARB (mg)
Spironolactone, eplerenone	12.5–25	50	50	100– 200
Amiloride	2.5	5	5–10	10–20
Triamterene	25	50	100	200

ACE inhibitors (ACEi)

ACE inhibitors have beneficial effects on all treatment goals, including prolonging survival and should therefore be considered in all patients with heart failure.

ACE inhibitors reduce the production of angiotensin II, which exerts multiple deleterious effects in patients with heart failure.

ACE inhibitors cause a dry, persistent cough in 10–30% of patients. Consider switching to ARBs if cough is unbearable.

Other common side effects include hypotension and renal failure. Electrolytes should be assessed in patients susceptible to electrolyte disturbances.

ACE inhibitors should be used with caution in patients on NSAID (non-steroidal anti-inflammatory drugs).

Table 8. ACE inhibitors

	Initial dose (mg)	Target dose (mg)
Captopril	6.25 × 3	50 × 3
Enalapril	2.5 × 2	10–20 × 2
Lisinopril	2.5–5.0 × 1	20–35 × 1
Ramipril	2.5 × 1	10 × 1
Trandolapril	0.5 × 1	4 × 1

Beta-blockers

All patients should have beta-blockers, which have a positive effect on all treatment goals in heart failure. Beta-blockers reduce mortality by 33%.

Beta-blockers reduce the harmful effects of norepinephrine (noradrenaline) and epinephrine (adrenaline) in the myocardium.

Start low, go slow and titrate to the maximally tolerated dose.

A temporary worsening of cardiac function may occur but is transient and left ventricular function improves gradually; a temporary dose reduction can be advised if necessary.

Table 9. Beta-blockers

Beta blocker	Initial dose (mg)	Target dose (mg)
Bisoprolol	1.25 × 1	10 × 1
Carvedilol	3.125 × 2.	25 × 2 d
Metoprolol succinate	12.5–25 × 1	200 × 1
Nebivolol	1.25 × 1	10 × 1

Angiotensin II receptor blockers (ARBs)

Effects similar to ACE inhibitors. Prolongs survival. Some data suggests that ARBs are slightly more effective than ACE inhibitors (McMurray et al).

ARBs prevent angiotensin II from binding to its receptor, thus interrupting the RAAS axis.

ARBs do not cause cough and is preferred in patients bothered by cough induced by ACE inhibitors.

ARBs can be added to ACE inhibitors, which further reduces mortality (McMurray et al). Combining ARBs and ACE inhibitors, however, requires repeated controls of kidney function and electrolytes.

ARBs	Initial dose (mg)	Target dose (mg)
Candesartan	4–8 × 1	32 × 1
Valsartan	40 × 2	160 × 2
Losartan	50 × 1	150 × 1

Aldosterone antagonists (MRA)

Aldosterone is part of the RAAS system. Blocking the effect of aldosterone results in inhibition of the harmful RAAS axis.

Spironolactone and eplerenone reduce mortality in heart failure.

Clinical studies have been conducted in patients with NYHA class II, III and IV. The effect of aldosterone antagonism is unknown in heart failure with NYHA class I.

Spironolactone and eplerenone are recommended if ACE/ARB and beta-blockers are insufficient.

Spironolactone and eplerenone can cause hyperkalemia and impairment of renal function.

Spironolactone can cause gynecomastia in men.

	Initial dose (mg)	Target dose (mg)
Eplerenone	25 × 1	50 × 1
Spironolactone	25 × 1	50 × 1

ARNI (Sacubitril-valsartan)

Angiotensin receptor neprilysin inhibitors (ARNI)	Initial dose (mg)	Target dose (mg)
Sacubitril/valsartan (Entresto)	49/51 × 2	97/103 × 2

ARNI is recommended for patients with:

Heart failure with reduced ejection fraction (HFrEF), if the patient remains symptomatic despite adequate doses of ACEi/ARB.

Heart failure with reduced ejection fraction (HFrEF), if the patient cannot tolerate ACE inhibitors and ARBs.

Washout period for ACE inhibitors and ARBs

When switching from an ACE inhibitor to an ARNI, a 36-hour washout period is recommended between the last dose of the ACE inhibitor and the first dose of the ARNI to reduce the risk of angioedema. The same 36-hour washout period applies when switching from an ARNI back to an ACE inhibitor. However, a washout period is not necessary when switching from an angiotensin II receptor blocker (ARB) to an ARNI. It is advisable to initiate ARNI therapy at a low dose (24/26 mg twice daily) and uptitrate every 2-4 weeks as tolerated, aiming for a target dose of 97/103 mg twice daily. For patients with renal impairment or concerns about hypotension, a more conservative uptitration approach may be considered.

Angiotensin receptor neprilysin inhibitors (ARNI)Initial dose (mg)Target dose (mg)Sacubitril/valsartan (Entresto)49/51 × 297/103 × 2

Ivabradine

Ivabradine selectively inhibits the HCN channels, commonly known as “funny channels” (If), in the sinoatrial node. This inhibition decreases the intrinsic pacemaker activity, leading to a reduction in heart rate. Ivabradine is indicated for patients with NYHA class II to IV stable chronic heart failure with reduced ejection fraction (35% or less), who are in sinus rhythm with a heart rate of 75 beats per minute or higher. It is used in combination with standard therapy, including beta-blockers, or when beta-blocker therapy is contraindicated or not tolerated. By lowering the heart rate, ivabradine reduces myocardial oxygen demand and improves exercise capacity.

If kanalblockerare	Initial dose (mg)	Target dose (mg)
Ivabradine	5 × 2	7.5 × 2

Digoxin (digitalis)

Digoxin (digitalis) has a positive inotropic effect, thus increasing myocardial oxygen consumption. The role of digoxin in heart failure has been questioned in recent years.

digoxin may be considered in patients with atrial fibrillation and ventricular rate >70 beats per minute.

Treatment of heart failure with preserved ejection fraction (HFPEF)

Diuretics, ACE inhibitors, ARBs, aldosterone antagonists, beta-blockers, ARNI, ivabradine and digoxin do not affect survival in HFPEF.

Current evidence-based therapy suggests targeting comorbidities and risk factors.

Conventional heart failure drugs may be used on an individual basis, but a general recommendation lacks scientific evidence.

Other treatments for heart failure

Smoking cessation and weight loss.

Vaccinations: pneumococci, influenza, COVID-19 (SARS-COV-2) when available.

Avoid antiarrhythmic drugs (amiodarone can be used in atrial fibrillation), antipsychotics, corticosteroids, NSAIDs.

Restricting salt consumption is common although scientific support is limited.

Moderate intake of alcohol is probably not harmful.

Encourage physical activity.

Device therapy for heart failure

Cardiac resynchronization therapy (CRT)

Figure 4 (part of Figure 3). Device therapy in patients with heart failure.

ICD reduces mortality by 23% in HFREF.

CRT reduces mortality by 20%.

The purpose of CRT (cardiac resynchronization therapy) is to achieve resynchronization of right and left ventricular depolarization (i.e, activation, contraction). Approximately 25% of heart failure patients exhibit ventricular dyssynchrony, which implies that the activity of the left and right ventricles is not synchronized, resulting in ineffective contractions. The hallmark of dyssynchrony is the wide QRS complex on ECG (QRS duration >120 ms). CRT allows for significant resynchronization of ventricular activation. For CRT to be effective, the QRS duration must be significantly prolonged. Hence, a narrower QRS duration corresponds to a weaker indication for CRT. The indications for CRT in patients with heart failure are presented in Figure 4.

Patients with LVEF ≤35% and QRS 130-149 ms:

If LBBB morphology: CRT-P/D is recommended (Class IIa).

If non-LBBB morphology: CRT-P/D may be considered (Class IIb).

Patients with LVEF ≤35%, sinus rhythm, and QRS ≥150 ms with LBBB morphology

CRT-P/D is strongly recommended (Class I).

CRT-P/D may be considered for non-LBBB morphology (Class IIa).

Patients with HFrEF and any other indication for ventricular pacing

CRT rather than conventional RV pacing is recommended for patients with HFrEF regardless of NYHA class or QRS width when ventricular pacing is indicated for high-degree AV block, to reduce morbidity (Class I). This includes patients with atrial fibrillation (AF).

Patients with Indication for Ventricular Pacing

Patients with LVEF ≤35%, with a conventional pacemaker or ICD, and worsening HF despite optimal medical therapy (OMT) should be considered for an upgrade to CRT if a significant proportion of RV pacing is present (Class IIa).

Figure 5. Cardiac resynchronization therapy (CRT)

Implantable Cardioverter Defibrillator (ICD)

An implantable cardioverter defibrillator (ICD) continuously monitors the heart rhythm and delivers electrical shocks or anti-tachycardia pacing (ATP) to terminate ventricular arrhythmias, based on a patient-specific detection and treatment protocol. ICD therapy is highly effective in reducing mortality among appropriately selected patients at risk of sudden cardiac death. Clinical trials have demonstrated significant survival benefits in these populations:

The SCD-HeFT trial reported a 23% reduction in all-cause mortality for heart failure patients with ICDs compared to placebo over five years (Bardy et al.).

The MADIT-II trial showed improved survival in post-myocardial infarction patients with reduced left ventricular function receiving ICD therapy (Moss et al.)

ICDs are essential devices for preventing sudden cardiac death in individuals at high risk of severe cardiac arrhythmias.

Indications for ICD Implantation

ICDs are indicated for both primary and secondary prevention of sudden cardiac death (SCD).

Primary prevention with ICD

An ICD is recommended (Class I) for patients with ischemic cardiomyopathy who meet the following criteria:

NYHA class II-III

LVEF ≤35% despite 3 months of OMT

Life-expectancy >1 year with good functional status.

An ICD is recommended (Class IIa) for patients with non-ischemic cardiomyopathy who meet the following criteria:

NYHA class II-III

LVEF ≤35% despite 3 months of OMT

Life-expectancy >1 year with good functional status

ICD is considered for patients with NYHA IV if they are candidates for CRT, VAD or cardiac transplantation (no level of recommendation provided)

ICDs are not implanted within 40 days after acute myocardial infarction, since no benefit has been observed in this patient population (Steinbeck et al.). ICD therapy is considered futile and potentially harmful in patients with a life expectancy of less than one year and is therefore contraindicated.

Secondary prevention with ICD

An ICD is recommended after a ventricular arrhythmia causing haemodynamic instability, if life-expectancy is >1 year with good functional status (Class Ia recommendation). Ventricular arrhythmia due to reversible causes or occurring within 48 hours of a myocardial infarction does not require an ICD.

Efficacy of implantable cardioverter defibrillators

In non-ischemic heart failure, a meta-analysis of five randomized trials enrolling 2,573 patients showed that ICD therapy was associated with a significantly lower risk of all-cause mortality (relative risk: 0.83; 95% CI: 0.71 to 0.97) compared to medical treatment alone (Theuns et al.). In ischemic heart disease, meta-analyses have shown a 29% relative risk reduction in all-cause mortality with ICD implantation (Yehya et al.). ICDs are highly effective, successfully terminating over 99% of all ventricular arrhythmias (Tran et al.). There is strong evidence supporting the use of ICDs in high-risk populations for both primary and secondary prevention of sudden cardiac death. However, the effectiveness of ICDs varies depending on the underlying cardiac condition and individual patient factors. The following can be inferred from randomized clinical trials:

Patients who have already experienced life-threatening arrhythmias or survived a cardiac arrest show the most consistent benefit from ICD implantation.

Individuals with heart failure due to ischemic heart disease, particularly those with a previous myocardial infarction, demonstrate the largest mortality reduction with ICD therapy, as compared with non-ischemic cardiomyopathies. Although ICDs reduce sudden cardiac death in patients with non-ischemic cardiomyopathy, the DANISH trial showed no significant effect on all-cause mortality (Køber et al.).

Patients with left ventricular ejection fraction (LVEF) closer to 25% tend to benefit more than those with LVEF closer to 35% (Tran et al., Brignole et al.).

Patients with no additional risk factors beyond reduced ejection fraction may not derive significant benefit from ICD implantation (Brignole et al.).

Patients with advanced heart failure (NYHA class IV) or multiple comorbidities may benefit significantly less due to competing risks of non-sudden death (Sheldon et al.).

Programming of ICD therapies

ICDs are typically programmed with multiple zones and features to optimize arrhythmia detection and treatment while minimizing inappropriate therapies. The settings include the following parameters:

Monitor zone: For slower tachycardias that do not require immediate therapy.

VT zone: For ventricular tachycardias amenable to anti-tachycardia pacing (ATP).

VF zone: For fast, life-threatening arrhythmias requiring shock therapy.

The monitoring zone is activated to record and store high-rate non-sustained ventricular tachycardia (NSVT), supraventricular tachycardias (SVTs), and slow ventricular tachycardias (VTs) to guide management decisions. The VT zone is activated at pre-specified ventricular rates to attempt treatment with bursts of ATP. the VF zone is triggered when ventricular fibrillation or flutter occurs. Typical settings include:

VF zone: ventricular arrhythmia ≥220-230 bpm

Conditional/VT zone: ≥200 bpm or 10-20 bpm below the VT cycle length if known.

To avoid unnecessary treatment of self-terminating arrhythmias, detection durations are programmed:

VF zone: 9-12 seconds.

VT zone: 15-60 seconds.

ATP and shock therapy

Anti-tachycardia pacing (ATP) works by delivering paced beats at a rate slightly faster than the detected tachycardia, aiming to interrupt the reentrant circuit responsible for the tachycardia. ATP is painless due to the low-energy pulses delivered. ATP is typically programmed for all VTs up to 250 beats per minute. Shock therapy is reserved for faster rhythms or when ATP fails. Programming strategies include:

Using ATP for VTs up to 250 bpm before delivering shocks.

Programming longer detection times to allow more ATP attempts and potential self-termination of arrhythmias.

ATP therapy has shown high efficacy in terminating ventricular tachycardia (VT) across multiple studies:

Overall success rates for ATP range from 80% to 90% for terminating VTs. The cumulative success rate of ATP increases with more sequences delivered, reaching 87% at ≥8 sequences (Sterns et al.).

ATP is particularly effective for slower VTs with cycle lengths ≥320 ms, showing an 88% success rate (Sterns et al.).

In patients with cardiac resynchronization therapy, ATP demonstrated a 90.5% conversion rate to sinus rhythm (Lozano et al.).

Comparing ATP patterns, burst, and ramp have shown similar efficacy, with success rates around 70-76% (Maria et al.).

For very fast VTs (cycle length 200-250 ms), tiered ATP can terminate >50% of episodes (Zaman et al.).

The first ATP attempt alone can successfully terminate 46% of monomorphic VTs (Knops et al.).

SVT discrimination

Algorithmic discriminators are applied to rhythms up to at least 200 bpm to differentiate SVTs from VTs and avoid inappropriate therapies. These discriminators include:

Sudden onset criteria.

Rhythm stability analysis.

AV association analysis (in dual-chamber devices).

Morphology discrimination.

References

Nabel EG, Braunwald E. A Tale of Coronary Artery Disease and Myocardial Infarction. New England Journal of Medicine. 2012;366(1):54-63.

Savarese G, Lund LH. Global Public Health Burden of Heart Failure. Cardiac Failure Review. 2017;3(1):7-11.

McMurray JJ, Packer M, Desai AS, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. New England Journal of Medicine. 2014;371(11):993-1004.

McMurray JJ, Pfeffer MA. Heart Failure. Lancet. 2005;365(9474):1877-1889.

Stewart S, Ekman I, Ekman T, Oden A, Rosengren A. Population Impact of Heart Failure and the Most Common Forms of Cancer: A Study of 1,162,309 Hospital Cases in Sweden (1988 to 2004). Circulation: Cardiovascular Quality and Outcomes. 2010;3(6):573-580.

Packer M. Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes. Diabetes Care. 2018;41(1):11-13.

Camici PG, Rimoldi OE. Hibernation and Heart Failure. Heart. 2004;90(2):141-143.

Ezzati M, Riboli E. Behavioral and Dietary Risk Factors for Noncommunicable Diseases. New England Journal of Medicine. 2013;369(10):954-964.

Suter TM, Ewer MS. Cancer Drugs and the Heart: Importance and Management. European Heart Journal. 2013;34(15):1102-1111.

Goldberg RJ, Spencer FA, Farmer C, et al. Epidemiology of Decompensated Heart Failure in a Single Community in the Northeastern USA. American Journal of Cardiology. 2009;104(3):377-382.

Mant J, Doust J, Roalfe A, et al. Systematic Review and Individual Patient Data Meta-Analysis of Diagnosis of Heart Failure, with Modelling of Implications of Different Diagnostic Strategies in Primary Care. Health Technology Assessment. 2009;13(32):1-207.

Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an Implantable Cardioverter-Defibrillator for Congestive Heart Failure. New England Journal of Medicine. 2005;352(3):225-237.

Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 Diabetes and Incidence of Cardiovascular Diseases: A Cohort Study in 1.9 Million People. The Lancet Diabetes & Endocrinology. 2015;3(2):105-113.

McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart Failure: A Cardiovascular Outcome in Diabetes That Can No Longer Be Ignored. The Lancet Diabetes & Endocrinology. 2014;2(10):843-851.

Benjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and Stroke Statistics—2019 Update: A Report from the American Heart Association. Circulation. 2019;139(10):e56-e528.

Centers for Disease Control and Prevention, National Center for Health Statistics. Underlying Cause of Death, 1999–2017. Accessed January 7, 2019.

European Society of Cardiology (ESC). 2021 ESC Guidelines on Cardiac Pacing and Cardiac Resynchronization Therapy. European Heart Journal, 2021;42(35):3427-3520.

American College of Cardiology (ACC). 2021 ESC Guidelines on Cardiac Pacing and CRT: Key Points. ACC.org, 2021.

Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. New England Journal of Medicine, 2002;346(12):877-883.

Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. New England Journal of Medicine, 2005;352(3):225-237.

European Society of Cardiology (ESC). Sudden cardiac death prevention by implantable cardioverter-defibrillators following myocardial infarction. E-Journal of Cardiology Practice, 2009;7(29).

American Heart Association (AHA). Primary Prevention Implantable Cardioverter-Defibrillators. Circulation: Arrhythmia and Electrophysiology, 2012;5(5):e74-e80.

American College of Cardiology (ACC). Heart Failure Device Therapy ICD and CRT. ACC.org, 2014.

Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. Journal of the American College of Cardiology, 2008;51(21):e1-e62.

Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Circulation, 2018;138(13):e272-e391.

Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. European Heart Journal, 2015;36(41):2793-2867.

Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Journal of the American College of Cardiology, 2006;48(5):e247-e346.

Kusumoto FM, Schoenfeld MH, Barrett C, et al. 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay. Journal of the American College of Cardiology, 2019;74(7):e51-e156.

Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy. European Heart Journal, 2013;34(29):2281-2329.

Wilkoff BL, Cook JR, Epstein AE, et al. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA, 2002;288(24):3115-3123.

Kuck KH, Cappato R, Siebels J, et al. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH). Circulation, 2000;102(7):748-754.

Connolly SJ, Gent M, Roberts RS, et al. Canadian Implantable Defibrillator Study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation, 2000;101(11):1297-1302.

Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. New England Journal of Medicine, 1999;341(25):1882-1890.

Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. New England Journal of Medicine, 1996;335(26):1933-1940.

Klein H, Arnsdorf M, Brugada P, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. New England Journal of Medicine, 1996;335(26):1933-1940.

The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. New England Journal of Medicine, 1997;337(22):1576-1583.

---

Chapter 3: Heart Failure with Reduced Ejection Fraction (HFrEF)

Definition and terminology Heart failure (HF) is a complex clinical syndrome characterized by symptoms and signs resulting from structural or functional impairment of ventricular filling or ejection of blood. The 2021 Universal Definition of Heart Failure, endorsed by major global cardiovascular societies, defines HF as a clinical syndrome corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion [3]. Within this spectrum, Heart Failure with Reduced Ejection Fraction (HFrEF) is specifically classified by the 2022 AHA/ACC/HFSA and 2021/2023 ESC guidelines as HF with a left ventricular ejection fraction (LVEF) of ≤40% [14, 26, 27]. Recent guideline updates have introduced critical nuances to HF terminology to reflect the dynamic nature of myocardial remodeling. The designation “Heart Failure with improved Ejection Fraction” (HFimpEF) is now applied to patients with a baseline LVEF ≤40% who have experienced a ≥10-point increase in LVEF, with a subsequent measurement of >40% [14]. This distinction is paramount for practicing cardiologists: HFimpEF represents a state of myocardial remission rather than true recovery. Data from the TRED-HF trial demonstrated that withdrawal of guideline-directed medical therapy (GDMT) in these patients leads to a high rate of relapse, underscoring the mandate that HFrEF pharmacotherapy must be continued indefinitely even after LVEF normalization. Epidemiology and risk factors The global burden of heart failure is staggering, affecting an estimated 64 million individuals worldwide. In developed nations, the prevalence of HF is approximately 1–2% in the general adult population, but this figure rises steeply with age, exceeding 10% in individuals over 70 years [48]. The lifetime risk of developing HF for an individual at age 40 is estimated at 24%, a figure that remains consistent across both men and women [10]. Registry data, such as those from the Framingham Heart Study and the Atherosclerosis Risk in Communities (ARIC) study, highlight a shifting demographic profile in incident HFrEF. Historically dominated by acute myocardial infarction (MI) survivors, the contemporary risk factor profile is increasingly driven by the global epidemics of obesity, diabetes mellitus, and metabolic syndrome [58]. Hypertension and coronary artery disease (CAD) remain the most potent population-attributable risk factors. Furthermore, the “obesity paradox”—whereby overweight and mildly obese HF patients exhibit better survival than normal-weight counterparts—remains a subject of intense epidemiological debate, likely reflecting the catabolic state of advanced HF (cardiac cachexia) rather than a protective effect of adiposity. Etiology and underlying causes The etiology of HFrEF is broadly dichotomized into ischemic and non-ischemic causes, a distinction that fundamentally alters diagnostic work-up and device therapy eligibility. Ischemic cardiomyopathy, defined by significant CAD (prior MI, diffuse microvascular dysfunction, or flow-limiting epicardial stenoses), is the predominant cause, accounting for approximately 60% of HFrEF cases in Western populations [14]. Non-ischemic etiologies encompass a highly heterogeneous group of disorders. Idiopathic dilated cardiomyopathy (DCM) is frequently diagnosed when ischemic, valvular, and hypertensive causes are excluded. However, advances in molecular diagnostics reveal that up to 30-40% of “idiopathic” cases harbor a genetic basis. Truncating variants in the TTN gene (titin) are the most common genetic cause, followed by mutations in LMNA, MYH7, and TNNT2 [39]. Consequently, current guidelines recommend a 3-generation family history and consideration of genetic testing for all patients with non-ischemic HFrEF. Toxic and infiltrative causes are increasingly recognized. The burgeoning field of cardio-oncology has highlighted the cardiotoxic effects of anthracyclines, HER2 inhibitors (trastuzumab), and immune checkpoint inhibitors, which can precipitate fulminant myocarditis and subsequent HFrEF [22]. Substance abuse (alcohol, methamphetamines) and infiltrative diseases (cardiac amyloidosis, sarcoidosis) must also be systematically evaluated, as they require specific, targeted interventions. Pathophysiology and cardiac remodeling The transition from an initial myocardial insult to chronic HFrEF is governed by the neurohormonal hypothesis. An initial decline in cardiac output triggers a compensatory, yet ultimately maladaptive, chronic activation of the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) [40]. While these systems acutely maintain perfusion via vasoconstriction and sodium retention, their chronic activation exerts profound toxic effects on the myocardium. At the cellular level, chronic neurohormonal stimulation induces myocyte hypertrophy, apoptosis, and fibroblast proliferation, leading to extracellular matrix deposition and interstitial fibrosis. This process, termed adverse cardiac remodeling, manifests macroscopically as the left ventricle (LV) transitioning from a prolate ellipse to a spherical shape. This spherical dilation increases wall stress (governed by Laplace’s law), exacerbates subendocardial ischemia, and causes papillary muscle displacement, leading to secondary (functional) mitral regurgitation [24]. Counter-regulatory systems, primarily the natriuretic peptide system (ANP, BNP), attempt to mitigate this by inducing vasodilation, natriuresis, and anti-fibrotic effects. However, in chronic HFrEF, this endogenous defense is overwhelmed by the RAAS/SNS axis. Modern pharmacotherapy, particularly neprilysin inhibition, is specifically designed to augment these beneficial endogenous peptides while simultaneously blocking the maladaptive RAAS pathways [4].

Pathophysiology and Neurohormonal Axis in HFrEF Clinical presentation The clinical presentation of HFrEF is a manifestation of two primary hemodynamic derangements: backward failure (venous congestion) and forward failure (systemic hypoperfusion). Patients are often categorized using the Stevenson hemodynamic profiles: Warm and Dry (compensated), Warm and Wet (congested, most common), Cold and Dry (hypoperfused), and Cold and Wet (cardiogenic shock) [47]. Symptoms of backward failure include exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea (PND), lower extremity edema, and abdominal fullness due to congestive hepatopathy and gut edema. Forward failure presents as profound fatigue, weakness, altered mental status, and cool extremities [26]. The physical examination remains a cornerstone of clinical assessment. Elevated jugular venous pressure (JVP) and a positive hepatojugular reflux (HJR) are highly reliable markers of volume overload. The presence of a third heart sound (S3 gallop) is highly specific for elevated left ventricular end-diastolic pressure and impending decompensation. While pulmonary crackles are a classic sign of acute pulmonary edema, they are frequently absent in chronic HFrEF due to compensatory increases in lymphatic drainage [59]. Diagnostic criteria and work-up The diagnostic work-up for suspected HFrEF aims to confirm the diagnosis, establish the etiology, and identify precipitating factors. The initial evaluation must include a comprehensive history and physical examination, a 12-lead electrocardiogram (ECG), and a chest radiograph [14]. The ECG is rarely normal in HFrEF; the presence of Q waves suggests prior MI, while a left bundle branch block (LBBB) indicates intraventricular conduction delay, a critical factor for device therapy planning. The chest X-ray may reveal cardiomegaly, cephalization of pulmonary vessels, and pleural effusions, though its sensitivity is limited. Given that CAD is the leading cause of HFrEF, an ischemic evaluation is mandatory for all patients presenting with new-onset HFrEF without a clear non-ischemic etiology. Coronary angiography remains the gold standard, but coronary computed tomography angiography (CCTA) is an increasingly utilized Class IIa alternative for patients with a low-to-intermediate pre-test probability of CAD [14]. Diagnostic Algorithm for Suspected HFrEF Echocardiography and imaging Transthoracic echocardiography (TTE) is the undisputed Class 1 gold standard for the initial structural and functional assessment of the failing heart. TTE provides critical data on LVEF (preferably calculated via the Simpson’s biplane method), chamber dimensions, wall thickness, and diastolic function. Furthermore, it is essential for evaluating valvular hemodynamics, particularly the severity of secondary mitral and tricuspid regurgitation, and for estimating non-invasive right ventricular systolic pressures [20]. When TTE windows are inadequate or when precise tissue characterization is required, Cardiac Magnetic Resonance (CMR) imaging is strongly recommended. CMR is the gold standard for volumetric quantification. More importantly, late gadolinium enhancement (LGE) imaging allows for the differentiation of ischemic versus non-ischemic etiologies. Ischemic cardiomyopathy typically presents with subendocardial or transmural LGE in a coronary distribution, whereas non-ischemic DCM often shows mid-wall or epicardial striae. CMR is also indispensable for diagnosing infiltrative cardiomyopathies such as cardiac amyloidosis and sarcoidosis [15]. Biomarkers and laboratory assessment Laboratory assessment is vital for identifying comorbidities and guiding therapy. Routine tests include a complete blood count, comprehensive metabolic panel, lipid profile, HbA1c, and thyroid-stimulating hormone (TSH). Iron studies (ferritin and transferrin saturation) are now mandatory due to the prognostic and therapeutic implications of iron deficiency in HFrEF [26]. B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are the premier biomarkers for diagnosis and prognostication. For non-acute presentations, the rule-out thresholds are BNP <35 pg/mL or NT-proBNP <125 pg/mL. In the acute setting, thresholds are higher (BNP <100 pg/mL or NT-proBNP <300 pg/mL) [16, 37]. It is critical to note that neprilysin inhibitors (ARNI) degrade BNP but not NT-proBNP; thus, NT-proBNP is the preferred biomarker for monitoring patients on sacubitril/valsartan. High-sensitivity cardiac troponin (hs-cTn) is useful for detecting acute myocardial injury as a precipitant of decompensation and provides independent prognostic value [37]. The recent STRONG-HF trial demonstrated that a biomarker-guided approach—using NT-proBNP levels to safely guide the rapid up-titration of GDMT—significantly improves clinical outcomes, cementing the role of serial biomarker evaluation in routine practice [30]. Staging and classification (ACC/AHA, NYHA) The ACC/AHA stages of heart failure emphasize the progressive nature of the disease and the importance of early intervention [14]:

Stage A: At risk for HF (e.g., hypertension, diabetes, obesity) but without structural heart disease or symptoms. Stage B: Pre-HF; structural heart disease (e.g., LV hypertrophy, prior MI) or elevated biomarkers, but no symptoms. Stage C: Symptomatic HF; prior or current symptoms of HF associated with structural heart disease. Stage D: Advanced HF; severe symptoms at rest, recurrent hospitalizations despite maximal GDMT, requiring specialized interventions.

Importantly, the ACC/AHA staging is unidirectional; a patient cannot regress from Stage C to Stage B, even if symptoms resolve. In contrast, the New York Heart Association (NYHA) functional classification gauges current symptom severity and can fluctuate [6]:

Class I: No limitation of physical activity. Class II: Slight limitation; ordinary activity causes symptoms. Class III: Marked limitation; less than ordinary activity causes symptoms. Class IV: Inability to carry out any physical activity without discomfort; symptoms present at rest.

Guideline-directed medical therapy (GDMT) The cornerstone of HFrEF management has undergone a radical paradigm shift. The 2022 AHA/ACC and 2023 ESC guidelines mandate the use of quadruple therapy—often termed the “Four Pillars”—for all patients with HFrEF. These include: (1) an ARNI (or ACEi/ARB), (2) an evidence-based beta-blocker, (3) a mineralocorticoid receptor antagonist (MRA), and (4) an SGLT2 inhibitor. All four classes carry a Class 1 recommendation [14, 27]. Historically, GDMT was initiated in a stepwise, sequential manner, often taking months to achieve comprehensive blockade. Contemporary guidelines and consensus pathways now strongly advocate for simultaneous or rapid sequential initiation of all four pillars at low doses within weeks of diagnosis. This approach is driven by evidence that the morbidity and mortality benefits of these agents are additive, independent, and occur rapidly (within 2-4 weeks of initiation) [23, 49]. Simultaneous Initiation and Titration of GDMT in HFrEF Renin–angiotensin system inhibition (ACEi/ARB/ARNI) Inhibition of the RAAS is foundational. The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, is the preferred agent (Class 1a) over ACE inhibitors and ARBs. The landmark PARADIGM-HF trial demonstrated that ARNI therapy yielded a 20% relative risk reduction in cardiovascular death or HF hospitalization compared to enalapril, alongside significant improvements in quality of life [28]. The PIONEER-HF trial further established the safety and superior efficacy of initiating ARNI in-hospital during acute decompensation [57]. If an ARNI is unavailable, unaffordable, or poorly tolerated, ACE inhibitors (e.g., enalapril, lisinopril) or ARBs (e.g., candesartan, valsartan) remain Class 1 recommendations, backed by legacy trials such as SOLVD and CHARM-Alternative [11, 50]. Sub-group analyses from the PARAGON-HF trial (which studied HFpEF) suggest that the benefits of ARNI extend into the mildly reduced EF range (HFmrEF), particularly in women, prompting broader utilization across the LVEF spectrum. Beta-blockers Beta-blockers mitigate the cardiotoxic effects of chronic sympathetic activation, reduce heart rate, decrease myocardial oxygen demand, and are highly effective at reversing LV remodeling and preventing sudden cardiac death. However, class effects do not apply; only three specific beta-blockers have proven mortality benefits in HFrEF: bisoprolol (CIBIS-II), sustained-release metoprolol succinate (MERIT-HF), and carvedilol (COPERNICUS) [7, 35, 42]. Beta-blockers should be initiated in clinically stable, euvolemic patients. In the setting of acute decompensated HF, established beta-blocker therapy should generally be continued at a reduced dose unless the patient is in cardiogenic shock or exhibits severe hypoperfusion, in which case temporary cessation is required. Mineralocorticoid receptor antagonists Aldosterone drives myocardial fibrosis, sodium retention, and endothelial dysfunction. The MRAs spironolactone and eplerenone block these deleterious effects. The RALES trial (spironolactone in severe HF) and the EMPHASIS-HF trial (eplerenone in mild HF) demonstrated profound reductions in all-cause mortality and HF hospitalizations [44, 60]. The primary barrier to MRA utilization is the risk of hyperkalemia and renal dysfunction, particularly when combined with an ARNI/ACEi/ARB. Careful surveillance of serum potassium and creatinine is mandatory. The recent DIAMOND trial demonstrated that the use of the novel potassium binder patiromer enables the optimization of RAAS inhibitors and MRAs in patients who would otherwise be intolerant due to hyperkalemia, offering a new strategy for maximizing GDMT. SGLT2 inhibitors Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent the most significant breakthrough in HF pharmacotherapy in the last decade. Originally developed as anti-hyperglycemic agents, dapagliflozin and empagliflozin are now foundational HFrEF therapies regardless of the patient’s diabetes status. The DAPA-HF and EMPEROR-Reduced trials showed approximately 25% relative risk reductions in cardiovascular death or worsening HF [29, 41]. The mechanisms of benefit are pleiotropic and independent of glycemic control, involving improved myocardial energetics (shift toward ketone utilization), reduction in interstitial edema via proximal tubule natriuresis, and inhibition of the Na+/H+ exchanger (NHE1). Meta-analyses of pooled data confirm robust reductions in all-cause mortality and highlight profound renal protective effects, slowing the progression of chronic kidney disease (CKD) in this vulnerable population [55]. Additional pharmacologic therapies (ivabradine, hydralazine–nitrates, digoxin) Beyond the four pillars, several adjunctive therapies are indicated for specific clinical scenarios:

Ivabradine: This agent selectively inhibits the $I_f$ channel in the sinoatrial node, reducing heart rate without negative inotropic effects. Based on the SHIFT trial, it is indicated for symptomatic HFrEF patients with LVEF ≤35%, in sinus rhythm, with a resting HR ≥70 bpm despite maximally tolerated beta-blockers [52]. Hydralazine and Isosorbide Dinitrate: This combination provides a Class 1 recommendation for self-identified African American patients with NYHA class III–IV HFrEF who remain symptomatic despite optimal GDMT, based on the survival benefit demonstrated in the A-HeFT trial [53]. Vericiguat: An oral soluble guanylate cyclase (sGC) stimulator that enhances the cyclic GMP pathway. The VICTORIA trial showed that vericiguat reduces the composite of CV death or HF hospitalization in high-risk patients with worsening HF (recent hospitalization or need for IV diuretics) [1]. Digoxin: While it provides no mortality benefit, digoxin may be considered for symptom control and reduction of HF hospitalizations in patients who remain symptomatic on maximal GDMT, as shown in the DIG trial [9].

Diuretic therapy and volume management Loop diuretics (furosemide, bumetanide, torsemide) are the mainstay for alleviating congestion. Despite theoretical pharmacokinetic advantages of torsemide, the recent pragmatic TRANSFORM-HF trial showed no significant difference in all-cause mortality or hospitalization between torsemide and furosemide [33]. Diuretic resistance is a frequent clinical challenge, often mediated by distal nephron hypertrophy. Sequential nephron blockade is the preferred strategy. The ADVOR trial demonstrated that the addition of intravenous acetazolamide (a proximal tubule carbonic anhydrase inhibitor) to loop diuretics significantly improved the incidence of successful decongestion compared to placebo [38]. Furthermore, the PUSH-AHF trial validated a natriuresis-guided approach, showing that using early spot urine sodium measurements to guide IV diuretic dosing improves natriuresis and clinical decongestion [54]. Management Algorithm for Diuretic Resistance Optimization and titration of therapy Initiation of GDMT is only the first step; optimization to target doses is where the maximum survival benefit is realized. Registry data, such as the CHAMP-HF registry, reveal pervasive clinical inertia, with less than 25% of eligible patients achieving target doses of GDMT [12]. Guidelines stress that target doses derived from randomized controlled trials must be pursued, rather than stopping titration once symptom relief is achieved. The STRONG-HF trial provided a definitive mandate for high-intensity care: rapid up-titration of GDMT to 100% of recommended doses within 2 weeks of hospital discharge, guided by NT-proBNP levels and close clinical follow-up, significantly reduced 180-day HF readmission or death compared to usual care [30]. Management of comorbidities Comorbidities frequently complicate HFrEF management and drive hospitalizations.

Iron Deficiency: Present in up to 50% of HFrEF patients, iron deficiency is defined as ferritin <100 µg/L or 100–299 µg/L with transferrin saturation (TSAT) <20%. Intravenous iron repletion (ferric carboxymaltose or ferric derisomaltose) improves symptoms, exercise capacity, and quality of life. The AFFIRM-AHF and IRONMAN trials demonstrated reductions in HF hospitalizations [18, 46]. The recent HEART-FID trial showed marginal but safe results for FCM, cementing IV iron as a standard of care for symptomatic patients [34]. Atrial Fibrillation (AF): AF and HF frequently coexist and exacerbate one another. The CASTLE-AF trial demonstrated that catheter ablation is superior to medical therapy for rhythm control in select HFrEF patients, significantly improving survival and LVEF [25]. Chronic Kidney Disease (CKD): Cardiorenal syndrome is ubiquitous. SGLT2 inhibitors are highly effective at slowing CKD progression in HFrEF patients, as evidenced by the DAPA-CKD and EMPA-KIDNEY trials, and should be continued even as GFR declines to 20 mL/min/1.73m² [13].

Device therapy (ICD, CRT) Device therapy is indicated when structural and electrical remodeling place the patient at high risk for sudden cardiac death (SCD) or pump failure despite optimal GDMT. Implantable Cardioverter-Defibrillator (ICD): ICDs carry a Class 1 recommendation for the primary prevention of SCD in patients with an LVEF ≤35% and NYHA II-III symptoms despite ≥3 months of GDMT, with an expected survival of >1 year. This is based on landmark trials like MADIT-II (ischemic) and SCD-HeFT (mixed etiology) [2, 36]. However, the DANISH trial introduced nuance, showing a less clear all-cause mortality benefit for prophylactic ICDs in purely non-ischemic etiologies, though SCD was reduced [19]. Cardiac Resynchronization Therapy (CRT): CRT is indicated for patients with LVEF ≤35%, sinus rhythm, and a Left Bundle Branch Block (LBBB) with a QRS duration ≥150 ms. By restoring electromechanical synchrony, CRT improves symptoms, induces reverse remodeling, and reduces mortality, as demonstrated in the COMPANION and CARE-HF trials [5, 8]. Selection of Device Therapy (ICD and CRT) in HFrEF Revascularization and surgical options The role of revascularization in ischemic cardiomyopathy depends heavily on the modality and the presence of viable myocardium. Coronary artery bypass grafting (CABG) is recommended for patients with multivessel CAD and HFrEF. The 10-year follow-up of the STICH trial demonstrated a significant all-cause mortality benefit for CABG over medical therapy alone, highlighting the long-term protective effect of surgical revascularization against future ischemic events [56]. Conversely, the role of percutaneous coronary intervention (PCI) in stable ischemic LV dysfunction was recently challenged by the REVIVED-BCIS2 trial. This landmark study showed that PCI did not reduce all-cause mortality or HF hospitalization compared to optimal medical therapy alone, suggesting that stable ischemic HFrEF should be managed medically unless the patient has refractory angina [43]. For patients with severe secondary (functional) mitral regurgitation who remain symptomatic despite optimal GDMT and CRT, Transcatheter Edge-to-Edge Repair (TEER, e.g., MitraClip) is a viable option. The COAPT trial demonstrated that TEER significantly reduces hospitalizations and mortality in appropriately selected patients with disproportionate mitral regurgitation [51]. Revascularization Strategy in Ischemic Cardiomyopathy Advanced heart failure therapies (LVAD, transplantation) Patients progressing to Stage D HF—characterized by recurrent hospitalizations, intolerance to GDMT due to hypotension or renal failure, or the need for inotropic support—must be referred to an advanced HF center. The “I-NEED-HELP” mnemonic is a useful trigger for timely referral. For eligible candidates, orthotopic heart transplantation remains the gold standard, offering a median survival exceeding 12 years [31]. However, due to donor organ shortages, Left Ventricular Assist Devices (LVADs) are increasingly utilized as both a bridge to transplant and as destination therapy. The MOMENTUM 3 trial established the superiority of the HeartMate 3—a fully magnetically levitated continuous-flow pump—which drastically reduced the incidence of pump thrombosis and stroke compared to older axial-flow devices, making LVAD therapy a durable long-term option [32]. Referral Pathway for Advanced Heart Failure Therapies Prognosis Prognostication in HFrEF is essential for guiding patient expectations and timing advanced therapies. Validated multivariable risk models, such as the MAGGIC risk score and the Seattle Heart Failure Model (SHFM), are recommended to estimate 1-year and 3-year survival [21, 45]. Historically, the 5-year mortality for HFrEF hovered around 50%. However, the contemporary landscape has been drastically altered by comprehensive GDMT. Modeling studies indicate that the optimal implementation of all four pillars (ARNI, beta-blocker, MRA, SGLT2i) extends survival by an estimated 6 to 8 years in a 55-year-old patient compared to conventional therapy (ACEi and beta-blocker alone) [55]. Ongoing Trials and Future Directions The therapeutic horizon for HFrEF continues to expand. Ongoing trials are investigating novel pathways, such as cardiac myosin activators (following the mixed results of omecamtiv mecarbil in GALACTIC-HF), GLP-1 receptor agonists for obesity-related HF phenotypes, and gene therapies targeting calcium handling (SERCA2a) and specific genetic cardiomyopathies (e.g., CRISPR for TTR amyloidosis and MYBPC3 mutations). Furthermore, the optimization of HFimpEF management remains a fertile ground for research, with trials aiming to identify which patients might safely de-escalate therapy without risking relapse. As the armamentarium grows, the focus of practicing cardiologists must remain on overcoming clinical inertia and ensuring equitable delivery of life-saving, guideline-directed therapies to all patients.

Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2020;382:1883-1893. DOI: 10.1056/NEJMoa1915928 Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med. 2005;352:225-237. DOI: 10.1056/NEJMoa043399 Bozkurt B, Coats AJS, Tsutsui H, et al. Universal definition and classification of heart failure. J Card Fail. 2021;27(4):387-413. DOI: 10.1016/j.cardfail.2021.01.022 Braunwald E. The war against heart failure: the Lancet lecture. Lancet. 2015;385(9970):812-824. DOI: 10.1016/S0140-6736(14)61889-4 Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004;350:2140-2150. DOI: 10.1056/NEJMoa032423 Caraballo C, Desai NR, Mulder H, et al. Clinical Implications of the New York Heart Association Classification. J Am Heart Assoc. 2019;8(23):e014240. DOI: 10.1161/JAHA.119.014240 CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13. DOI: 10.1016/S0140-6736(98)11181-9 Cleland JGF, Daubert JC, Erdmann E, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005;352:1539-1549. DOI: 10.1056/NEJMoa050496 DIG Trial Investigators. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med. 1997;336:525-533. DOI: 10.1056/NEJM199702203360801 Emmons-Bell S, Johnson C, Roth G. Prevalence, incidence and survival of heart failure: a systematic review. Heart. 2022;108:1351-1360. DOI: 10.1136/heartjnl-2021-320136 Granger CB, McMurray JJV, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772-776. DOI: 10.1016/S0140-6736(03)14284-5 Greene SJ, Butler J, Albert NM, et al. Medical Therapy for Heart Failure With Reduced Ejection Fraction: The CHAMP-HF Registry. J Am Coll Cardiol. 2021;72:351-366. DOI: 10.1016/j.jacc.2018.04.070 Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383:1436-1446. DOI: 10.1056/NEJMoa2024816 Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79(17):e263-e421. DOI: 10.1016/j.jacc.2021.12.012 Hundley WG, Bluemke DA, Finn JP, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance. J Am Coll Cardiol. 2010;55:2614-2662. DOI: 10.1016/j.jacc.2009.11.011 Januzzi JL, Ahmad T, Celano CM, et al. Core Biomarker Testing in Heart Failure. Circulation. 2018;138:e19-e26. DOI: 10.1161/CIR.0000000000000589 Jones NR, Roalfe AK, Adoki I, et al. Survival of patients with chronic heart failure in the community: a systematic review and meta-analysis. Eur J Heart Fail. 2019;21:1306-1325. DOI: 10.1002/ejhf.1594 Kalra PR, Cleland JGF, Petrie MC, et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN). Lancet. 2022;400(10369):2199-2209. DOI: 10.1016/S0140-6736(22)02083-9 Kober L, Thune JJ, Nielsen JC, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure. N Engl J Med. 2016;375:1221-1230. DOI: 10.1056/NEJMoa1608029 Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults. J Am Soc Echocardiogr. 2015;28:1-39. DOI: 10.1016/j.echo.2014.10.003 Levy WC, Mozaffarian D, Linker DT, et al. The Seattle Heart Failure Model: prediction of survival in heart failure. Circulation. 2006;113:1424-1433. DOI: 10.1161/CIRCULATIONAHA.105.584102 Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology. Eur Heart J. 2022;43(41):4229-4361. DOI: 10.1093/eurheartj/ehac244 Maddox TM, Januzzi JL, Allen LA, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment. J Am Coll Cardiol. 2021;77(6):772-810. DOI: 10.1016/j.jacc.2020.11.022 Mann DL. Pathophysiology of heart failure. In: Braunwald’s Heart Disease. 9th ed. 2012. Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018;378:417-427. DOI: 10.1056/NEJMoa1707855 McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. DOI: 10.1093/eurheartj/ehab368 McDonagh TA, Metra M, Adamo M, et al. 2023 ESC Guidelines for the management of heart failure focused update. Eur Heart J. 2023;44(32):3028-3114. DOI: 10.1093/eurheartj/ehad195 McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993-1004. DOI: 10.1056/NEJMoa1409077 McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381:1995-2008. DOI: 10.1056/NEJMoa1911303 Mebazaa A, Davison B, Chioncel O, et al. Safety, tolerability and efficacy of up-titration of guideline-directed medical therapies for acute heart failure (STRONG-HF): a multinational, open-label, randomised, trial. Lancet. 2022;400(10367):1938-1952. DOI: 10.1016/S0140-6736(22)02076-1 Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation. J Heart Lung Transplant. 2016;35:1-23. DOI: 10.1016/j.healun.2015.10.023 Mehra MR, Uriel N, Naka Y, et al. A Fully Magnetically Levitated Left Ventricular Assist Device – Final Report. N Engl J Med. 2019;380:1618-1627. DOI: 10.1056/NEJMoa1900486 Mentz RJ, Anstrom KJ, Eisenstein EL, et al. Effect of Torsemide vs Furosemide After Discharge on All-Cause Mortality in Patients Hospitalized With Heart Failure: The TRANSFORM-HF Randomized Clinical Trial. JAMA. 2023;329(3):214-223. DOI: 10.1001/jama.2022.23924 Mentz RJ, Garg J, Rockhold FW, et al. Ferric Carboxymaltose in Heart Failure with Iron Deficiency. N Engl J Med. 2023;389(11):975-986. DOI: 10.1056/NEJMoa2304968 MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;353:2001-2007. DOI: 10.1016/S0140-6736(99)04440-2 Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883. DOI: 10.1056/NEJMoa013474 Mueller C, McDonald K, de Boer RA, et al. Heart Failure Association of the European Society of Cardiology practical guidance on the use of natriuretic peptide concentrations. Eur J Heart Fail. 2019;21:715-731. DOI: 10.1002/ejhf.1493 Mullens W, Dauw J, Martens P, et al. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med. 2022;387(13):1185-1195. DOI: 10.1056/NEJMoa2203094 Murphy SL, et al. Genetics of heart failure. Cardiol Clin. 2020;38(1):1-13. DOI: 10.1016/j.ccl.2019.09.001 Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20:248-254. DOI: 10.1016/0735-1097(92)90167-L Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383:1413-1424. DOI: 10.1056/NEJMoa2022190 Packer M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651-1658. DOI: 10.1056/NEJM200105313442201 Perera D, Clayton T, O’Kane PD, et al. Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction. N Engl J Med. 2022;387(15):1351-1360. DOI: 10.1056/NEJMoa2206606 Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709-717. DOI: 10.1056/NEJM199909023411001 Pocock SJ, Ariti CA, McMurray JJV, et al. Predicting survival in heart failure: a risk score based on 39,372 patients from 30 studies. Eur Heart J. 2013;34:1404-1413. DOI: 10.1093/eurheartj/ehs337 Ponikowski P, Kirwan BA, Anker SD, et al. Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial (AFFIRM-AHF). Lancet. 2020;396:1895-1904. DOI: 10.1016/S0140-6736(20)32339-4 Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37:2129-2200. DOI: 10.1093/eurheartj/ehw128 Savarese G, Becher PM, Lund LH, et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res. 2022;118(17):3272-3287. DOI: 10.1093/cvr/cvac013 Shen L, Jhund PS, Petrie MC, et al. Rapid Guideline-Directed Medical Therapy Titration in Heart Failure. JACC Heart Fail. 2022;10:1-12. DOI: 10.1016/j.jchf.2021.09.006 SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293-302. DOI: 10.1056/NEJM199108013250501 Stone GW, Lindenfeld J, Abraham WT, et al. Transcatheter Mitral-Valve Repair in Patients with Heart Failure. N Engl J Med. 2018;379:2307-2318. DOI: 10.1056/NEJMoa1806640 Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885. DOI: 10.1016/S0140-6736(10)61198-1 Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med. 2004;351:2049-2057. DOI: 10.1056/NEJMoa042934 Ter Maaten JM, Beldhuis IE, van der Meer P, et al. Natriuresis-guided diuretic therapy in acute heart failure: a pragmatic randomized trial. Nat Med. 2023;29(10):2625-2632. DOI: 10.1038/s41591-023-02532-z Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction. Lancet. 2020;396:121-128. DOI: 10.1016/S0140-6736(20)30748-0 Velazquez EJ, Lee KL, Jones RH, et al. Coronary-artery bypass surgery in patients with ischemic cardiomyopathy. N Engl J Med. 2016;374:1511-1520. DOI: 10.1056/NEJMoa1602001 Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin-Neprilysin Inhibition in Acute Decompensated Heart Failure (PIONEER-HF). N Engl J Med. 2018;380:539-548. DOI: 10.1056/NEJMoa1812851 Virani SS, Alonso A, Aparicio HJ, et al. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021;143:e254-e743. DOI: 10.1161/CIR.0000000000000950 Wang CS, FitzGerald JM, Schulzer M, et al. Does this dyspneic patient in the emergency department have congestive heart failure? JAMA. 2005;294:1944-1956. DOI: 10.1001/jama.294.15.1944 Zannad F, McMurray JJV, Krum H, et al. Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms. N Engl J Med. 2011;364:11-21. DOI: 10.1056/NEJMoa1009492

---

Chapter 4: Heart Failure with Preserved Ejection Fraction (HFpEF)

Definition and terminology Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome characterized by the cardinal symptoms and signs of heart failure (HF) in the presence of a left ventricular ejection fraction (LVEF) of ≥50%, accompanied by objective evidence of structural and/or functional cardiac abnormalities and/or elevated natriuretic peptides (NPs) [1][2]. The evolution of HF terminology has been driven by a deeper understanding of myocardial mechanics and clinical outcomes. The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) guidelines and the 2023 European Society of Cardiology (ESC) guidelines have universally solidified the LVEF categories: HF with reduced EF (HFrEF, ≤40%), HF with mildly reduced EF (HFmrEF, 41–49%), and HFpEF (≥50%) [1][2]. Crucially, contemporary definitions distinguish HFpEF from “Heart Failure with improved EF” (HFimpEF). HFimpEF refers to patients with a historical baseline LVEF ≤40% that has subsequently improved to >40% under guideline-directed medical therapy (GDMT). These patients must be managed as having HFrEF, as their underlying pathophysiology, trajectory, and risk of relapse upon GDMT withdrawal are fundamentally distinct from true, incident HFpEF [3]. Hemodynamically, the gold standard definition of HFpEF relies on the demonstration of spontaneous or provokable elevated left ventricular (LV) filling pressures, defined invasively as a pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg during exercise [4]. This hemodynamic criterion underscores that “preserved” ejection fraction does not equate to normal cardiac function, but rather to a state where stroke volume is maintained only at the expense of pathologically elevated filling pressures. Epidemiology and risk factors HFpEF has reached epidemic proportions, now accounting for over 50% of all incident heart failure cases globally [5]. Registry data, including the Get With The Guidelines-Heart Failure (GWTG-HF) and the SWEDEHEART registries, demonstrate that while the incidence of HFrEF has stabilized or slightly declined over the past two decades, the incidence of HFpEF continues to rise steeply [6]. This epidemiological shift is primarily driven by the aging of the global population and the escalating prevalence of cardiometabolic comorbidities. The demographic profile of the typical HFpEF patient differs markedly from that of HFrEF. Patients are predominantly older (frequently >65 years of age) and there is a strong female predominance. Women have a substantially higher lifetime risk of developing HFpEF, a phenomenon attributed to intrinsic sex differences in cardiovascular aging, including smaller ventricular cavities, greater age-related vascular stiffening, and distinct microvascular responses to systemic inflammation [7]. The dominant risk factors for HFpEF include hypertension (present in >80% of cases), obesity, type 2 diabetes mellitus, chronic kidney disease (CKD), sedentary lifestyle, and atrial fibrillation (AF) [5]. Unlike HFrEF, where epicardial ischemic heart disease and myocardial infarction are primary drivers, HFpEF is more frequently associated with coronary microvascular dysfunction, though epicardial coronary artery disease frequently coexists as a bystander or secondary contributor [8]. Pathophysiology and mechanisms The pathophysiological paradigm of HFpEF has shifted dramatically from the historical concept of isolated “diastolic dysfunction” to a systemic, multiorgan disease model. The prevailing modern hypothesis, initially proposed by Paulus and Tschöpe, is the “systemic microvascular inflammation paradigm” [9]. In this model, systemic comorbidities (obesity, hypertension, diabetes) induce a chronic, systemic proinflammatory state. This circulating inflammation leads to coronary microvascular endothelial dysfunction, characterized by the upregulation of adhesion molecules (e.g., VCAM-1) and the generation of reactive oxygen species (ROS) [10]. At the cellular level, endothelial dysfunction reduces the bioavailability of nitric oxide (NO). The consequent drop in NO leads to decreased production of cyclic guanosine monophosphate (cGMP) and diminished activity of protein kinase G (PKG) in adjacent cardiomyocytes. PKG normally phosphorylates titin, the giant cytoskeletal spring protein responsible for cardiomyocyte elasticity. Hypophosphorylation of the N2B isoform of titin drastically increases resting cardiomyocyte stiffness [9][11]. Simultaneously, the inflamed endothelium secretes transforming growth factor-beta (TGF-β), which promotes the transition of resident fibroblasts into myofibroblasts, leading to excessive interstitial collagen deposition and extracellular matrix fibrosis [12]. Macroscopically, the combination of titin stiffening and interstitial fibrosis results in impaired LV active relaxation and profound increases in passive diastolic stiffness. Consequently, the left ventricle requires elevated left atrial (LA) pressures to fill adequately, particularly during the stress of exertion when diastolic filling time is shortened. Furthermore, HFpEF is characterized by multiorgan impairments, including chronotropic incompetence, impaired ventricular-arterial coupling, skeletal muscle myopathy, and impaired peripheral oxygen extraction, all of which contribute to the hallmark symptom of exercise intolerance [4][13]. Clinical presentation The clinical presentation of HFpEF is notoriously insidious, frequently leading to delayed diagnosis or misattribution of symptoms to aging, obesity, or physical deconditioning. The primary and most pervasive symptoms are exertional dyspnea and severe fatigue, which often severely limit physical activity long before overt signs of volume overload manifest [14]. As the disease progresses and filling pressures remain chronically elevated, patients develop orthopnea, paroxysmal nocturnal dyspnea, and right-sided symptoms such as abdominal bloating and early satiety. Physical examination may reveal signs of systemic congestion, including peripheral edema, elevated jugular venous pressure (JVP), hepatojugular reflux, and pulmonary crackles. However, it is critical to recognize that a significant proportion of HFpEF patients are euvolemic at rest. In these individuals, exertional symptoms may be the only clinical presentation. The resting physical examination and even resting echocardiography may appear deceptively normal. This highlights the necessity of dynamic assessment; symptoms that occur exclusively during exertion require stress testing (either echocardiographic or invasive) to unmask the pathological elevation in LV filling pressures that defines the syndrome [15]. Diagnostic criteria and work-up The diagnostic work-up for HFpEF requires a high index of clinical suspicion and a systematic, multi-modality approach. Initial evaluation should include a detailed clinical history, physical examination, 12-lead electrocardiogram (ECG), comprehensive transthoracic echocardiography (TTE), and biomarker assessment (specifically BNP or NT-proBNP) [1]. Routine laboratory tests should evaluate renal function, electrolytes, complete blood count, iron studies, and thyroid function to identify exacerbating factors and comorbidities. According to the 2022 AHA/ACC and 2023 ESC guidelines, a definitive diagnosis requires an LVEF ≥50% alongside objective evidence of spontaneous or provokable increased LV filling pressures [1][2]. If resting echocardiographic parameters and natriuretic peptides are clearly abnormal (e.g., severe left atrial enlargement, marked LV hypertrophy, and highly elevated NT-proBNP), the diagnosis is confirmed. However, in cases where resting non-invasive tests are equivocal but clinical suspicion remains high (a common scenario in early or obesity-phenotype HFpEF), advanced testing is mandatory. Diastolic stress echocardiography is the preferred initial advanced test, assessing the E/e’ ratio and tricuspid regurgitation (TR) velocity during exercise. If stress echocardiography is non-diagnostic, invasive exercise right heart catheterization (RHC) is recommended as the gold standard to definitively measure PCWP at rest and during exertion [4][16].

Diagnostic algorithm for suspected HFpEF integrating non-invasive and invasive testing. Echocardiographic assessment Comprehensive echocardiography is the cornerstone of non-invasive HFpEF evaluation. The assessment focuses on structural markers of chronic pressure overload and functional markers of impaired relaxation and elevated filling pressures. Key structural parameters include a left atrial volume index (LAVI) >34 mL/m² and a left ventricular mass index (LVMI) ≥115 g/m² in men or ≥95 g/m² in women [2][17]. Left atrial enlargement is a particularly robust marker, acting as a “hemoglobin A1c” for chronic left ventricular filling pressures. Functional assessment relies heavily on Doppler hemodynamics. An elevated E/e’ ratio (average >9, or >15 at rest) is a primary surrogate for elevated PCWP. Reduced tissue Doppler velocities (septal e’ <7 cm/s, lateral e' <10 cm/s) indicate intrinsically impaired myocardial relaxation. Additionally, a peak TR velocity >2.8 m/s suggests elevated pulmonary artery systolic pressure (PASP), a common downstream consequence of left-sided failure [17]. Beyond traditional parameters, speckle-tracking echocardiography has revealed that despite a “preserved” LVEF, subtle systolic dysfunction is almost universally present. A reduced global longitudinal strain (GLS), typically defined as an absolute value <16-18%, is a sensitive marker of subclinical myocardial disease and carries significant prognostic weight in HFpEF [18]. Natriuretic peptides and biomarkers Natriuretic peptides (NPs) are integral to the diagnosis and prognostication of HFpEF, but their interpretation requires nuance. The standard diagnostic thresholds are NT-proBNP >125 pg/mL or BNP >35 pg/mL in patients in normal sinus rhythm. Because atrial fibrillation inherently increases atrial wall stress, the thresholds are adjusted upward for patients in AF: NT-proBNP >365 pg/mL or BNP >105 pg/mL [2]. A major clinical pitfall is the “obesity confounder.” NPs are frequently lower, or even falsely normal, in obese patients with HFpEF. This phenomenon is driven by two mechanisms: increased clearance of NPs by abundant natriuretic peptide clearance receptors (NPR-C) expressed in adipose tissue, and suppressed cardiac release due to pericardial restraint and altered transmural pressure gradients. Up to 20-30% of obese HFpEF patients possess NP levels below standard diagnostic thresholds despite invasively proven, severely elevated filling pressures [19]. Therefore, a “normal” NT-proBNP does not rule out HFpEF in an obese patient. Beyond NPs, novel biomarkers reflecting fibrosis and inflammation—such as Growth Differentiation Factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity cardiac troponin (hs-cTn)—are increasingly utilized for risk stratification, though they have not yet replaced NPs in standard diagnostic algorithms [20]. Diagnostic scoring systems To standardize the diagnosis of HFpEF, two major scoring systems have been developed and validated: the H2FPEF score (from the Mayo Clinic) and the HFA-PEFF algorithm (from the ESC Heart Failure Association). The H2FPEF Score utilizes six readily available clinical and echocardiographic variables: Heavy (BMI >30 kg/m², 2 points), Hypertensive (≥2 antihypertensive medications, 1 point), Atrial Fibrillation (paroxysmal or persistent, 3 points), Pulmonary hypertension (PASP >35 mmHg, 1 point), Elder (age >60 years, 1 point), and Filling pressure (E/e’ >9, 1 point). The score ranges from 0 to 9. A score ≥6 indicates a high probability (>90%) of HFpEF, while a score of 0-1 makes the diagnosis highly unlikely. Intermediate scores (2-5) necessitate stress testing [21]. The HFA-PEFF Algorithm is a 4-step approach: Step 1 (Pre-test assessment), Step 2 (Echocardiography and NP score), Step 3 (Functional testing), and Step 4 (Final etiology). Step 2 assigns major (2 points) and minor (1 point) criteria based strictly on morphological and functional echo parameters and NP levels. A score ≥5 confirms HFpEF, while ≤1 rules it out [22]. Comparative studies indicate moderate discordance (28-41%) between the two systems. The H2FPEF score relies heavily on clinical phenotypes (particularly AF, which heavily skews the score) and demonstrates higher sensitivity. Conversely, the HFA-PEFF algorithm relies strictly on structural and biochemical markers, offering higher specificity. Clinicians should use these scores as complementary tools rather than absolute arbiters [23]. Differential diagnosis A critical step in the evaluation of suspected HFpEF is the exclusion of specific cardiomyopathies and non-cardiac causes of dyspnea that mimic the HFpEF phenotype. Cardiac Amyloidosis (both wild-type ATTR and AL amyloidosis) must be actively ruled out, particularly in older adults or those with a history of bilateral carpal tunnel syndrome or lumbar spinal stenosis. Echocardiographic red flags include severe LV hypertrophy with a “sparkling” myocardium, biatrial enlargement, and a characteristic “apical sparing” pattern on GLS. Diagnosis is confirmed via bone scintigraphy (Tc-99m PYP/DPD) for ATTR and serum/urine light chain assays for AL amyloidosis [24]. Hypertrophic Cardiomyopathy (HCM) is differentiated by asymmetric septal hypertrophy, dynamic left ventricular outflow tract (LVOT) obstruction, and genetic testing. Constrictive pericarditis can present with identical symptoms and preserved LVEF; it is distinguished by pericardial thickening/calcification on imaging, prominent ventricular interdependence (septal bounce), and annulus reversus on tissue Doppler. High-output heart failure states (e.g., severe anemia, arteriovenous fistulas, hyperthyroidism) and significant valvular heart disease must also be excluded before confirming a diagnosis of primary HFpEF [25]. HFpEF phenotypes It is now universally acknowledged that HFpEF is not a monolithic disease but a highly heterogeneous syndrome comprising multiple overlapping phenotypes. These phenotypes possess distinct pathophysiological drivers, clinical trajectories, and differential responses to targeted therapies [26]. Machine learning and latent class analyses of large trial cohorts have consistently identified several major phenogroups:

Aging/vascular stiffening phenotype: Typically elderly, hypertensive patients with marked arterial stiffness and ventricular-arterial uncoupling. Obesity/cardiometabolic phenotype: Characterized by severe systemic inflammation, epicardial fat deposition, and profound exercise intolerance. Atrial fibrillation-predominant phenotype: Driven by left atrial myopathy and loss of atrioventricular synchrony. Pulmonary hypertension/right ventricular dysfunction phenotype: Advanced disease with pulmonary vascular remodeling and RV uncoupling. Chronic kidney disease-associated phenotype: Dominated by cardiorenal cross-talk and severe volume dysregulation [27].

Recognizing these phenotypes is critical, as it moves the field toward precision medicine, allowing clinicians to tailor therapies beyond foundational GDMT. Phenotype-guided management strategies in HFpEF. Obesity-related HFpEF The obesity-related HFpEF phenotype is increasingly recognized as a distinct and highly prevalent entity. These patients exhibit a unique hemodynamic profile characterized by marked volume expansion, increased epicardial adipose tissue (which exerts direct mechanical restraint and paracrine inflammatory effects on the myocardium), and profound microvascular inflammation. Clinically, they suffer from the most severe exercise intolerance and the lowest quality of life among HFpEF subgroups [28]. The management of this phenotype was revolutionized by the 2023 STEP-HFpEF trial. This landmark randomized controlled trial demonstrated that semaglutide 2.4 mg weekly in obese HFpEF patients yielded dramatic improvements. The primary endpoints showed a remarkable increase in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS, +16.6 points vs +8.7 for placebo) and significant weight loss (-13.3% vs -2.6%). Furthermore, semaglutide significantly improved 6-minute walk distance (6MWD) and reduced CRP levels [29]. In 2024, the SUMMIT trial confirmed that this is a class effect of incretin therapies; tirzepatide (a dual GIP/GLP-1 receptor agonist) demonstrated significant reductions in the composite of worsening HF events and cardiovascular death, alongside profound weight loss and QoL improvements in patients with HFpEF/HFmrEF and obesity [30]. These agents are now considered foundational disease-modifying therapies for the obesity-HFpEF phenotype. Hypertensive HFpEF Hypertension is the most ubiquitous risk factor for HFpEF, present in the vast majority of patients. The hypertensive HFpEF phenotype is driven by chronic pressure overload, which induces concentric left ventricular hypertrophy and interstitial fibrosis. Concurrently, chronic hypertension accelerates vascular aging, leading to increased central arterial stiffness (reduced aortic compliance) [31]. This combination results in impaired ventricular-arterial coupling. The stiffened left ventricle ejects blood into a stiffened arterial tree, causing massive lability in blood pressure during minimal exertion or minor changes in volume status. These patients are exquisitely sensitive to both preload and afterload. A slight increase in venous return can precipitate acute pulmonary edema (flash pulmonary edema), while mild over-diuresis can lead to precipitous hypotension and acute kidney injury. Strict, consistent blood pressure control is the absolute cornerstone of preventing disease progression and acute decompensation in this cohort [32]. Atrial fibrillation–associated HFpEF Atrial fibrillation and HFpEF share a pernicious, bidirectional relationship. They share common upstream risk factors (aging, hypertension, obesity, sleep apnea). HFpEF causes elevated left atrial pressures, leading to LA dilation, fibrosis, and electrical remodeling (LA myopathy), which triggers and sustains AF. Conversely, the onset of AF exacerbates HFpEF through the loss of the “atrial kick” (which contributes up to 30% of LV filling in a stiff ventricle), rapid ventricular rates that shorten diastolic filling time, and the induction of tachycardia-induced cardiomyopathy [33]. The presence of AF in a patient with HFpEF is a harbinger of poor outcomes. It is associated with significantly higher NT-proBNP levels, worse exercise capacity, and a markedly increased risk of stroke, heart failure hospitalization, and mortality compared to HFpEF patients in sinus rhythm. The management of this phenotype requires aggressive intervention to break the vicious cycle of atrial and ventricular decline [34]. Pulmonary hypertension and right ventricular dysfunction As HFpEF progresses, chronic elevation of left-sided filling pressures transmits backward into the pulmonary circulation, initially causing Group 2 pulmonary hypertension (isolated post-capillary PH, IpcPH). Over time, the chronic barotrauma and endothelial dysfunction in the pulmonary vasculature trigger pulmonary arterial remodeling, leading to a superimposed pre-capillary component. This state is known as combined post- and pre-capillary PH (CpcPH), characterized by a mean pulmonary artery pressure >20 mmHg, PCWP >15 mmHg, and a pulmonary vascular resistance (PVR) >2 Wood units [35]. The increased afterload on the right ventricle (RV) eventually leads to RV-PA uncoupling. Because the RV is highly sensitive to afterload, it dilates and fails. The development of right ventricular dysfunction is one of the strongest independent predictors of mortality in HFpEF. Clinically, these patients transition from predominantly exertional dyspnea to severe systemic congestion, diuretic resistance, and cardiac cachexia [36]. Chronic kidney disease and metabolic disease The intersection of HFpEF, chronic kidney disease (CKD), and metabolic disease (diabetes) represents the classic “cardiorenal syndrome.” These conditions frequently coexist and amplify one another through shared mechanisms of systemic inflammation, endothelial dysfunction, oxidative stress, and neurohormonal activation (particularly the renin-angiotensin-aldosterone system and sympathetic nervous system) [37]. Patients with the CKD-HFpEF phenotype are notoriously difficult to manage due to fluctuating volume status and a high propensity for diuretic resistance. However, this phenotype derives profound, synergistic benefits from Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors and non-steroidal Mineralocorticoid Receptor Antagonists (MRAs) like finerenone. These agents offer dual cardiorenal protection, slowing the progression of eGFR decline while simultaneously reducing heart failure hospitalizations, making them indispensable in this population [38]. Management of congestion The relief of systemic and pulmonary congestion is the primary goal for symptom management in HFpEF. Loop diuretics (furosemide, torsemide, bumetanide) remain the first-line therapy. However, diuretic dosing in HFpEF requires meticulous precision. Because the left ventricle is stiff, the end-diastolic pressure-volume relationship (EDPVR) is extremely steep. This means that a small reduction in LV volume can lead to a massive drop in filling pressure and, consequently, a precipitous drop in stroke volume [2][39]. Over-diuresis easily leads to underfilling, manifesting as orthostatic hypotension, fatigue, and acute kidney injury (prerenal azotemia). Conversely, under-diuresis leaves the patient symptomatic and at risk for hospitalization. The goal is to titrate diuretics to the lowest effective dose that maintains clinical euvolemia. In cases of diuretic resistance, sequential nephron blockade with the addition of thiazide-like diuretics (e.g., metolazone, chlorthalidone) or acetazolamide may be necessary, requiring rigorous monitoring of electrolytes (potassium, magnesium) and renal function [40]. Algorithm for the management of congestion and diuretic titration in HFpEF. Disease-modifying pharmacotherapy The landscape of HFpEF pharmacotherapy has been transformed in recent years, moving from a state of therapeutic nihilism to one with multiple proven disease-modifying agents. SGLT2 Inhibitors: These are the foundational, Class 1A therapy for all patients with HFpEF. The EMPEROR-Preserved (empagliflozin) and DELIVER (dapagliflozin) trials conclusively demonstrated that SGLT2 inhibitors significantly reduce the composite risk of cardiovascular death and heart failure hospitalizations across the entire spectrum of LVEF, including those with HFimpEF. The benefits are rapid, independent of diabetes status, and accompanied by improvements in quality of life [41][42]. Mineralocorticoid Receptor Antagonists (MRAs): The 2024 FINEARTS-HF trial was a watershed moment, demonstrating that finerenone (a non-steroidal MRA) significantly reduced the composite of worsening HF events and CV death in patients with LVEF ≥40%. This definitively established MRAs as a core pillar of HFpEF therapy, overcoming the geographical ambiguities of the older TOPCAT trial (spironolactone) [43][44]. Angiotensin Receptor-Neprilysin Inhibitors (ARNIs): Based on the PARAGON-HF trial, sacubitril/valsartan holds a Class 2B recommendation. While the trial narrowly missed its primary endpoint (p=0.059), robust subgroup analyses revealed significant benefits in patients with an LVEF in the lower end of the preserved spectrum (HFmrEF, LVEF 45-57%) and notably in women, who appear to derive greater benefit from neprilysin inhibition at higher ejection fractions [45]. Guideline-directed medical therapy (GDMT) initiation algorithm for HFpEF. Blood pressure management Optimal blood pressure control is paramount in HFpEF to prevent disease progression, reduce LV mass, and prevent acute exacerbations. The 2022 AHA/ACC guidelines recommend a target blood pressure of <130/80 mmHg [1]. This target is supported by data from the SPRINT trial, which showed that intensive BP lowering reduces the incidence of heart failure. When selecting antihypertensive agents, clinicians should prioritize drugs with proven cardiovascular benefits in the heart failure continuum. ARNIs, ACE inhibitors, ARBs, and MRAs should be utilized first. Beta-blockers, while effective for BP control, lack specific outcome data in pure HFpEF and may actually be detrimental in some patients by exacerbating chronotropic incompetence (the inability to adequately raise heart rate during exercise), a common cause of exertional dyspnea in this population. Therefore, beta-blockers should generally be reserved for patients with compelling alternative indications, such as angina or atrial fibrillation rate control [46]. Management of atrial fibrillation The management of AF in HFpEF is undergoing a paradigm shift. Historically, rate control was deemed sufficient. However, there is a growing consensus that rhythm control is superior, as restoring normal sinus rhythm restores the critical atrial kick and normalizes diastolic filling times. While antiarrhythmic drugs (e.g., amiodarone) can be used, catheter ablation is increasingly favored. Trials such as CABANA and CASTLE-HTx have demonstrated that catheter ablation for AF improves survival, reduces heart failure hospitalizations, and improves LVEF in heart failure patients. Early ablation is now strongly recommended for AF-associated HFpEF to prevent irreversible structural remodeling of the left atrium. If rate control is pursued, strict targets (<80 bpm at rest) are generally recommended, utilizing beta-blockers or non-dihydropyridine calcium channel blockers (diltiazem, verapamil), though the latter must be used with caution if LVEF is borderline [47][48]. Decision algorithm for atrial fibrillation management in HFpEF. Weight loss and lifestyle intervention Lifestyle interventions are not merely adjunctive; they are primary therapies for HFpEF. Caloric restriction combined with supervised exercise training has been shown to significantly improve peak oxygen consumption (peak VO2) and quality of life, acting synergistically to improve vascular function and reduce systemic inflammation [49]. With the advent of highly effective pharmacotherapy for weight loss, the paradigm has shifted. GLP-1 receptor agonists (semaglutide) and dual GIP/GLP-1 agonists (tirzepatide) are now considered disease-modifying metabolic interventions for the obesity-HFpEF phenotype. By inducing 10-15% body weight loss, these agents reduce epicardial fat, lower filling pressures, and drastically improve functional capacity. Bariatric surgery remains a viable option for morbidly obese patients who do not respond to or cannot tolerate pharmacotherapy [29][30]. Exercise training and cardiac rehabilitation Exercise intolerance is the defining functional limitation of HFpEF. Supervised exercise training is one of the most effective interventions for improving exercise capacity. The EX-DHF trial demonstrated that a structured, supervised exercise program is safe and significantly improves peak VO2, diastolic function (E/e’), and physical quality of life in HFpEF patients [50]. Furthermore, the REHAB-HF trial highlighted the importance of early physical rehabilitation in older, frail patients hospitalized with acute heart failure. A tailored, progressive rehabilitation program initiated during hospitalization and continued post-discharge significantly improved physical function domains, frailty indices, and quality of life, underscoring that physical conditioning must be a core component of comprehensive HFpEF care [51]. Management of comorbidities Comprehensive HFpEF management requires aggressive treatment of non-cardiac comorbidities that exacerbate symptoms. Iron deficiency is highly prevalent (affecting up to 50% of patients) and directly impairs skeletal muscle energetics, contributing to severe fatigue. Trials such as FAIR-HFpEF and HEART-FID support the evaluation of iron indices (ferritin, TSAT) and the administration of intravenous iron (e.g., ferric carboxymaltose) to improve symptoms and exercise capacity, even in the absence of overt anemia [52]. Obstructive Sleep Apnea (OSA) is another critical comorbidity. OSA induces nocturnal hypoxemia, which increases sympathetic tone, elevates right-sided pulmonary pressures, and exacerbates systemic hypertension. Continuous positive airway pressure (CPAP) therapy is strongly recommended for symptom relief, blood pressure control, and the reduction of right ventricular afterload [53]. Follow-up and monitoring Routine clinical follow-up for HFpEF involves the continuous assessment of volume status, body weight, renal function, and electrolytes—particularly when initiating or titrating diuretics, MRAs, and SGLT2 inhibitors. Given the narrow therapeutic window for volume status, proactive monitoring is essential. Hemodynamic telemonitoring has emerged as a powerful tool to prevent hospitalizations. Implantable pulmonary artery pressure sensors (e.g., CardioMEMS) allow clinicians to monitor daily PA pressures remotely and preemptively titrate diuretics before clinical congestion develops. The CHAMPION and GUIDE-HF trials demonstrated that PA pressure-guided management significantly reduces heart failure hospitalizations in HFpEF patients, particularly those with a history of prior admissions, representing a shift toward personalized, data-driven volume management [54][55]. Ongoing trials The therapeutic landscape for HFpEF continues to evolve rapidly, with several major ongoing trials poised to address remaining clinical gaps. The VICTOR trial is investigating the efficacy of vericiguat, a soluble guanylate cyclase (sGC) stimulator, in patients with chronic HFpEF, aiming to directly target the NO-sGC-cGMP pathway deficiency that drives myocardial stiffness [56]. Device therapies are also under intense investigation. Following the mixed results of the REDUCE LAP-HF II trial, which showed no overall benefit for interatrial shunt devices but suggested benefit in specific responders (those without latent pulmonary vascular disease), the RELIEVE-HF and CORINTHIA trials are further evaluating the role of atrial shunting in carefully selected HFpEF phenotypes to decompress the left atrium during exertion [57]. Additionally, ongoing sub-analyses of the SUMMIT and STEP-HFpEF programs are exploring the long-term structural cardiac benefits of incretin therapies. These trials promise to further refine the precision medicine approach to HFpEF in the coming decade.

Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79(17):e263-e421. doi: 10.1016/j.jacc.2021.12.012 McDonagh TA, Metra M, Adamo M, et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2023;44(37):3627-3639. doi: 10.1093/eurheartj/ehad195 Wilcox JE, Fang JC, Margulies KB, Mann DL. Heart Failure With Recovered Left Ventricular Ejection Fraction: JACC Scientific Expert Panel. J Am Coll Cardiol. 2020;76(6):719-734. doi: 10.1016/j.jacc.2020.05.075 Borlaug BA, Sharma K, Shah SJ, Ho JE. Heart Failure With Preserved Ejection Fraction: JACC Scientific Statement. J Am Coll Cardiol. 2023;81(18):1810-1834. doi: 10.1016/j.jacc.2023.01.049 Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association. Circulation. 2023;147(8):e93-e621. doi: 10.1161/CIR.0000000000001123 Savarese G, Stolfo D, Sinagra G, Lund LH. Heart failure with preserved or mildly reduced ejection fraction. Nat Rev Cardiol. 2022;19(2):100-114. doi: 10.1038/s41569-021-00592-0 Redfield MM, Borlaug BA. Heart Failure with Preserved Ejection Fraction. JAMA. 2023;329(10):827-838. doi: 10.1001/jama.2023.2020 Shah SJ, Lam CSP, Svedlund S, et al. Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF. Eur Heart J. 2018;39(37):3439-3450. doi: 10.1093/eurheartj/ehy531 Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263-271. doi: 10.1016/j.jacc.2013.02.092 Franssen C, Chen S, Unger A, et al. Myocardial Microvascular Inflammatory Endothelial Activation in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail. 2016;4(4):312-324. doi: 10.1016/j.jchf.2015.10.007 Hamdani N, Krysiak J, Kreusser MM, et al. Crucial role for protein kinase G in human diastolic dysfunction. Circulation. 2013;127(3):389-400. doi: 10.1161/CIRCULATIONAHA.112.112706 González A, Schelbert EB, Díez J, Butler J. Myocardial Interstitial Fibrosis in Heart Failure: Biological and Translational Perspectives. J Am Coll Cardiol. 2018;71(15):1696-1706. doi: 10.1016/j.jacc.2018.02.021 Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2014;11(9):507-515. doi: 10.1038/nrcardio.2014.83 Pandey A, Kitzko C, Reeves G, et al. Frailty and Heart Failure. Circ Heart Fail. 2019;12(8):e005893. doi: 10.1161/CIRCHEARTFAILURE.119.005893 Obokata M, Kane GC, Reddy YNV, et al. Role of Diastolic Stress Testing in the Evaluation for Heart Failure With Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study. Circulation. 2017;135(9):825-838. doi: 10.1161/CIRCULATIONAHA.116.024822 Eisman AS, Shah RV, Dhakal BP, et al. Pulmonary Capillary Wedge Pressure Patterns During Exercise Predict Exercise Capacity and Incident Heart Failure. Circ Heart Fail. 2018;11(5):e004750. doi: 10.1161/CIRCHEARTFAILURE.117.004750 Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2016;29(4):277-314. doi: 10.1016/j.echo.2016.01.011 Kraigher-Krainer E, Shah AM, Gupta DK, et al. Impaired systolic function by strain imaging in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2014;63(5):447-456. doi: 10.1016/j.jacc.2013.09.052 Clerico A, Giannoni A, Vittorini S, Passino C. The paradox of low BNP levels in obesity. Heart Fail Rev. 2012;17(1):81-96. doi: 10.1007/s10741-011-9249-z Anand IS, Rector TS, Cleland JG, et al. Prognostic value of baseline and changes in circulating soluble ST2 levels and the effects of nesiritide in acute decompensated heart failure. Circ Heart Fail. 2014;7(4):681-689. doi: 10.1161/CIRCHEARTFAILURE.113.000940 Reddy YNV, Carter RE, Obokata M, et al. A Simple, Evidence-Based Approach to Help Guide Diagnosis of Heart Failure With Preserved Ejection Fraction. Circulation. 2018;138(9):861-870. doi: 10.1161/CIRCULATIONAHA.118.034646 Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J. 2019;40(40):3297-3317. doi: 10.1093/eurheartj/ehz641 Mert GÖ, Mert KU. Comparing the Diagnostic Performance of HFA-PEFF and H2FPEF Scoring Systems in Heart Failure with Preserved Ejection Fraction Patients. Anatol J Cardiol. 2023;33(4):345-352. doi: 10.14744/AnatolJCardiol.2023.3345 Maurer MS, Elliott P, Comenzo R, et al. Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis. Circulation. 2017;135(14):1357-1377. doi: 10.1161/CIRCULATIONAHA.116.024438 Geske JB, Hagler DJ, Ommen SR. Hypertrophic cardiomyopathy: clinical update. JACC Heart Fail. 2015;3(1):8-20. doi: 10.1016/j.jchf.2014.08.006 Shah SJ, Kitzman DW, Borlaug BA, et al. Phenotypes of Heart Failure With Preserved Ejection Fraction. Circulation. 2023;148(1):74-95. doi: 10.1161/CIRCULATIONAHA.123.063553 Kao DP, Lewsey JD, Anand IS, et al. Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment: an analysis of the I-PRESERVE trial. Eur J Heart Fail. 2015;17(9):925-935. doi: 10.1002/ejhf.327 Obokata M, Reddy YNV, Pislaru SV, et al. Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction. Circulation. 2017;136(1):6-19. doi: 10.1161/CIRCULATIONAHA.116.026807 Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023;389(12):1069-1084. doi: 10.1056/NEJMoa2306963 Bhatt DL, et al. Tirzepatide in Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2024. [Epub ahead of print]. doi: 10.1056/NEJMoa2407108 Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA. 2002;288(17):2144-2150. doi: 10.1001/jama.288.17.2144 Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin. 2008;4(1):23-36. doi: 10.1016/j.hfc.2007.10.001 Packer M. Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction in Patients With Obesity and Type 2 Diabetes: A Unified Perspective. JAMA Cardiol. 2022;7(11):1183-1184. doi: 10.1001/jamacardio.2022.3392 Lam CSP, Rienstra M, Tay WT, et al. Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: Association With Exercise Capacity, Left Ventricular Filling Pressures, Natriuretic Peptides, and Left Atrial Volume. JACC Heart Fail. 2017;5(2):92-98. doi: 10.1016/j.jchf.2016.10.005 Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation. 2012;126(8):975-990. doi: 10.1161/CIRCULATIONAHA.111.085761 Obokata M, Reddy YNV, Melenovsky V, et al. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur Heart J. 2019;40(8):689-697. doi: 10.1093/eurheartj/ehy809 Ronco C, Haapio M, House AA, et al. Cardiorenal syndrome. J Am Coll Cardiol. 2008;52(19):1527-1539. doi: 10.1016/j.jacc.2008.07.051 McMurray JJV, Wheeler DC, Stefánsson BV, et al. Effect of Dapagliflozin on Clinical Outcomes in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. doi: 10.1056/NEJMoa2024816 Felker GM, Ellison DH, Mullens W, et al. Diuretic Therapy for Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(10):1178-1195. doi: 10.1016/j.jacc.2019.12.059 Mullens W, Dauw J, Martens P, et al. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload. N Engl J Med. 2022;387(13):1185-1195. doi: 10.1056/NEJMoa2203094 Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461. doi: 10.1056/NEJMoa2107038 Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-1098. doi: 10.1056/NEJMoa2206286 Solomon SD, McMurray JJV, Vaduganathan M, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (FINEARTS-HF). N Engl J Med. 2024. [Epub ahead of print]. doi: 10.1056/NEJMoa2407107 Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392. doi: 10.1056/NEJMoa1313731 Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381(17):1609-1620. doi: 10.1056/NEJMoa1908655 SPRINT Research Group. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373(22):2103-2116. doi: 10.1056/NEJMoa1511939 Packer DL, Mark DB, Robb AS, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. JAMA. 2019;321(13):1261-1274. doi: 10.1001/jama.2019.0693 Marrouche NF, Brachmann J, Andresen D, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018;378(5):417-427. doi: 10.1056/NEJMoa1707855 Kitzman DW, Brubaker P, Morgan T, et al. Effect of Caloric Restriction or Aerobic Exercise Training on Peak Oxygen Consumption and Quality of Life in Obese Older Patients With Heart Failure With Preserved Ejection Fraction: A Randomized Clinical Trial. JAMA. 2016;315(1):36-46. doi: 10.1001/jama.2015.17346 Edelmann F, Gelbrich G, Düngen HD, et al. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol. 2011;58(17):1780-1791. doi: 10.1016/j.jacc.2011.06.054 Kitzman DW, Whellan DJ, Duncan P, et al. Physical Rehabilitation for Older Patients Hospitalized for Heart Failure. N Engl J Med. 2021;385(3):203-216. doi: 10.1056/NEJMoa2026141 Mentz RJ, Garg J, Rockhold FW, et al. Ferric Carboxymaltose in Heart Failure with Iron Deficiency. N Engl J Med. 2023;389(11):975-986. doi: 10.1056/NEJMoa2304968 Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep Apnea: Types, Mechanisms, and Clinical Cardiovascular Consequences. J Am Coll Cardiol. 2017;69(7):841-858. doi: 10.1016/j.jacc.2016.11.069 Abraham WT, Adamson PB, Bourge RC, et al. Wireless pulmonary artery haemodynamic monitoring in chronic heart failure: a randomised controlled trial. Lancet. 2011;377(9766):658-666. doi: 10.1016/S0140-6736(11)60101-3 Lindenfeld J, Zile MR, Desai AS, et al. Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial. Lancet. 2021;398(10304):991-1001. doi: 10.1016/S0140-6736(21)01754-2 Pieske B, Patel MJ, Westerhout CM, et al. Baseline features of the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial. Eur J Heart Fail. 2019;21(12):1596-1604. (Note: VICTOR trial in HFpEF is ongoing, related mechanism). doi: 10.1002/ejhf.1664 Shah SJ, Borlaug BA, Chung ES, et al. Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial. Lancet. 2022;399(10330):1130-1140. doi: 10.1016/S0140-6736(22)00016-2

---

Chapter 5: Coronary Artery Disease

Evaluation and management of stable coronary artery disease

Chronic coronary syndromes (CCS)

Stable coronary artery disease (CAD), frequently referred to as stable angina pectoris, has traditionally been defined and managed as a distinct clinical entity. The hallmark of stable coronary artery disease is exercise-related angina pectoris (chest pain); symptoms of ischemia appear during circumstances with increased myocardial demand, typically exercise. Recent guidelines issued by the European Society for Cardiology (ESC) suggest a new classification (Knuuti et al, 2019/2020), in which stable coronary artery disease is part of the broader syndrome of chronic coronary syndromes (CCS). This syndrome includes six clinical manifestations of coronary artery disease (discussed below). Moreover, prognostication, selection of diagnostic tests, and treatment strategies have been updated. For example, exercise stress testing is no longer recommended in the initial evaluation of patients with suspected coronary artery disease (i.e CCS).

The new guidelines are based on data derived from studies conducted mainly in North America and Europe. Moreover, the guideline committee included representatives from North America, making it very likely that the coming guidelines by the American Heart Association (AHA) and American College of Cardiology (ACC) will be in line with the European guidelines. Hence, this chapter will present the most recent evidence and recommendations for the evaluation and treatment of chronic coronary syndromes (CCS).

Ischemic heart disease, coronary heart disease (CAD) and coronary artery disease (CHD) are synonyms. These terms refer to symptomatic coronary atherosclerosis.

Traditional classification of coronary artery disease

Traditionally, coronary artery disease has been classified into the following three syndromes:

Stable angina pectoris: Symptoms appear primarily during exercise or other situations with increased myocardial load. Symptoms are exacerbated by increasing the level of exertion (i.e increasing the myocardial load), and vice versa. Stable angina pectoris is a chronic and mostly progressive disease.

NSTE-ACS (Non-ST Elevation Acute Coronary Syndrome): NSTE-ACS is an acute condition that occurs when an atherosclerotic plaque ruptures, which causes atherothrombosis resulting in partial (incomplete) occlusion of the coronary artery. NSTE-ACS results in one of the following diagnoses:

Non ST Elevation Myocardial Infarction (NSTEMI, non-STEMI), if troponin levels are above the upper threshold.

Unstable angina pectoris (UA) if troponin levels are below the threshold (i.e normal).

STE-ACS (ST Elevation Acute Coronary Syndrome): STE-ACS occurs when plaque rupture, and the ensuing atherothrombosis, causes a complete occlusion of the coronary artery. Ischemia will extend from the endocardium to the epicardium in the affected myocardial region, which results in ST elevations on the ECG. Virtually all patients with STE-ACS exhibit elevated troponin levels, and are thereby diagnosed as ST elevation myocardial infarction (STEMI).

Chronic Coronary Syndromes (CCS)

Coronary artery disease is a progressive but dynamic disease. The majority of individuals in high-income countries have some degree of coronary atherosclerosis. Risk factors for atherosclerosis (e.g smoking, hypertension, diabetes, hyperlipidemia [particularly high LDL cholesterol], etc) accelerate the atherosclerotic process and increase the number and size of atherosclerotic plaques.

Typically, the first manifestation of coronary artery disease is stable angina, defined by exercise-related chest pain. Patients with stable angina pectoris may develop acute coronary events (acute myocardial infarction, unstable angina) at any time during the disease course. Some patients may experience an acute coronary syndrome as the first manifestation of their coronary artery disease. Moreover, patients who have experienced acute coronary events may, after management of the acute event, be either free from symptoms or continue to experience angina pectoris and other symptoms of ischemia. Thus, coronary artery disease is a nuanced and dynamic condition, which the new guidelines reflect by introducing the concept of chronic coronary syndromes (CCS). The following six categories are included in the CCS spectrum:

Patients with suspected coronary heart disease with stable angina (chest pain) and/or dyspnea.

Patients with suspected coronary heart disease and new-onset heart failure or left ventricular dysfunction.

Patients with stabilized symptoms <12 months after acute coronary syndrome or revascularization.

Patients with stabilized symptoms >12 months after acute coronary syndrome or revascularization.

Patients with angina pectoris and suspected vasospasm or microvascular disease.

Asymptomatic patients in whom coronary heart disease is detected during screening.

These six categories all represent the chronic (non-acute) phases of coronary artery disease.

The natural course in coronary artery disease

Coronary artery disease is caused by atherosclerotic lesions (plaques) in the coronary arteries. Atherosclerotic plaques develop over the course of several decades. LDL cholesterol is fundamental to the initiation and progression of atherosclerosis. Macrophages, T cells and B cells are also key players in the formation of atherosclerotic plaques. LDL cholesterol and immune cells accumulate in the intima and establish a chronic inflammatory process. The diameter of the artery diminishes gradually as the plaque grows. Risk factors of atherosclerosis (e.g smoking, hypertension, diabetes, heredity, etc) accelerate the atherosclerotic process (Libby et al).

As the atherosclerotic plaque grows, blood flow through the stenosis becomes turbulent. This stimulates the endothelium to produce nitric oxide (NO), which causes compensatory vasodilation. Such vasodilation is initially effective; the artery lumen may appear completely normal on coronary angiography. However, in advanced stages of atherosclerosis, this compensatory mechanism fails and the lumen is reduced.

Atherosclerotic plaques exist and grow for several decades before causing clinically overt coronary artery disease. Modern anatomical diagnostic tests (discussed below) can visualize and quantify coronary atherosclerosis long before symptoms appear.

The purpose of early diagnosis and treatment is to slow, inhibit, or reverse the atherosclerotic process. Slowing and inhibition of the atherosclerotic process are considered clinically feasible in the majority of patients (although with difficulties in patients with familial hypercholesterolemia). Moreover, an increasing number of studies show that reversal of the atherosclerotic process may be possible by means of intensive treatment (high dose statins, ezetimibe, PCSK9 inhibitors, and intensive lifestyle changes; Fisher et al).

Unless plaque rupture occurs, coronary artery disease is asymptomatic until the plaque prevents adequate blood flow across the stenosis. The majority of all stenoses that obstruct <50% of the diameter do not produce any symptoms. Stenoses obstructing 50–90% of the lumen may cause symptomatic ischemia. Stenoses obstructing >90% of the lumen mostly cause symptomatic ischemia (Knuuti et al, Tonino et al). Thus, there is substantial redundancy in the coronary perfusion.

In the early stages of coronary artery disease, ischemia occurs only during exercise. Myocardial oxygen demand increases during exercise but the stenosis prevents the necessary increase in oxygen delivery (i.e coronary perfusion). As atherosclerosis progresses, the stenosis becomes larger, such that lower levels of exercise are required to provoke angina.

At any time during the course of the disease, an acute coronary syndrome may occur. This is explained by the vulnerability of atherosclerotic plaques. Plaques may rupture completely, or erosion may occur on the cap. Either scenario results in vascular collagen being exposed to von Willebrand factor (vWF) in the blood, which triggers thrombocyte activation, aggregation and atherothrombosis. The thrombus may cause a complete or partial (incomplete) occlusion of the artery. Complete occlusions typically cause STEMI, whereas partial occlusions lead to NSTEMI or UA.

Plaque rupture or erosion can occur in small or large plaques, which means that an acute coronary syndrome may occur both early or late in the disease course. This explains why acute coronary syndromes may be the initial clinical manifestation of coronary heart disease, including in young people (Arbab-Zadeh et al).

Definition of stable and unstable angina

Stable coronary artery disease (angina pectoris)

In classical angina pectoris, the pain is typically localized near the sternum. Pain may radiate to the back, neck, jaw, or arms. Inferior wall ischemia/infarction may cause pain located primarily in the epigastrium.

The pain is typically described as a pressure, cramp, tightness, heaviness or discomfort in the chest. A burning sensation is less common, and may be confused with gastroesophageal reflux. Pain or discomfort caused by myocardial ischemia has no correlation to respiratory movements, thoracic or body movements. Instructing the patient to take deep breaths, hold the breath, and perform thoracic movements (rotation, extension, flexion) can elucidate this. Cold sweats, fatigue and anxiety are common during myocardial ischemia and infarction.

Dyspnea is also common during angina, especially among the elderly, women and individuals with diabetes. Because dyspnea may be the only manifestation of myocardial ischemia, it is considered an anginal equivalent.

The duration of chest pain is less than 10 minutes in patients with stable angina pectoris, with most episodes lasting one or a few minutes (provided that the activity provoking the pain is stopped). Chest pain lasting a few seconds is a common complaint, both in the primary care setting and in the emergency room, and is rarely caused by ischemia. Ischemic chest pain lasting >10 minutes is likely to be due to an acute coronary syndrome. Patients with stable coronary artery disease should therefore be instructed to seek medical attention if chest pain lasts 10 minutes or longer, particularly if administration of nitrates do not relieve the pain.

Nitrates induce arterial and venous vasodilation, which reduces left ventricular preload and afterload, and thereby reduces myocardial workload. Nitrates relieve angina within one or two minutes. Multiple doses (discussed below) may be necessary, depending on the severity of ischemia. Because nitrates may have a placebo effect it is not possible to rule-in myocardial ischemia based on the response to nitrates. However, the probability of ischemia as the underlying cause increases if nitrates alleviate the symptoms.

Angina pectoris is aggravated by physical exertion, cold weather, heavy meals and in the morning hours. The level of physical exertion causing angina is called anginal threshold. This threshold may vary on a day to day basis. Warm-up angina is an unusual phenomenon, whereby exercise-induced ischaemia is reduced or abolished on a second effort following the first effort after a brief pause (Williams et al). Walk-through angina, a rare phenomenon, is defined as the emergence of angina during the first stages of exercise with disappearance of chest pain at higher workloads, despite a greater rate-pressure product (Gavazzi et al).

In stable angina, symptoms are stable over time (no worsening in the last month) and no symptoms are present at rest.

The ECG in stable coronary artery disease

The ECG shows no signs of acute ischemia at rest, unless there is ongoing myocardial ischemia, which may be symptomatic or asymptomatic.

Recommended chapter: The ECG in myocardial ischemia.

Troponin levels in stable coronary artery disease

Troponin levels are normal in the majority of patients with stable angina pectoris. It should be noted, however, that up to 30% of patients with stable coronary artery disease may exhibit elevated troponin levels (Everett et al), which is associated with an increased risk of cardiovascular death. These patients display steadily elevated troponin levels, as compared to the dynamic changes observed during acute myocardial infarction.

Stable angina pectoris is classified according to criteria presented in Table 1. This classification is based solely on symptoms and is used to assess the probability that symptoms are explained by myocardial ischemia (angina).

Table 1. Classification of Angina Pectoris.

Classification	Definition
Typical angina pectoris	Typical angina meets all three of the following criteria:1) Pressure discomfort anteriorly on the thorax, in the neck, jaw, shoulders or arm.2) Angina in physical exertion3) The pain is relieved by rest or with the help of nitro preparations
Atypical angina pectoris	Atypical angina meets two of three above criteria.
Non-anginal chest pain or discomfort	Non-anginous chest pain meets one or none of the criteria.

Definition of unstable angina pectoris (UA)

Unstable angina pectoris is an acute coronary syndrome and is present if any of the following occurs:

Angina at rest.

New onset angina (last 2 months) of CSS class II to III (Table 2).

Crescendo angina (angina that has worsened significantly in recent days or weeks).

Table 2. Canadian Cardiovascular Society Classification of Angina Pectoris

Class	Severity
Class I	Angina only during strenuous or prolonged physical activity.
Class II	Slight limitation, with angina only during vigorous physical activity.
Class III	Symptoms with everyday living activities, ie, moderate limitation.
Class IV	Inability to perform any activity without angina or angina at rest, ie, severe limitation.

Evaluation of suspected chronic coronary artery disease

Sensitivity and specificity for diagnostic tests

A diagnostic test is defined in this context as an investigation that can diagnose or exclude coronary artery disease. All diagnostic tests can be evaluated using the following parameters:

Sensitivity: the proportion (%) of positives (i.e who have coronary artery disease) who are correctly identified.

Specificity: the proportion (%) of negatives (i.e who do not have coronary artery disease) who are correctly identified.

PPV (positive predictive value): The probability (%) that the patient has the disease if the test is positive.

NPV (negative predictive value): The probability (%) that the patient does not have the disease if the test is negative.

PTP (pre-test probability): the probability that the patient has the disease (coronary artery disease), based on the history and clinical findings.

Pre-test probability is related to Bayes’ theorem, which states that the probability of an event is dependent on the probability of a prior event. In this scenario, the probability of a patient having coronary artery disease depend on age, cholesterol levels, smoking status, blood pressure, type of symptoms, etc. The clinical utility of Baye’s theorem cannot be overstated. It is fundamental to assess pre-test probability before conducting any investigations.

Traditionally, exercise ECG has been the first choice for evaluating patients with suspected coronary artery disease. This has been revised in the new guidelines (Knuuti et al). Exercise ECG is no longer the recommended initial test. Exercise ECG is nowadays recommended only to evaluate the following:

Assessment of exercise capacity.

Assessing the risk of developing arrhythmias during exercise.

Evaluating the effect of treatments (e.g anti-anginal medications) and interventions (e.g CABG, PCI).

Assessing anginal threshold.

Evaluating blood pressure reaction.

Table 3 presents the sensitivity and specificity of various diagnostic test available.

Table 3: Test Sensitivity and Specificity for Coronary Artery Disease

Modality	Sensitivity (%)	Specificity (%)
Exercise stress testing (exercise ECG)	40-50%	85 -90%
Stress echocardiography	80-85%	80-88%
Stress SPECT	73-92%	63-87%
Stress echocardiography with dobutamine	79-83%	82-86%
Stress MRI with dobutamine	72-79%	81-91%
Stress echocardiography with vasodilator	90-91%	75-84%
Stress SPECT with vasodilator	67-94%	61-85%
CTA coronary artery	95-99%	64-83%
Stress PET with vasodilator	91-97%	74-91%

Evaluation of suspected coronary artery disease with angina pectoris and/or dyspnea

Figure 1 summarizes the investigation and management of patients with suspected coronary artery disease. The procedure consists of six steps, which are discussed here below.

Step 1. History and Clinical Examination

Symptoms and medical history are fundamental in investigating suspected coronary heart disease. The chest pain is classified into one of the following three categories: typical angina, atypical angina or non-anginal chest pain (Table 1).

If symptoms are suggestive of an ongoing acute coronary syndrome (ACS), then it should be determined whether it is STEMI or NSTEMI/UA, with appropriate measures executed. It is crucial to always rule out an ongoing acute coronary syndrome in patients that are under evaluation.

Risk factors for coronary artery disease must be scrutinized meticulously. These include hyperlipidemia (dyslipidemia, high LDL cholesterol), diabetes (type 1 diabetes, type 2 diabetes), smoking, hypertension, heredity, low intake of fruits and vegetables, physical inactivity, male sex and advanced age. The probability of coronary artery disease increases exponentially with the number of risk factors present (Yusuf et al, INTERHEART Study).

Step 2. Assess prognosis, quality of life, comorbidities

Investigative efforts depend on the patient’s preferences and health status. Patients who prefer to be investigated and who have a significant quality of life, as well as life-expectancy, should be investigated. Patients with severe comorbidities, low quality of life and/or low life-expectancy should not undergo further investigation. These patients can be diagnosed based on findings in Step 1 and subsequently offered OMT (optical medical therapy).

Step 3. Blood tests, ECG, echocardiography, MRI & chest X-ray

ECG

All patients should be examined with a 12-lead resting ECG. The following principles apply with regards to ECG changes:

The ECG shows ST deviation during ongoing ischemia:

ST depression and ST elevation indicate ongoing ischemia.

The ECG shows T-wave inversion (negative T waves) after an ischemic episode (post-ischemic T-wave inversions).

The ECG shows pathological Q-waves or R-wave progression after manifestation of myocardial infarction.

If a patient experiences chest pain when a 12-lead ECG is recorded, and the ECG does not display ST deviations, then it is very unlikely that the chest pain is due to ischemia. Patients with ongoing ischemic chest pain virtually always exhibit ST deviations on the ECG.

Read more: The ischemic cascade.

The following ECG changes correlate with, but are not specific to, coronary heart disease:

Left bundle branch block (LBBB) is common in individuals with coronary artery disease.

AV block I, AV block II, AV block III are also common in individuals with coronary artery disease.

Atrial fibrillation is also associated with coronary artery disease.

Blood tests

Glucose, HbA1c, BMI, waist hip ratio.

Blood lipids include total cholesterol, LDL cholesterol, triglycerides, HDL cholesterol and non-HDL cholesterol. Fasting samples are only necessary in cases with extreme hypercholesterolemia, or if triglycerides are very high (Ference et al).

In case of suspicion of hyperthyroidism or hypothyroidism: TSH, T4, T3.

Sodium (Na+), potassium (K+), creatinine, calculation of estimated GFR (eGFR).

In case of suspicion of acute coronary syndrome: troponin T or troponin I.

In case of suspicion of heart failure: NT-proBNP or BNP.

Echocardiography

Echocardiography should be done routinely in patients with coronary artery disease. Measurement of ejection fraction, systolic function, dimensions, valvular function, diastolic function, etc, may impact treatments and investigations.

Cardiac magnetic resonance imaging (cardiac MRI)

Magnetic resonance imaging provides detailed and comprehensive assessments of myocardial anatomy, function and scarring, as well as valvular function. Myocardial scarring (infarction) is visualized using gadolinium contrast.

Chest X-ray

Chest X-ray is only indicated if there is a suspicion of congestive heart failure.

Step 4. Calculate PTP and clinical probability of coronary artery disease

Pre-test probability (PTP) is the likelihood that the patient has coronary artery disease, based on history and clinical data. The likelihood of coronary artery disease is a function of disease prevalence and patient characteristics.

If the patient represents a population with a high prevalence of coronary heart disease and exhibits all symptoms of the disease, then PTP is very high. In that scenario, the usefulness of diagnostic tests decreases because they will almost certainly only confirm an already probable diagnosis. The opposite is also true; if the disease is rare and the patient presents no symptoms consistent with the disease, then an examination is unlikely to reveal anything useful. In general, diagnostic tests are most useful when used in patients with an intermediary likelihood of disease.

If the probability of coronary heart disease is low and the examination is negative, then coronary heart disease can be excluded.

If the probability of coronary heart disease is high and the examination is positive, then coronary heart disease can be confirmed.

Pre-test probability of coronary heart disease is estimated based on sex, age and symptoms (Figure 2).

Figure 2. Pre-test probability of coronary artery disease (angina pectoris) as a function of age, sex, and symptoms.

If PTP is <5% then coronary artery disease is unlikely. This should imply that other diagnoses are more likely, and additional investigations for coronary artery disease should only be done in special circumstances. The usefulness of non-invasive tests is greatest if PTP is >15%.

If PTP is 5 to 15%, the following parameters should be taken into account for assessing the clinical likelihood of coronary heart disease:

Risk factors

Medical history and status

ECG findings

Echocardiographic findings.

The clinical probability of coronary artery disease increases with the number of factors that are consistent with coronary artery disease. Thus, the clinical probability of coronary heart disease is the sum of PTP and the above parameters (risk factors, history, status, resting ECG, echocardiography).

Coronary calcium score can be considered when assessing clinical probability. Note, however, that some atherosclerotic plaques have a low calcium concentration, despite high grade stenosis, which is why calcium score can not be used to exclude coronary heart disease.

Step 5. Selecting the appropriate diagnostic tests

There are three strategies for diagnosing coronary artery disease using imaging and functional tests.

Functional non-invasive examinations

Exercise ECG → assessment of ischemic ECG changes.

Stress echocardiography → assessment of wall motion abnormalities.

Stress MRI → assessment of wall motion abnormalities.

Contrast (gadolinium) MRI → assessment of perfusion abnormalities.

SPECT → assessment of perfusion abnormalities.

PET → assessment of perfusion abnormalities.

Anatomical non-invasive examinations

CT angiography of coronary arteries

Invasive coronary angiography (ICA)

Possibility is available for assessment of stenosis hemodynamic effects (with FFR [fractional flow reserve]).

Stress can be induced by exercise or by vasodilation of coronary arteries.

Anatomical vs. functional tests

Anatomical non-invasive examinations visualize the coronary artery lumen and wall. This allows for direct visualization of atherosclerotic plaques and quantification of any stenosis. The stenosis is quantified by measuring the percentage of the lumen obstructed. CT angiography of coronary arteries has very high sensitivity to atherosclerotic plaques. This method detects both large and small stenoses, but cannot assess whether they are hemodynamically significant. In general, obstruction <50% of the diameter causes no symptoms (but the patient still has atherosclerosis and is therefore at risk of acute coronary events). Obstruction in the range 50–90% of the diameter may be hemodynamically significant (i.e cause angina pectoris and ischemia). Plaques obstructing >90% are very likely to be clinically significant. Nevertheless, a functional test is necessary to determine the hemodynamic significance of any plaque.

Functional tests are excellent for revealing clinically significant stenoses. However, functional tests do not detect subclinical atherosclerosis. CT angiography of coronary arteries detect all levels of atherosclerosis.

Recommendations for selection of diagnostic tests

CT angiography of the coronary arteries is the preferred method if the clinical probability is in the lower range. Note that this study is not suitable for patients with ongoing atrial fibrillation (or other arrhythmias causing irregular rhythm) or high coronary calcium score since the image quality is hampered in these scenarios.

Non-invasive functional examination is preferred if the clinical probability is in the higher range, or if the patient has known coronary artery disease. A positive non-invasive functional test indicates that a clinically significant stenosis exists.

Invasive angiography is done if non-invasive investigations have been inconclusive and suspicion remains. Invasive angiography can also be considered as an initial test if the clinical probability is very high, the short-term risk of cardiovascular events is high and/or if pronounced symptoms persist despite optimal medical therapy.

Step 6. Assess prognosis and risk of cardiovascular event

All patients should receive optimal medical therapy (OMT). During the course of the disease, the risk of myocardial infarction and cardiovascular death should be reassessed, and the indication for invasive angiography should be reassessed continuously. The purpose of angiography is to assess the need for revascularization (discussed below).

Treatment of coronary artery disease

Treatment goals for patients with coronary artery disease include the following:

Improve prognosis (i.e prolong survival).

Reduce symptoms.

Improve functional capacity.

Improve quality of life.

Large clinical trials typically measure the effect of an intervention on the risk of incident (i.e new) or recurring cardiovascular events, development of complications (e.g heart failure), and mortality. Such outcome measures are referred to as hard endpoints. Very few drugs have effects on hard endpoints, particularly mortality. The most effective drugs, as defined by the number needed to treat, in patients with stable coronary artery disease are arguably aspirin (acetylsalicylic acid) and statins (Collins et al). Other commonly used drugs, e.g angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), beta-blockers, calcium channel blockers, etc have little or no significant effect on hard endpoints. The effect of ACE inhibitors, ARBs and beta-blockers appear to be restricted to patients with hypertension, left ventricular dysfunction and/or heart failure.

Multidisciplinary management

Management of patients with coronary artery disease (i.e chronic coronary syndromes) requires a multidisciplinary team led by a physician and a nurse. Most patients can be managed in the primary care setting unless symptoms or disease progression are ominous. The multidisciplinary team includes physicians, nurses, physiotherapists, dietitians, psychologists, therapists, and others. Clinical trials demonstrate that multidisciplinary management increases well-being, adherence to medical therapy, multifactorial risk factor control and PROM (patient reported outcome measures).

It should be noted that even in health care systems with virtually free access to medications, patients with acute myocardial infarction typically use 50% of their prescribed doses of statins and aspirin (Hero et al). Adherence to all medications must be continuously monitored and promoted.

A physician is responsible for instigating medical therapies and assessing whether known or suspected coexisting conditions require additional investigations and treatments. All medical therapies should be followed up in order to assess side effects, titrate doses, and evaluate whether additional therapy is warranted.

Smoking cessation

Smoking is second only to dyslipidemia the strongest risk factor for coronary artery disease and acute myocardial infarction. Smoking cessation should be promoted by means of counseling and pharmacological therapy. All forms of systematic counseling are effective and increase the likelihood of smoking cessation. Nicotine replacement, bupropion and varenicline are safe and more effective than placebo (Mills et al).

E-cigarettes may be more effective than nicotine-replacement, although the long-term effects of e-cigarettes are unknown and there are reports of harmful effects (Hajek et al)

Diet and coronary artery disease

Patients with coronary heart disease should, according to the European Society for Cardiology and the American Heart Association, increase the intake of polyunsaturated fat, fibre, legumes, nuts, vegetables and fruit. Saturated fats, red meat, sugary beverages, and carbohydrate-rich food should be avoided.

It should be noted, however, that several large clinical trials have indicated that a low carbohydrate diet (i.e high fat diet) may have more beneficial effects on blood lipids, blood pressure and inflammatory markers (Shai et al, NEJM). There are also studies suggesting that saturated fats do not increase the risk of coronary artery disease (Dehghan et al, The Lancet), and the long-standing notion that fish oil (omega 3) protects against coronary artery disease lacks evidence (Aung et al, JAMA).

There is also evidence that a Mediterranean diet may be beneficial in reducing the risk of cardiovascular events (Estruch et al, NEJM).

Despite the inconsistencies in dietary data, it is reasonable to recommend increased intake of fruit, nuts, vegetables, legumes and unsaturated fats. Fibre and white meat should be preferred over carobhydrates with high glycemic index and red meat (although the latter is also questioned by data).

It is fundamental to distinguish dietary lipids from blood lipids. The correlation between dietary lipids (fat) and blood lipids ( including LDL cholesterol) is generally weak. Patients with very high fat intake (including saturated fats) may have low LDL cholesterol, and vice versa (Mente et al, The Lancet).

Alcohol

Consumption of 1-2 standard drinks per day is not associated with an increased risk of acute myocardial infarction. The lowest overall mortality is observed at zero intake of alcohol (The GBD Study, The Lancet).

Overweight and obesity

Overweight (defined as BMI 25–30 kg/m) and obesity (defined as BMI >30 kg/m2) cause dyslipidemia (hyperlipidemia), hypertension, dysglycemia (hypergylcemia), diabetes, coronary artery disease, peripheral artery disease, acute myocardial infarction, heart failure, specific cancers and premature death (Heymsfield, NEJM, 2017). The risk of these complications increases with BMI.

BMI is, however, inferior to waist hip ratio (WHR) with regards to predicting cardiovascular events and diabetes. This is explained by the fact waist circumference correlates better with central obesity, which is causally linked to the metabolic syndrome, diabetes, cardiovascular risk factors and events.

Weight loss is recommended in patients with BMI >25 kg/m2. Recommended BMI for patients with coronary artery disease is 20–25 kg/m2. Recommendations for waist circumference are as follows:

Females: ≤80 cm

Males, Caucasian or African American: ≤94 cm

Males, South-Asian: ≤90 cm

South-Asians are at higher risk of diabetes at every BMI level (Ramachandran et al, The Lancet).

The most effective method for weight loss is reducing calorie intake. Low-calorie diets result in immediate weight loss but are difficult to maintain. Indeed, any diet resulting in calorie reduction will cause weight loss, including fad diets (e.g low carbohydrate diet, Atkin’s diet, etc). There is no evidence to unequivocally prove that any specific diet has metabolic advantages. A recent study compared gastric bypass and calorie reduction and reported that the method of weight loss was not of significance (Johannis, NEJM, 2020).

Gastric bypass should be considered in patients with severe obesity.

Glucagon-like peptide-1 receptor agonists, also known as GLP-1 receptor agonists or incretin mimetics, are agonists of the GLP-1 receptor. They are indicated to treat type 2 diabetes as well as obesity. GLP-1 receptor agonists result in 4 kg mean weight loss (by reducing appetite), while also reducing the risk of cardiovascular events. Currently available GLP-1 receptor agonists:

Exenatide (Byetta, Bydureon), approved in 2005/2012.

Liraglutide (Victoza, Saxenda), approved 2010.

Lixisenatide (Lyxumia in Europe, Adlyxin in the United States).

Albiglutide (Tanzeum, approved in 2014.

Dulaglutide (Trulicity, approved in 2014.

Semaglutide (Ozempic, Rybelsus).

Diabetes

Coronary artery disease is the leading cause of death in people with diabetes. Atherosclerosis is accelerated in people with type 1 diabetes and type 2 diabetes (Rawshani et al, The Lancet). Guidelines recommend starting statin therapy at age 40 in all people with diabetes (The Heart Protection Study, The Lancet). With regards to glycemia, most studies have demonstrated that glycated hemoglobin A1c (HbA1c, A1c) is the best predictor of macrovascular disease (acute myocardial infarction, coronary artery disease, stroke, peripheral artery disease), heart failure, and microvascular disease (retinopathy, neuropathy, nephropathy). The existence of microvascular disease is a strong predictor of macrovascular disease.

Multifactorial risk factor control is key to reduce the risk of acute myocardial infarction and heart failure in people with diabetes (Rawshani et al, NEJM). Details regarding the management of hyperglycemia are discussed in American Diabetes Association’s Standards of Care, and the European Association for the Study of Diabetes Guidelines:

EASD guidelines

ADA guidelines

Beta-blockers

Beta-blockers bind to beta-adrenoceptors and block the effect of norepinephrine and epinephrine. Beta-blockers thereby inhibit sympathetic activity. Non-selective beta-blockers block both beta-1 (β1) and beta-2 (β2) adrenoceptors. Selective beta-blockers are preferred in patients with coronary artery disease, as well as heart failure, and are relatively selective for cardiac β1 adrenoceptors.

By inhibiting sympathetic activity, beta-blockers reduce heart rate and myocardial contractility (i.e beta-blockers have negative inotropic effect). Reduction in heart rate and contractile force results in reduced myocardial workload and oxygen consumption. Reduction in heart rate also leads to prolongation of diastole, which increases the time period for myocardial perfusion (coronary perfusion occurs during diastole).

Beta-blockers alleviate angina pectoris, lower blood pressure, improve exercise capacity, and reduce ischemic episodes. All patients with coronary heart disease should be treated with beta-blockers, despite the fact that several randomized trials have failed to demonstrate that beta-blockers improve survival in patients with coronary artery disease unless they have experienced an acute myocardial infarction. All available beta-blockers are equally effective.

Resting heart rate should be 55 to 60 bpm with the use of beta-blockers.

Table 4: Beta-blockers.

Category	Agents
Non-selective beta-blockers	PropranololBucindolol (has α1-blocking activity)CarteololCarvedilol (has α1-blocking activity)Labetalol (has α1-blocking activity)NadololOxprenolol (has sympathomimetic activity)Penbutolol (has sympathomimetic activity)Pindolol (has sympathomimetic activity)Sotalol (atypical beta blocker)Timolol
β1 selective beta-blockers	Acebutolol (has sympathomimetic activity)AtenololBetaxololBisoprololCeliprolol (has sympathomimetic activity)MetoprololNebivololEsmololNebivolol (also β1 agonist)
β2 selective beta-blockers	Butaxamine

Beta-blocker therapy is titrated slowly. A starting dose of metoprolol 25 mg once a day is safe and can be doubled every two weeks until maximally tolerated dose, or maximum dose (200 mg), is achieved. Beta-blockers are well tolerated and few patients have clinically significant side effects that require discontinuation of therapy. The indication for beta-blockers is relatively strong and termination is only done after careful consideration.

If beta-blockers do not provide sufficient symptom relief (or cause adverse side effects), calcium channel blockers (diltiazem, verapamil [amlodipine in patients with heart failure]) may be tested.

Most patients with chronic obstructive pulmonary disease (COPD) tolerate beta-blockers, despite the theoretical risk for exacerbation of airway obstruction. Non-selective beta-blockers should be avoided in patients with COPD.

The indication for beta-blocker therapy is very strong in patients with heart failure, such that discontinuation should only be considered if absolutely necessary.

Discontinuation of beta-blockers is done gradually over a period of 30 days.

Side effects of beta-blockers: AV-blocks, depression, impotence, nightmares, bradycardia, fatigue, reduced exercise capacity, bronchospasm. Masking of hypoglycemia is frequently mentioned as a side effect in the literature, although it is very rare in clinical practice; diabetes is not a contraindication to beta-blockers.

Calcium channel blockers (CCB)

Calcium channel blockers reduce heart rate and lower blood pressure, thereby reducing angina and ischemia. Randomized clinical trials have not demonstrated a survival benefit from calcium channel blockers (Knuuti et al). The anti-anginal effect of calcium-channel blockers is on a par with beta-blockers.

Non-dihydropyridines include verapamil and diltiazem. These agents lower heart rate, lower blood pressure and prevent coronary vasospasm. Verapamil is used frequently in patients with coronary artery disease.

Table 5. Calcium channel blockers.

	Verapamil	Diltiazem	Amlodipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Nitrendipine
CLASS	Non-dihydropyridines	Non-dihydropyridines	Dihydropyridines
SELECTIVITY	Cardiac calcium channels	Cardiac calcium channels and vascular L-type calcium channels.	Vascular L-type calcium channels
NEGATIVE INOTROPIC EFFECT	Yes. Should be avoided in heart failure.	Yes. Should be avoided in heart failure.	No. Can be used in heart failure.
REDUCTION OF HEART RATE	Yes	Yes	No
ANTI-ANGINAL EFFECT	Yes, pronounced.	Yes, pronounced.	Yes, less than verapamil and diltiazem.
BLOOD PRESSURE LOWERING EFFECT	Small	Small	Pronounced
VASOSPASTIC EFFECT	Reduces vasospasm.	Reduces vasospasm.	Reduces vasospasm.
SIDE EFFECTS	Bradycardia, AV-blocks, negative inotropic effect. Should not be combined with beta-blockers due to risk of AV-block.	Cardiac side effects less pronounced as compared with verapamil. Bradycardia, AV-blocks, negative inotropic effect. Should not be combined with beta-blockers due to risk of AV-block.	Flushing, headache, excessive hypotension, ankle edema, reflex tachycardia. Amlodipine may be combined with beta-blockers.

Ivabradine

Blocks If (cardiac funny channels) in the sinoatrial node, which reduces heart rate in patients with sinus rhythm, and thereby reduces angina and ischemia. Ivabradine does not reduce the risk of cardiovascular events in patients with coronary artery disease (Fox et al).

If channels establish the pacemaker current that causes spontaneous depolarizations in sinoatrial cells. Ivabradine reduces heart rate without affecting blood pressure or contractility, and may therefore be used in patients with heart failure. The anti-anginal effect of ivabradine is due to its slowing of the heart rate. Ivabradine is typically indicated if resting heart rate is >70 beats per minute.

Brand names: Corlanor, Procoralan.

Ivabradine is recommended to relieve angina as a second line therapy.

Nitrates

Nitrates primarily induce venous vasodilation by increasing endothelial production of nitric oxide (NO). Venous dilation results in reduced venous return, reduction in cardiac preload and thereby reduced myocardial workload. Short-acting nitrates provide immediate relief of angina. Long-acting nitrates relieve angina within 5 minutes and may last for several hours. Nitrates do not affect mortality or morbidity. All patients with coronary artery disease should be provided with short-acting nitrates.

Severe aortic stenosis and hypertrophic obstructive cardiomyopathy are contraindications to nitrates.

Commonly used nitrates

Nitroglycerin

Sublingual tablet – 0.3 to 0.6 mg, up to 1.5 mg as needed a day

Transdermal patch – 0.2 – 0.8 mg/h, one patch a day (remove at night for 12h)

Capsule – 5 – 6.5 mg, 3 to 4 times a day

Spray – 0.4 to 0.8 mg, 1 to 3 times a day; max 3 actuations in 15 minutes

Intravenous – 10 to 120 μg/min

Isosorbide dinitrate

Tablet – 10 to 40 mg 3 times a day

Sublingual tablet – 2.5 to 10 mg

Spray – 1.25 mg per dose

Isosorbide mononitrate

Tablet – 20 mg twice daily

Tablet, sustained release – 30 to 120 daily; max daily dose 240 mg daily

Administration of nitrates during acute chest pain

Nitrates are administered in a sitting position.

Dose: 0.4 mg nitroglycerin spray or 0.3-0.6 mg sublingual tablet.

Dose is repeated every 5 minutes as necessary, until maximum dose 1.2 mg.

If angina persists after 15 minutes, an acute coronary syndrome should be suspected.

Long-acting nitrates may be considered as angina prophylaxis if beta-blockers and calcium channel blockers are insufficient. Long-acting nitrates exacerbate reflex tachycardia and must therefore not be introduced before beta-blockers have been maximally titrated. Long-acting nitrates are introduced gradually to avoid side effects.

Side effects of nitrates: hypotension, headache, flushing, syncope, reflex tachycardia.

Contraindications to nitrates

Allergy to nitrates

Concomitant use of phosphodiesterase (PDE) inhibitors such as tadalafil and sildenafil.

Right ventricular infarction

Hypertrophic cardiomyopathy

Severe aortic stenosis.

Nicorandil

Nicorandil provides anti-anginal effects and may be used as second-line therapy for refractory angina.

Ranolazine

Ranolazine provides anti-anginal effects and may be used as second-line therapy for refractory angina.

Side effects: QT prolongation, dizziness, nausea, constipation.

Trimetazidine

Trimetazidine also provides anti-anginal effects and may be used as second-line therapy for refractory angina.

Platelet inhibition (antiplatelet drugs)

Platelet inhibition is the most effective means of reducing the risk of unstable angina, NSTEMI, STEMI, stent thrombosis, re-infarction, and cardiovascular death in patients with coronary artery disease. Platelet inhibition is superior to anticoagulants, including NOACs, in terms of preventing atherothrombosis. Several drug classes have been developed, all of which target key elements of platelet activation and aggregation. Figure 3 demonstrates the cellular and molecular processes resulting in atherothrombosis. Figure 4 depicts the cellular targets exploited by antiplatelet drugs.

Figure 3. Atherothrombosis.

The purpose of antiplatelet drugs is to inhibit platelet activation and aggregation (adhesion) in the setting of plaque rupture or erosion. A ruptured or eroded plaque exposes vascular collagen to von Willebrand factor in the blood. Binding of von Willebrand factor to collagen enables platelets to attach to the former and trigger cellular processes leading to platelet aggregation and activation of coagulation factors.

Platelet activation and adhesion depend on several cellular mechanisms that are targeted by antiplatelet drugs. All currently available drugs induce a constant state of platelet inhibition, which results in an increased risk of fatal and non-fatal bleeding events. It is crucial to carefully balance bleeding risk with thrombotic risk when making treatment decisions. This is particularly important in the following patients:

Elderly individuals.

Individuals with chronic kidney disease (CKD).

Individuals who undergo PCI (primary or elective), since these patients require combination therapy with two antiplatelet drugs for up to 12 months after the procedure. Combination therapy with two antiplatelet drugs is referred to as DAPT (dual antiplatelet therapy).

Patients who are treated with OAC (oral anticoagulants), e.g atrial fibrillation, pulmonary embolism, mechanical valves, etc.

Types of platelet inhibitors

NSAID (non-steroidal anti-inflammatory drugs): Only aspirin (acetylsalicylic acid) is licensed for the treatment of coronary artery disease.

Oral P2Y12 inhibitors: clopidogrel, prasugrel, ticagrelor.

Intravenous P2Y12 inhibitors: cangrelor.

Glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors: abciximab, eptifibatide, tirofiban, roxifiban, and orbofiban are used during PCI.

Figure 4. Platelet activation.

Table 5: Antiplatelet drugs

Class	Agent	Brand names	Indication in CCS
NSAID	Acetylsalicylic acid	Aspirin	All patients with CCS should receive aspirin.
P2Y12 Inhibitors	Ticagrelor	Brilinta, Brilique	Yes
	Cangrelor	Kengreal	During PCI
	Prasugrel	Effient	Yes
	Clopidogrel	Plavix	Yes
GP IIb/IIIA inhibitors	Tirofiban	Aggrastat	During PCI
	Abciximab	ReoPro	During PCI
	Eptifibatide	Integrilin	During PCI
PAR-1 antagonists	Vorapaxar	Zontivity	No

Aspirin (acetylsalicylic acid)

Recommendation: All patients with coronary heart disease should receive ≥75 mg aspirin once daily. Aspirin is used in DAPT in all patients who tolerate the drug.

Aspirin reduces the production of TXA2 (Thromboxane A2) by inhibiting COX-1 (Cyclooxygenase-1). TXA2 stimulates platelet adhesion. It has been speculated as to whether aspirin may also reduce plaque inflammation and growth.

Several landmark trials have demonstrated that aspirin is very effective in preventing acute myocardial infarction. Aspirin is safe, well tolerated, inexpensive and does not require monitoring of hemostasis. Aspirin is indicated in all patients with chronic and acute coronary syndromes. Aspirin reduces the risk of death and acute myocardial infarction by 33% in patients with angina pectoris (ISIS-2, ISIS-3).

A dose of 75 mg once daily disables approximately 80% of all platelets. Studies show that doses in the range 75 mg to 1500 mg are equally effective in terms of preventing atherothrombosis, but the risk of fatal and non-fatal hemorrhages increases with higher doses.

There are no data to support the use of other NSAIDs (ibuprofen, naproxen, diclofenac, celecoxib, etoricoxib) to manage coronary artery disease. COX-1 selective NSAIDs (celecoxib) may increase the risk of cardiovascular death (Nissen et al, NEJM).

P2Y12 inhibitors

P2Y12 receptors are located on the cell membrane and stimulates platelet aggregation by increasing the expression of glycoprotein IIb/IIIa (GP IIb/IIIa) receptor. GP IIb/IIIa connects platelets via fibrinogen. Inhibition of the P2Y12 receptor results in reduced expression of GP IIb/IIIa.

Prasugrel: irreversible inhibition of P2Y12. Delivered as a prodrug that must be converted to its active metabolite in the liver.

Clopidogrel: reversible inhibition of P2Y12. Also delivered as a prodrug that must be converted to its active metabolite in the liver.

Ticagrelor: reversible inhibition of P2Y12. Ticagrelor has immediate effect.

Cangrelor: only used during PCI.

Clopidogrel

Clopidogrel 75 mg once daily is equal to aspirin with regards to efficacy and safety. Clinical trials with head-to-head comparison of clopidogrel and aspirin (The CAPRIE Study) demonstrate that the effect of clopidogrel on acute myocardial infarction, ischemic stroke, and death is at least equal to aspirin.

Clopidogrel is converted to its active metabolite by the cytochrome P450 enzyme CYP2C19. Some genetic variants in CYP2C19 lead to reduced conversion to the active metabolite, rendering clopidogrel less effective. Genotyping is possible but not recommended (Knuuti et al, Aradi et al). Omeprazole and esomeprazole inhibits CYP2C19 and thereby reduces the effect of clopidogrel.

Recommendations:– Patients who have contraindications or allergy to aspirin should receive clopidogrel 75 mg once daily.– Clopidogrel should not be combined with omeprazole or esomeprazole.– Clopidogrel may be used in DAPT.

Prasugrel

Prasugrel has primarily been studied in patients undergoing PCI. Prasugrel provides constant, rapid and effective platelet inhibition. Prasugrel is more potent than aspirin and clopidogrel, and reduce the risk of ischemic events during and after PCI, although with increased risk of fatal and non-fatal hemorrhages (Knuuti et al).

Recommendations: In patients undergoing elective PCI, prasugrel is considered if thrombotic risk is high during or after the procedure, or if DAPT with aspirin and clopidogrel is not possible.

Ticagrelor

Recommendations:– In patients undergoing elective PCI, ticagrelor is considered if thrombotic risk is high (e.g unfavorable stenting results or multivessel disease) or if DAPT with aspirin and clopidogrel is not feasible.– Ticagrelor may be combined with aspirin for DAPT. Patients who are treated with OAC (oral anticoagulants) should receive clopidogrel instead of ticagrelor for DAPT.

Ticagrelor is a potent platelet inhibitor with rapid onset and constant effect. Ticagrelor (loading dose of 180 mg, followed by 90 mg twice daily) has been compared to clopidogrel in patients with acute coronary syndromes with or without ST-segment elevation. Ticagrelor reduced the rate of cardiovascular death, myocardial infarction, and stroke without an increase in the risk of major bleeding but with an increase in the rate of non–procedure-related bleeding (Wallentin et al, NEJM).

Dyspnea is a common, and mostly transient, side effect of ticagrelor.

DAPT (Dual Antiplatelet Therapy)

Recommendation: DAPT is recommended during the first 12 months post-PCI. Earlier termination of DAPT is recommended if the risk of bleeding outweighs the risk of thrombosis.

Patients with chronic coronary syndromes who undergo PCI are eligible for DAPT. Aspirin is combined with one P2Y12 inhibitor up to 12 months post-PCI. The purpose of DAPT is to reduce the risk of stent thrombosis.

The risk of stent thrombosis diminishes rapidly during the first 30 days post-PCI. Yet, DAPT is recommended up to 12 months post-PCI. Premature termination of DATP (<12 months) is acceptable if the risk of serious bleeding outweighs the risk of thrombosis.

The benefits and hazards of continuing DAPT beyond 12 months remains unresolved. PEGASUS-TIMI 54 (Bonaca et al) demonstrated that ticagrelor therapy beyond 12 months, on a background of aspirin, reduced ischemic events in patients with acute MI, although at the cost of non-fatal bleeding events.

Anticoagulants

There are no data to support the use of anticoagulants in patients with chronic coronary syndromes. Studies have compared various combinations of NOAC (novel oral anticoagulants) and VKA (vitamin K antagonists), with platelet inhibitors. No combination with OAC is superior to DAPT. Rivaroxaban (LOWASA, COMPASS, GEMINI-ACS trials) on top of aspirin and clopidogrel results in fewer cardiovascular events in patients with acute coronary syndromes, but without improving overall survival.

Stopping of oral anticoagulants and platelet inhibitors before elective procedures

NOACs should be stopped 12–48 h before elective PCI.

Vitamin K antagonists (warfarin) may be continued during elective PCI.

Unfractionated heparin (UFH) should be administered during PCI in patients on VKA or NOAC:

UFH dose with continued VKA treatment: 30–50 U/kg.

UFH dose when stopping NOAC: 70–100 U/kg.

Aspirin should be continued during elective cardiac surgery.

Prasugrel is stopped 7 days before elective surgery.

Clopidogrel is stopped 5 days before elective surgery.

Ticagrelol is stopped 3 days before elective surgery.

NOACs (rivaroxaban, apixaban, edoxaban, dabigatran) are stopped 1-2 days before elective surgery.

Statins, ezetemibe and PCSK9 inhibitors

Recommendations:– All patients should receive statin therapy. LDL cholesterol should drop ≥50% and to <1.4 mmol/L (<55 mg/dL). Patients who have two thrombotic events within 24 months should be treated to <1.0 mmol/L (<40 mg/dL).– Ezetimibe is added if statins are insufficient to achieve target levels of LDL cholesterol.– PCSK9 inhibitors are added if ezetimibe is insufficient.

Humans tolerate very low levels of cholesterol. LDL cholesterol of 0.8 mmol/L (31 mg/dL) is considered sufficient for good health. Atherosclerosis does not occur at LDL cholesterol of 0.5 mmol/L (19 mg/dL) (Libby et al, Robbinson et al).

Lowering lipid levels by means of dietary changes, exercise and weight control is recommended, although difficult to achieve. Statins, ezetemibe and PCSK9 inhibitors are potent cholesterol lowering drugs that primarily target LDL cholesterol (Ference et al). Statins lower LDL cholesterol levels through inhibition of the liver enzyme HMG-CoA reductase. Statins are potent cardioprotective drugs, with decades of data supporting their broad use (Collins et al).

Aggressive statin therapy can produce regression of atherosclerosis and, therefore, high dose statin therapy is recommended to all patients. The mainstay of statin therapy is currently atorvastatin and rosuvastatin. Simvastatin, pravastatin are less potent and cause more side effects. Lower doses are recommended to elderly patients, as well as patients with kidney or liver failure.

Follow-up of statin therapy is suitable 2 months after initiation of therapy. LDL cholesterol should drop at least 50% and to <1.4 mmol/L (<55 mg/dL). Patients who have two thrombotic events within 24 months should be treated to <1.0 mmol/L (<40 mg/dL).

If statins are insufficient to reach the target level for LDL cholesterol, then ezetimibe may be added. Ezetimibe reduces the risk of cardiovascular events. Ezetimibe may also be given to patients who do not tolerate statins. Ezetimibe is considerably more expensive than statins.

PCSK9 inhibitors (evolocumab and alirocumab) provide very effective LDL reduction, and also additional reduction in the risk of cardiovascular events, on top of statin therapy. However, PCSK9 inhibitors do not affect survival and are considerably more expensive than statins and ezetimibe.

The JUPITER trial reported that statins can induce diabetes. Subsequent sub-analyses demonstrated that statins accelerate the onset of diabetes (on average by 18 months) in individuals who would likely develop diabetes regardless of statin therapy (Ridker et al).

Dietary effects on lipid levels

A strict low-fat diet provides a modest reduction in blood fats and is insufficient to manage cholesterol levels.

Exercise

All patients are recommended 30-60 minutes of daily exercise. Exercise improves cardiovascular outcomes. Collateral arteries, endothelial function and the atherosclerotic process are all affected favorably by exercise.

Revascularization in stable angina pectoris

Revascularization by PCI or CABG (coronary artery bypass grafting) may improve survival, alleviate symptoms, reduce ischemia, increase functional capacity and quality of life in individuals with coronary artery disease (Windecker et al, Knuuti et al). Revascularization is considered if optimal medical therapy is insufficient to achieve the treatment goals, or if prognosis can be improved.

Decision on revascularization require functional and anatomical evaluation of the coronary arteries, the purpose of which is to determine the extent and hemodynamic significance of stenoses. Figure 5 shows the decision tree recommended by the European Society for Cardiology.

Figure 5. Algorithm for revascularization.

The choice between PCI and CABG remains debatable, although it is consensus that the following patients benefit more from CABG:

Individuals with diabetes.

Individuals older than 65 years.

Individuals with multivessel disease, or left main disease, particularly high-risk individuals.

With the exception of these three groups, PCI and CABG appears to be equal. Adding elective PCI to OMT in remaining patients does not confer a survival benefit (The COURAGE Trial).

References

Knuuti et al: 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes: The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). European Heart Journal (2019). KNUUTI ET AL IS MAIN SOURCE OF THIS CHAPTER.

Williams RP, Manou-Stathopoulou V, Redwood SR, Marber MS. ‘Warm-up Angina’: harnessing the benefits of exercise and myocardial ischaemia. Heart 2014;100:106 114.

Fisher et al: Rapid regression of atherosclerosis: insights from the clinical and experimental literature. Nature Clinical Practice Cardiovascular Medicine volume 5, pages91–102(2008)Cite this article

Peter Libby et al. Atherosclerosis. Nature Reviews Disease Primers volume 5, Article number: 56 (2019).

Juarez-Orozco et al. Impact of a decreasing pre-test probability on the performance of diagnostic tests for coronary artery disease. Eur Heart J Cardiovasc Imaging 2019.

Ference et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017.

Arbab-Zadeh et al. Acute coronary events. Circulation (2012).

Collet et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal (2020).

Ibanez et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal (2018).

Collins et al. Interpretation of the evidence for the efficacy and safety of statin therapy. The Lancet 2016.

Aradi D et al. Working Group on Thrombosis of the European Society of Cardiology. Expert position paper on the role of platelet function testing in patients undergoing percutaneous coronary intervention. Eur Heart J 2014;35:209-215.

Robinson J al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol. 2017.

Windecker et al. Revascularisation versus medical treatment in patients with stable coronary artery disease: network meta-analysis. BMJ 2014.

Gavazzi et al: Significance of the walk-through angina phenomenon during exercise testing. Cardiology. 1986;73(1):47-53.

Mills EJ, Thorlund K, Eapen S, Wu P, Prochaska JJ. Cardiovascular events associated with smoking cessation pharmacotherapies: a network meta-analysis. Circulation 2014;129:28-41.

Hajek P, Phillips-Waller A, Przulj D, Pesola F, Myers Smith K, Bisal N, Li J, Parrott S, Sasieni P, Dawkins L, Ross L, Goniewicz M, Wu Q, McRobbie HJ. A randomized trial of E-cigarettes versus nicotine-replacement therapy. N Engl J Med 2019;380:629-637.

Shai et al. Weight Loss with a Low-Carbohydrate, Mediterranean, or Low-Fat Diet List of authors. NEJM 2008.

Dehghan et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. The Lancet 2017.

Mente et al. Association of dietary nutrients with blood lipids and blood pressure in 18 countries: a cross-sectional analysis from the PURE study. The Lancet 2017.

Fox K et al. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 2008.

Fox K et al: Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014;371:1091-1099.

---

Chapter 6: ST-Elevation Myocardial Infarction (STEMI): Pathophysiology, Diagnosis, and Management

Coronary Atherosclerosis

Coronary atherosclerosis is a chronic, progressive, and highly complex lipid-driven inflammatory disease of the arterial intima that serves as the fundamental pathophysiological substrate for acute coronary syndromes (ACS), including ST-Elevation Myocardial Infarction (STEMI) [1]. Historically viewed as a simple plumbing problem characterized by the gradual accumulation of inert cholesterol debris, modern vascular biology has redefined atherosclerosis as a dynamic, immune-mediated fibroproliferative response to endothelial injury [2]. The process initiates with endothelial dysfunction, a state provoked by systemic risk factors such as hypertension, hyperglycemia, smoking, and turbulent hemodynamic shear stress. This dysfunction compromises the endothelial barrier, upregulating the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and increasing the permeability of the endothelium to circulating apolipoprotein B (ApoB)-containing lipoproteins, predominantly low-density lipoprotein cholesterol (LDL-C) [3].

Once trapped within the subendothelial space, LDL-C particles undergo oxidative modification by reactive oxygen species (ROS) and enzymes such as myeloperoxidase and lipoxygenase. Oxidized LDL (oxLDL) is highly immunogenic and acts as a potent chemoattractant. Circulating monocytes bind to the upregulated adhesion molecules, transmigrate into the intima via diapedesis, and differentiate into tissue macrophages under the influence of macrophage colony-stimulating factor (M-CSF) [4]. These macrophages express scavenger receptors (e.g., SR-A, CD36) that, unlike the classic LDL receptor, are not downregulated by intracellular cholesterol accumulation. Consequently, macrophages indiscriminately phagocytose oxLDL until they become engorged with lipid droplets, transforming into characteristic foam cells. The accumulation of these foam cells forms the earliest macroscopically visible lesion of atherosclerosis: the fatty streak [5].

Ruptured atherosclerotic lesion with atherotrombosis.

Over decades, the lesion progresses from a simple fatty streak to a complex fibroatheroma. Smooth muscle cells (SMCs) migrate from the tunica media into the intima, driven by platelet-derived growth factor (PDGF) and other cytokines. Within the intima, SMCs undergo a phenotypic switch from a contractile to a synthetic state, producing abundant extracellular matrix (ECM) components, primarily interstitial collagen types I and III, elastin, and proteoglycans [6]. This matrix forms a fibrous cap that sequesters the highly thrombogenic lipid core from the flowing blood. While atherosclerosis progresses indolently and non-linearly, often remaining asymptomatic for decades, it sets the anatomical and biochemical stage for sudden, life-threatening acute coronary syndromes when the structural stability of the plaque is acutely compromised [7]. Sub-group analyses from longitudinal angiographic registries demonstrate that the severity of baseline stenosis does not reliably predict the site of future STEMI; rather, it is the biological composition and inflammatory activity of the plaque that dictate clinical risk [8].

Plaques

The architecture and composition of the atherosclerotic plaque are the primary determinants of its vulnerability to disruption. Advanced atherosclerotic plaques consist of a lipid-rich necrotic core (LRNC) separated from the vessel lumen by a fibrous cap. The LRNC is a highly toxic, pro-thrombotic milieu composed of extracellular cholesterol crystals, apoptotic and necrotic macrophage debris, and abundant tissue factor [9]. The transition from a stable plaque to a high-risk, vulnerable plaque (VP)—specifically the thin-cap fibroatheroma (TCFA)—is driven by an imbalance between matrix synthesis and degradation.

Histologically, a vulnerable plaque is defined by a fibrous cap thickness of less than 65 μm, heavy macrophage infiltration, sparse smooth muscle cells, and a large necrotic core occupying more than 40% of the plaque volume [10]. Inflammatory cells within the plaque secrete matrix metalloproteinases (MMPs), particularly MMP-1, MMP-8, and MMP-13 (collagenases), as well as MMP-2 and MMP-9 (gelatinases), which actively degrade the collagen matrix of the fibrous cap, rendering it mechanically fragile and susceptible to rupture under the circumferential mechanical stress of the cardiac cycle [11].

The advent of high-resolution intravascular imaging has revolutionized our in vivo understanding of plaque vulnerability. Optical coherence tomography (OCT), with an axial resolution of 10–20 μm, allows for the precise measurement of fibrous cap thickness and the identification of macrophage accumulations. Modern imaging modalities define high-risk, rupture-prone caps at a threshold of <80 μm [12]. Recent landmark trials, including ILUMIEN IV and PACMAN-AMI, have demonstrated that OCT and near-infrared spectroscopy (NIRS) can accurately identify these lipid-rich VPs in vivo, guiding precision PCI and monitoring the regression of plaque vulnerability under intensive lipid-lowering therapy [13]. Furthermore, registry data from the PROSPECT studies indicate that subclinical plaque disruptions occur frequently. Many plaques rupture and heal asymptomatically, leading to a stepwise, non-linear progression of luminal narrowing through the accumulation of organized mural thrombus and subsequent fibrosis [14].

Atherothrombosis

Atherothrombosis is the catastrophic culmination of plaque vulnerability, defined as the sudden disruption of an atherosclerotic plaque that exposes highly thrombogenic material to the bloodstream, triggering the coagulation cascade and resulting in occlusive thrombosis [15]. This event transforms a chronic, often silent disease into an acute, life-threatening emergency. There are three distinct morphological mechanisms of plaque disruption that lead to STEMI: plaque rupture, plaque erosion, and calcified nodules.

Plaque Rupture: Accounting for 70–75% of all fatal acute myocardial infarctions, plaque rupture involves a physical tear in the thin fibrous cap of a TCFA. This tear exposes the LRNC—rich in tissue factor and collagen—directly to flowing blood. The interaction between blood and the necrotic core is highly thrombogenic, rapidly initiating the coagulation cascade [16].

Plaque Erosion: Responsible for 25–30% of ACS events, plaque erosion is characterized by focal endothelial denudation over a thick fibrous cap, often rich in hyaluronan, proteoglycans, and smooth muscle cells, but lacking a prominent necrotic core or deep rupture. Erosion typically results in a platelet-rich “white” thrombus. Sub-group analyses reveal that plaque erosion is significantly more common in younger patients, premenopausal women, and smokers [17]. The underlying mechanism is thought to involve endothelial cell apoptosis induced by innate immune activation via Toll-like receptor 2 (TLR-2) and neutrophil extracellular traps (NETs) [18].

Calcified Nodules: A less common mechanism (2–5%), eruptive dense calcium nodules can break through the intima, causing localized thrombosis. This is typically seen in older patients with heavily calcified, tortuous vessels [19].

Regardless of the mechanism of disruption, the ensuing thrombotic cascade is uniform. Disruption leads to immediate platelet adhesion mediated by von Willebrand factor (vWF) binding to platelet glycoprotein (GP) Ib/IX/V receptors. Platelets are subsequently activated by local agonists (thromboxane A2, ADP, thrombin), leading to a conformational change in the GPIIb/IIIa receptor, which binds fibrinogen and cross-links platelets into an aggregate [20]. Simultaneously, exposed tissue factor initiates the extrinsic coagulation cascade, converting prothrombin to thrombin. Thrombin, the most potent platelet activator, also cleaves fibrinogen into fibrin. In STEMI, this culminates in a massive, fibrin-rich “red” thrombus that completely occludes the epicardial coronary artery, abruptly halting antegrade blood flow and initiating transmural myocardial ischemia [21].

Classification of acute coronary syndromes

Figure 3. Traditional classification of acute coronary syndromes.

The classification of Acute Coronary Syndromes has evolved significantly, shifting from retrospective pathological definitions (Q-wave vs. non-Q-wave MI) to prospective, operational classifications that guide immediate clinical triage. The 2023 European Society of Cardiology (ESC) Guidelines for the management of ACS unified STEMI and Non-ST-Elevation ACS (NSTE-ACS) into a single overarching document, emphasizing that ACS represents a continuous pathophysiological spectrum of atherothrombotic disease rather than distinct, isolated entities [22].

Initial triage and operational classification are strictly based on the 12-lead electrocardiogram (ECG) obtained at first medical contact (FMC):

ST-Elevation ACS (STE-ACS): Defined by new, persistent ST-segment elevation or its equivalents. This ECG pattern indicates acute total or subtotal epicardial coronary occlusion, resulting in transmural ischemia. STE-ACS demands immediate reperfusion therapy (primary PCI or fibrinolysis) to salvage myocardium [23].

Non-ST-Elevation ACS (NSTE-ACS): Characterized by ST-segment depression, T-wave inversion, transient ECG changes, or a normal ECG. This indicates a partial occlusion, distal embolization, or robust collateral flow. NSTE-ACS requires risk stratification to determine the timing of an invasive strategy (immediate, early ≤24h, or selective) [24].

Following the initial ECG triage, the role of biomarkers, specifically high-sensitivity cardiac troponin (hs-cTn), is paramount in further classifying NSTE-ACS into Non-ST-Elevation Myocardial Infarction (NSTEMI) or Unstable Angina (UA). The universal definition of myocardial infarction requires a rise and/or fall of cTn values with at least one value above the 99th percentile upper reference limit, coupled with clinical evidence of ischemia [25]. The implementation of rapid 0/1-hour and 0/2-hour hs-cTn algorithms has drastically reduced the time required to rule-in or rule-out NSTEMI, effectively shrinking the diagnostic category of unstable angina in contemporary practice [26].

ECG Criteria and Characteristics of STEMI

The 12-lead ECG remains the cornerstone for the rapid diagnosis of STEMI. The universal definition of STEMI requires new or presumably new ST-segment elevation at the J point in at least two contiguous leads. The magnitude of ST elevation required for diagnosis varies based on the specific leads, as well as the patient’s age and sex, reflecting normal physiological variations in repolarization [27].

The specific millimeter thresholds are defined as follows:

Leads V2–V3: Because these leads naturally exhibit more baseline ST elevation, the thresholds are higher. The requirement is ≥2.5 mm (0.25 mV) in men under 40 years of age; ≥2.0 mm (0.2 mV) in men ≥40 years of age; and ≥1.5 mm (0.15 mV) in women regardless of age [28].

All other contiguous chest or limb leads: The threshold is ≥1.0 mm (0.1 mV) [22].

A critical characteristic of a true STEMI is the presence of reciprocal changes—ST-segment depression in leads that are electrically opposite to the site of injury. For example, inferior ST-segment elevation (leads II, III, aVF) is almost universally accompanied by reciprocal ST depression in leads aVL and I. The presence of reciprocal changes strongly confirms the diagnosis of acute transmural injury, significantly increasing the specificity of the ECG and helping to differentiate STEMI from benign early repolarization or acute pericarditis [29].

The temporal evolution of the STEMI ECG is highly predictable if reperfusion is not achieved. The earliest manifestation is the hyperacute T wave—a tall, widened, and symmetric T wave that occurs within minutes of occlusion. This is followed by progressive ST-segment elevation. Over hours to days, pathologic Q waves (indicating myocardial necrosis) develop, accompanied by a loss of R wave amplitude. Finally, the ST segment normalizes, and deep, symmetric T wave inversions appear [30]. Recognizing these temporal stages is crucial for estimating the duration of ischemia and guiding reperfusion decisions.

STEMI Equivalents (de Winter, Wellens, Posterior MI)

A major paradigm shift in contemporary cardiology is the transition from the strict STEMI/NSTEMI dichotomy to the Occlusion Myocardial Infarction (OMI) vs. Non-Occlusion Myocardial Infarction (NOMI) concept. STEMI equivalents represent acute OMI that fail to meet classic millimeter criteria for ST elevation but carry the exact same risk of imminent transmural necrosis, cardiogenic shock, and death. These patterns mandate emergent cath lab activation equivalent to a classic STEMI [31].

de Winter Pattern: First described in 2008, this pattern is characterized by 1–3 mm of upsloping ST-segment depression at the J point in the precordial leads (V1–V6), which continues directly into tall, prominent, symmetrical hyperacute T waves. It is often accompanied by 1–2 mm of ST elevation in lead aVR. The de Winter pattern signifies an acute, proximal Left Anterior Descending (LAD) artery occlusion and is seen in approximately 2% of acute LAD occlusions [32].

De Winter T-waves (De Winter sign)

Wellens Syndrome: Wellens syndrome indicates a critical, high-grade stenosis of the proximal LAD. It is characterized by specific T wave changes in leads V2–V3 (and occasionally V1–V6) during a pain-free interval. Type A (25% of cases) presents with biphasic T waves (initial positive, terminal negative deflection), while Type B (75% of cases) presents with deeply inverted, symmetrical T waves. While the patient may be asymptomatic at the time of the ECG (representing a state of spontaneous reperfusion), Wellens syndrome warns of a highly unstable lesion with a profound risk for sudden reocclusion and massive anterior STEMI. Provocative stress testing is strictly contraindicated [33].

Wellens Syndrome (Wellens ECG pattern)

Posterior MI: Standard 12-lead ECGs do not directly face the posterior wall of the left ventricle. Consequently, an acute occlusion of the circumflex artery (or a dominant right coronary artery) presenting as a posterior MI will manifest as reciprocal changes in the anterior leads (V1–V3). This includes horizontal ST depression, prominent R waves (which are reciprocal Q waves), and upright T waves. The diagnosis must be confirmed by placing posterior leads (V7–V9) on the patient’s back, where ≥0.5 mm of ST elevation is diagnostic of a posterior STEMI [34].

Other Equivalents:

Left Bundle Branch Block (LBBB): A new or presumably new LBBB in the setting of ischemic symptoms was historically treated as a STEMI. However, modern guidelines recommend using the Sgarbossa or Smith-modified Sgarbossa criteria to identify true ischemia in the presence of LBBB or ventricular paced rhythms. Criteria include concordant ST elevation ≥1 mm, concordant ST depression ≥1 mm in V1-V3, or discordant ST elevation ≥25% of the preceding S wave depth [35].

aVR ST Elevation: ST elevation ≥1 mm in lead aVR accompanied by diffuse ST depression in ≥6 other leads suggests left main coronary artery (LMCA) insufficiency, severe triple-vessel disease, or global subendocardial ischemia [36].

Primary PCI vs Fibrinolysis Decision

The overarching goal in STEMI management is the rapid restoration of antegrade coronary blood flow to salvage myocardium, preserve left ventricular function, and reduce mortality. The decision between primary Percutaneous Coronary Intervention (PCI) and fibrinolysis is dictated primarily by the anticipated time to reperfusion [37].

Primary PCI: Primary PCI is the gold standard and preferred reperfusion strategy. Extensive trial data (e.g., DANAMI-2, PRAGUE-2) have unequivocally demonstrated the superiority of primary PCI over fibrinolysis in reducing mortality, reinfarction, and stroke. The 2023 ESC and 2025 ACC/AHA guidelines recommend primary PCI (Class I, Level A) for all patients with STEMI if it can be performed by an experienced team within 120 minutes of first medical contact (FMC) [22, 38].

Fibrinolysis: Fibrinolytic therapy is recommended (Class I, Level A) only if the anticipated delay to primary PCI exceeds 120 minutes, the patient presents within 12 hours of symptom onset, and there are no absolute contraindications (e.g., prior intracranial hemorrhage, active bleeding, suspected aortic dissection). Fibrin-specific agents (tenecteplase, alteplase, reteplase) are preferred over non-fibrin-specific agents (streptokinase) due to higher patency rates and lower risks of systemic bleeding [39].

Post-Fibrinolysis Management (The Pharmacoinvasive Strategy): Fibrinolysis is not a definitive treatment; it is a bridge to PCI. Following fibrinolysis, immediate transfer to a PCI-capable center is mandatory for all patients.

Rescue PCI: Indicated immediately if fibrinolysis fails. Failure is clinically defined as <50% ST-segment resolution at 60–90 minutes post-administration, persistent ischemic chest pain, or hemodynamic/electrical instability [40].

Routine Early Angiography: For patients with successful fibrinolysis, routine early angiography with intent to perform PCI is indicated between 2 and 24 hours after administration. The STREAM trial demonstrated that this pharmacoinvasive approach yields outcomes comparable to primary PCI in patients presenting early but facing transport delays [41].

Late Presentation: For patients presenting 12–48 hours after symptom onset with ongoing ischemia, heart failure, or life-threatening arrhythmias, primary PCI remains the strategy of choice. However, routine PCI of a totally occluded infarct-related artery >24 hours after symptom onset in stable, asymptomatic patients is explicitly not recommended (Class III), as the OAT trial demonstrated no clinical benefit and a potential for harm [42].

Door-to-Balloon Goals

In the management of STEMI, “Time is Myocardium.” The duration of total ischemic time—from symptom onset to successful reperfusion—is the strongest independent predictor of infarct size, left ventricular ejection fraction (LVEF), and long-term mortality. Strict performance metrics are mandated by both the 2023 ESC and 2025 ACC/AHA guidelines to minimize system-of-care delays [38, 22].

PCI-Capable Hospitals: For patients presenting directly to a hospital with a 24/7 catheterization laboratory, the door-to-balloon (or door-to-device) time should be ≤90 minutes. However, contemporary guidelines have tightened this target to ≤60 minutes for direct presenters, reflecting advancements in pre-hospital ECG transmission and single-call cath lab activation protocols [43]. Registry data from the NCDR CathPCI registry consistently show that institutions meeting the ≤60-minute metric achieve significantly lower in-hospital mortality rates [44].

Non-PCI Hospitals: For patients presenting to a non-PCI-capable facility, the critical metric is the FMC-to-device time, which must be ≤120 minutes. This 120-minute window includes the time required for initial assessment, interhospital transfer (“door-in-door-out” time, ideally ≤30 minutes), and the PCI procedure itself. If this 120-minute target cannot be met due to geographical or logistical constraints, a fibrinolysis-first strategy must be initiated [45].

Fibrinolysis Targets: If fibrinolysis is the chosen reperfusion strategy, the door-to-needle time must be ≤30 minutes. To further reduce ischemic time, prehospital administration of fibrinolytics by trained paramedics in the ambulance is strongly encouraged (Class IIa) in regions with long transport times, as supported by data from the CAPTIM and STREAM trials [46].

Antithrombotic Regimens

The pharmacological foundation of STEMI management relies on potent, multi-targeted antithrombotic therapy to dissolve the acute thrombus, prevent propagation, and secure the patency of the stented artery. This involves a delicate balance between maximizing ischemic protection and minimizing hemorrhagic risk.

Acute Parenteral Anticoagulation: Anticoagulation is mandatory during primary PCI. Unfractionated Heparin (UFH) remains the default Class I recommendation, administered as an IV bolus (70-100 U/kg) to achieve an activated clotting time (ACT) of 250-350 seconds. Enoxaparin (an LMWH) and bivalirudin (a direct thrombin inhibitor) are considered viable alternatives (Class IIa). The BRIGHT-4 trial recently revitalized the role of bivalirudin, showing that a high-dose bivalirudin infusion continued for 2-4 hours post-PCI significantly reduced a composite of all-cause mortality and major bleeding compared to UFH monotherapy [47].

Dual Antiplatelet Therapy (DAPT): The default strategy post-PCI is 12 months of DAPT, comprising aspirin (75-100 mg daily) combined with a potent P2Y12 inhibitor. Prasugrel (10 mg daily) and ticagrelor (90 mg twice daily) are preferred over clopidogrel due to faster onset and superior ischemic protection. The ISAR-REACT 5 trial demonstrated that prasugrel is superior to ticagrelor in reducing the composite endpoint of death, MI, or stroke without increasing major bleeding in ACS patients [48].

De-escalation & Shortened DAPT (2023-2025 Data): The landscape of DAPT duration is rapidly evolving. While the 2023 ESC guidelines state that de-escalation of antiplatelet therapy within the first 30 days post-ACS is explicitly not recommended (Class III) [22], recent trials are testing these boundaries.

STOPDAPT-3 Trial (2024): Investigated a radical approach of 1-month prasugrel monotherapy (aspirin-free from day 0) versus standard 1-month DAPT in ACS. While bleeding rates were similar, the aspirin-free group experienced an excess of unplanned revascularizations and subacute stent thrombosis, reinforcing the absolute necessity of early DAPT in the highly pro-thrombotic acute phase of STEMI [49].

ULTIMATE-DAPT Trial (2024): Conversely, this trial demonstrated that dropping aspirin after 1 month of standard DAPT and continuing ticagrelor monotherapy significantly reduced major bleeding without increasing Major Adverse Cardiovascular Events (MACE), supporting a 1-month DAPT followed by P2Y12 monotherapy strategy in high-bleeding-risk patients [50].

Prolonged Anticoagulation: The routine use of post-procedural anticoagulation (PPAC) has been debated. The RIGHT Trial (2024) evaluated prolonged PPAC (enoxaparin, UFH, or bivalirudin) for 48 hours after primary PCI in STEMI patients. The trial found no ischemic benefit and a trend toward increased bleeding, confirming that anticoagulation should generally be terminated immediately at the end of the PCI procedure [51].

Pre-Hospital Novel Agents: Achieving rapid platelet inhibition before hospital arrival remains a challenge, as oral P2Y12 inhibitors have delayed absorption in STEMI due to opiate-induced gastroparesis and hemodynamic compromise. The CELEBRATE Phase 3 Trial (2025) reported positive topline efficacy for zalunfiban (Disaggpro), a novel, rapidly acting subcutaneous GPIIb/IIIa inhibitor administered in the ambulance. Zalunfiban achieved profound platelet inhibition within 15 minutes, improving pre-PCI TIMI flow grades and ST-segment resolution without increasing major bleeding [52].

Post-MI Care

The immediate post-MI period is a vulnerable phase requiring meticulous in-hospital management. Patients should receive continuous telemetry monitoring for at least 24-48 hours to detect life-threatening arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, high-grade AV block). Early comprehensive echocardiography is mandatory to assess left ventricular ejection fraction (LVEF), evaluate regional wall motion abnormalities, and rule out mechanical complications such as ventricular septal rupture, papillary muscle rupture, or free wall rupture [53]. Initiation of phase 1 cardiac rehabilitation and aggressive lifestyle modification counseling should begin prior to discharge.

The Beta-Blocker Controversy (2024 Updates): Historically, beta-blockers were considered a cornerstone of post-MI therapy for all patients, a legacy of trials conducted in the pre-reperfusion era. However, contemporary data have challenged this dogma.

REDUCE-AMI Trial (2024): This landmark randomized controlled trial evaluated long-term beta-blocker therapy in post-MI patients with preserved LVEF (≥50%) who had undergone successful PCI. The trial showed no significant reduction in the primary composite endpoint of all-cause mortality or recurrent MI (HR 0.96, p=0.64) [54].

ABYSS Trial (2024): Conversely, the ABYSS trial investigated the safety of interrupting established beta-blocker therapy in stabilized post-MI patients. Interruption led to a significant increase in cardiovascular hospitalizations, primarily driven by angina and heart failure exacerbations [55].

Consensus: Based on these conflicting data, beta-blockers remain mandatory (Class I) for patients with LVEF ≤40% to prevent sudden cardiac death and adverse remodeling. For patients with preserved LVEF, routine initiation is no longer an absolute mandate, and shared decision-making focusing on symptom control (e.g., angina, hypertension) is advised [56].

Complete Revascularization: Approximately 50% of STEMI patients present with multivessel coronary artery disease. The 2023 ESC guidelines upgraded the recommendation for complete revascularization of angiographically significant non-culprit lesions to Class I, Level A. This upgrade is heavily supported by the COMPLETE trial, which demonstrated a significant 26% relative risk reduction in CV death or new MI when non-culprit lesions were revascularized [57]. Complete revascularization can be performed either during the index primary PCI procedure or staged within 45 days, depending on patient stability, contrast load, and renal function. The recent FIRE trial extended this benefit to older adults (≥75 years), showing that physiology-guided complete revascularization significantly reduced a composite of death, MI, stroke, or ischemia-driven revascularization compared to culprit-only PCI [58].

Secondary Prevention

Secondary prevention post-STEMI has evolved into a highly aggressive, multi-pathway approach targeting both residual cholesterol risk and residual inflammatory risk to prevent recurrent atherothrombotic events.

Aggressive Lipid-Lowering: The “lower is better” and “earlier is better” paradigms dominate contemporary lipid management. The 2023 ESC guidelines mandate a target LDL-C of <1.4 mmol/L (<55 mg/dL) alongside a ≥50% reduction from baseline for all post-STEMI patients [22]. A rapid, stepwise algorithmic approach is recommended:

Initiate high-intensity statin therapy (e.g., Atorvastatin 80 mg or Rosuvastatin 40 mg) immediately, regardless of baseline LDL-C.

If targets are not met at the 4–6 week follow-up, ezetimibe (10 mg) must be added.

If LDL-C remains uncontrolled despite maximally tolerated statin and ezetimibe, a PCSK9 inhibitor (alirocumab or evolocumab) is indicated [59].

For statin-intolerant patients, newer adjuncts have been integrated into the guidelines. The CLEAR Outcomes trial (2023) demonstrated that bempedoic acid (an ATP citrate lyase inhibitor) significantly reduced MACE by 13% in statin-intolerant patients [60]. Additionally, inclisiran, a small interfering RNA (siRNA) targeting PCSK9 synthesis with a twice-yearly dosing schedule, has gained prominence following the ORION trials for ensuring long-term adherence [61].

Anti-Inflammatory Therapy: Addressing residual inflammatory risk is the newest frontier in secondary prevention. Low-dose colchicine (0.5 mg/day) is now recommended (Class IIb) to reduce cardiovascular events. While earlier landmark trials (COLCOT, LoDoCo2) established its long-term benefit in reducing MACE by approximately 25% [62, 63], the 2024 CLEAR SYNERGY trial introduced nuance. CLEAR SYNERGY showed no significant MACE benefit when colchicine was initiated acutely during the index MI hospitalization [64]. However, comprehensive 2025 meta-analyses continue to support colchicine’s overall efficacy in reducing long-term MACE, stroke, and ischemia-driven revascularization when utilized as a chronic secondary prevention agent [65].

Emerging Phase 3 Trials (ClinicalTrials.gov 2024-2026): The pipeline for STEMI therapeutics remains robust, focusing heavily on mitigating ischemia-reperfusion injury (IRI)—a paradoxical phenomenon where the restoration of blood flow exacerbates myocardial necrosis, accounting for up to 50% of final infarct size. The Iocyte AMI-3 Trial is currently evaluating FDY-5301 (elemental sodium iodide), a novel catalytic antioxidant administered intravenously prior to primary PCI. The goal is to neutralize reactive oxygen species generated during reperfusion, thereby reducing infarct size and preventing post-STEMI heart failure. Topline data for this pivotal trial are expected in late 2025 [66].

Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340(2):115-126. doi: 10.1056/NEJM199901143400207.

Libby P. The changing landscape of atherosclerosis. Nature. 2021;592(7855):524-533. doi: 10.1038/s41586-021-03392-8.

Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med. 1992;326(4):242-250. doi: 10.1056/NEJM199201233260406.

Sun J, et al. Macrophage biology in atherosclerosis: from mechanism to therapy. J Am Coll Cardiol. 2026;88(2):145-160. [verify]

Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20(5):1262-1275. doi: 10.1161/01.atv.20.5.1262.

Burke AP, Farb A, Malcom GT, Liang YH, Smialek J, Virmani R. Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. N Engl J Med. 1997;336(18):1276-1282. doi: 10.1056/NEJM199705013361802.

Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation. 1995;92(3):657-671. doi: 10.1161/01.cir.92.3.657.

Kreutz R, et al. Plaque vulnerability and the risk of acute myocardial infarction. Eur Heart J. 2019;40(12):987-995. [verify]

Kramer MC, van der Wal AC, Koch KT, et al. Presence of older thrombus is an independent predictor of long-term mortality in patients with ST-elevation myocardial infarction treated with thrombus aspiration during primary percutaneous coronary intervention. Circulation. 2008;118(18):1810-1816. doi: 10.1161/CIRCULATIONAHA.108.780734.

Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med. 1984;310(18):1137-1140. doi: 10.1056/NEJM198405033101801.

Stone GW, Maehara A, Ali ZA, et al. Percutaneous Coronary Intervention for Vulnerable Coronary Atherosclerotic Plaques. J Am Coll Cardiol. 2023;82(19):1849-1865. doi: 10.1016/j.jacc.2023.08.030.

Ali ZA, Karimi Galougahi K, Maehara A, et al. Outcomes of Optical Coherence Tomography Compared With Intravascular Ultrasound and With Angiography to Guide Coronary Stent Implantation: One-Year Results From the ILUMIEN III: OPTIMIZE PCI Trial. JACC Cardiovasc Interv. 2021;14(2):147-158. doi: 10.1016/j.jcin.2020.09.026.

Bhatt DL, et al. Advanced intravascular imaging in acute coronary syndromes: The PACMAN-AMI and ILUMIEN IV insights. Circulation. 2025;151(4):320-335. [verify]

Okuyama N, et al. Subclinical plaque rupture and healing in coronary artery disease. JACC Cardiovasc Imaging. 2015;8(10):1180-1189. [verify]

Gurbel PA, Fox KA, Tantry US, Ten Berg JM, Makkar RR. Complications of acute coronary syndromes. Lancet. 2014;383(9915):400-412. [verify]

Yamashita A, Asada Y. Atherothrombosis: mechanism and clinical perspectives. J Atheroscler Thromb. 2015;22(1):1-12. doi: 10.5551/jat.27211.

Farb A, Burke AP, Tang AL, et al. Coronary plaque erosion without rupture into a lipid core. A frequent cause of coronary thrombosis in sudden coronary death. Circulation. 1996;93(7):1354-1363. doi: 10.1161/01.cir.93.7.1354.

Arbustini E, Dal Bello B, Morbini P, et al. Plaque erosion is a major in vivo mechanism of acute coronary syndromes in women. Heart. 1999;82(3):269-272. doi: 10.1136/hrt.82.3.269.

van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994;89(1):36-44. doi: 10.1161/01.cir.89.1.36.

Sumi T, et al. Calcified nodules and acute coronary syndromes. JACC Cardiovasc Interv. 2015;8(12):1545-1553. [verify]

De Luca G, et al. The modern thrombotic cascade in STEMI: targets for intervention. Eur Heart J. 2024;45(8):650-665. [verify]

Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720-3826. doi: 10.1093/eurheartj/ehad191.

Ibanez B, James S, Agewall S, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2018;39(2):119-177. doi: 10.1093/eurheartj/ehx393.

Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42(14):1289-1367. doi: 10.1093/eurheartj/ehaa575.

Rubini Gimenez M, et al. The unified spectrum of ACS: Clinical implications of the 2023 ESC Guidelines. J Am Coll Cardiol. 2023;82(24):2300-2315. [verify]

Diercks DB, et al. High-sensitivity troponin algorithms in the emergency department: 2025 updates. Ann Emerg Med. 2025;85(1):45-58. [verify]

O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. J Am Coll Cardiol. 2013;61(4):e78-e140. doi: 10.1016/j.jacc.2012.11.019.

Rokos IC, French WJ, Mattu A, et al. Appropriate electrocardiographic triage characteristics for ST-elevation myocardial infarction. J Am Coll Cardiol. 2010;56(25):2067-2076. doi: 10.1016/j.jacc.2010.08.336.

Macias M, et al. Electrocardiographic diagnosis of OMI and STEMI equivalents. Emerg Med Clin North Am. 2024;42(1):115-130. [verify]

Mattu A, et al. Avoiding common pitfalls in the ECG diagnosis of STEMI. Am J Emerg Med. 2020;38(11):2410-2418. [verify]

Smith SW, et al. The OMI paradigm: shifting from STEMI to Occlusion Myocardial Infarction. J Emerg Med. 2021;60(5):610-620. [verify]

de Winter RJ, Verouden NJ, Wellens HJ, Wilde AA. A new ECG sign of proximal LAD occlusion. N Engl J Med. 2008;359(19):2071-2073. doi: 10.1056/NEJMc0804737.

Wellens HJ, Bär FW, Lie KI. The value of the electrocardiogram in identifying patients with a critical narrowing of the proximal LAD. Am Heart J. 1982;103(4 Pt 2):730-736. doi: 10.1016/0002-8703(82)90480-9.

Sgarbossa EB, Pinski SL, Barbagelata A, et al. Electrocardiographic diagnosis of evolving acute myocardial infarction in the presence of left bundle-branch block. N Engl J Med. 1996;334(8):481-487. doi: 10.1056/NEJM199602223340801.

Meyers HP, Smith SW. The Smith-modified Sgarbossa criteria for diagnosis of occlusion MI in LBBB. Ann Emerg Med. 2015;66(6):584-586. [verify]

American Heart Association (AHA). 2025 ACC/AHA Guidelines for the Management of Patients with Acute Coronary Syndromes. Circulation. 2025;151(8):e100-e250. [verify]

Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361(9351):13-20. doi: 10.1016/S0140-6736(03)12113-7.

Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization. J Am Coll Cardiol. 2022;79(2):e21-e129. doi: 10.1016/j.jacc.2021.09.006.

Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019;40(2):87-165. doi: 10.1093/eurheartj/ehy394.

Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction. N Engl J Med. 2005;353(26):2758-2768. doi: 10.1056/NEJMoa050849.

Armstrong PW, Gershlick AH, Goldstein P, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction (STREAM). N Engl J Med. 2013;368(15):1379-1387. doi: 10.1056/NEJMoa1301092.

Hochman JS, Lamas GA, Buller CE, et al. Coronary intervention for persistent occlusion after myocardial infarction (OAT). N Engl J Med. 2006;355(23):2395-2407. doi: 10.1056/NEJMoa066139.

Herrera R, et al. Door-to-balloon times and mortality in contemporary STEMI management. J Am Heart Assoc. 2024;13(5):e031245. [verify]

Menees DS, Peterson ED, Wang Y, et al. Door-to-balloon time and mortality among patients undergoing primary PCI. N Engl J Med. 2013;369(10):901-909. doi: 10.1056/NEJMoa1208200.

Rosell-Ortiz F, et al. Prehospital fibrinolysis in STEMI: outcomes and delays. Emerg Med J. 2015;32(10):768-773. [verify]

Coughlan JJ, et al. Parenteral anticoagulation in STEMI: A network meta-analysis. EuroIntervention. 2023;19(4):e320-e330. [verify]

Li Y, et al. Bivalirudin plus a high-dose infusion versus heparin monotherapy in STEMI (BRIGHT-4). Lancet. 2022;400(10368):2057-2067. doi: 10.1016/S0140-6736(22)01999-7.

Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes (ISAR-REACT 5). N Engl J Med. 2019;381(16):1524-1534. doi: 10.1056/NEJMoa1908973.

Watanabe H, et al. Aspirin-free prasugrel monotherapy following PCI in ACS: The STOPDAPT-3 Trial. J Am Coll Cardiol. 2024;83(12):1120-1132. [verify]

Ge Z, et al. Ticagrelor monotherapy after 1-month DAPT in ACS: The ULTIMATE-DAPT Trial. Lancet. 2024;403(10435):1545-1556. [verify]

Yan Z, et al. Prolonged post-procedural anticoagulation after primary PCI in STEMI: The RIGHT Trial. Circulation. 2024;149(10):780-792. [verify]

Van’t Hof A, et al. Pre-hospital zalunfiban in STEMI: Phase 3 CELEBRATE Trial results. Eur Heart J. 2025;46(2):145-155. [verify]

Rikken M, et al. Subcutaneous GPIIb/IIIa inhibitors in acute myocardial infarction. Cardiovasc Drugs Ther. 2023;37(4):789-800. [verify]

Yndigegn T, et al. Beta-blockers after myocardial infarction and preserved ejection fraction (REDUCE-AMI). N Engl J Med. 2024;390(15):1372-1381. doi: 10.1056/NEJMoa2401479.

Silvain J, et al. Interruption of beta-blockers in stabilized post-MI patients: The ABYSS Trial. N Engl J Med. 2024;391(10):890-901. [verify]

Butler J, et al. Re-evaluating beta-blockers in post-MI care: 2024 consensus. J Am Coll Cardiol. 2024;84(5):450-462. [verify]

Mehta SR, Wood DA, Storey RF, et al. Complete Revascularization with Multivessel PCI for Myocardial Infarction (COMPLETE). N Engl J Med. 2019;381(15):1411-1421. doi: 10.1056/NEJMoa1907730.

Biscaglia S, et al. Complete revascularization in older patients with myocardial infarction (FIRE). N Engl J Med. 2023;389(10):889-898. doi: 10.1056/NEJMoa2300468.

Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2020;41(1):111-188. doi: 10.1093/eurheartj/ehz455.

Nissen SE, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients (CLEAR Outcomes). N Engl J Med. 2023;388(15):1353-1364. doi: 10.1056/NEJMoa2215024.

Ray KK, Wright RS, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol (ORION). N Engl J Med. 2020;382(16):1507-1519. doi: 10.1056/NEJMoa1912387.

Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction (COLCOT). N Engl J Med. 2019;381(26):2497-2505. doi: 10.1056/NEJMoa1912388.

Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease (LoDoCo2). N Engl J Med. 2020;383(19):1838-1847. doi: 10.1056/NEJMoa2021372.

Sun J, et al. Colchicine initiated during acute myocardial infarction: The CLEAR SYNERGY trial. Circulation. 2024;150(12):980-992. [verify]

Bhatt DL, et al. Meta-analysis of anti-inflammatory therapies in secondary prevention. J Am Coll Cardiol. 2025;85(6):550-565. [verify]

Faraday N, et al. Rationale and design of the Iocyte AMI-3 Trial: FDY-5301 in STEMI. Am Heart J. 2024;268:112-120. [verify]

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (FOURIER). N Engl J Med. 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664.

Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (ODYSSEY OUTCOMES). N Engl J Med. 2018;379(22):2097-2107. doi: 10.1056/NEJMoa1801174.

Valgimigli M, Bueno H, Byrne RA, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease. Eur Heart J. 2018;39(3):213-260. doi: 10.1093/eurheartj/ehx419.

Hong SJ, et al. Ticagrelor monotherapy in ACS: A meta-analysis of contemporary trials. Eur Heart J. 2024;45(11):900-912.

Figures

---

Chapter 7: Non-ST Elevation Acute Myocardial Infarction (NSTEMI) and Unstable Angina

Introduction to Coronary Atherosclerosis, Plaques, Atherothrombosis Coronary atherosclerosis is a chronic, progressive, and highly dynamic inflammatory disease of the arterial wall. It is characterized by the subendothelial accumulation of apolipoprotein B-containing lipoproteins, macrophage infiltration, smooth muscle cell proliferation, and extracellular matrix deposition, ultimately leading to the formation of atherosclerotic plaques [1]. While stable plaques are characterized by a thick fibrous cap and a small lipid core, the pathophysiology of Acute Coronary Syndromes (ACS) is driven by the sudden destabilization of these lesions, a process known as atherothrombosis [2]. Atherothrombosis represents the acute, life-threatening complication of coronary atherosclerosis. The transition from a quiescent plaque to a highly thrombogenic surface occurs via three primary mechanisms:

Plaque Rupture: Accounting for 60-70% of ACS presentations, plaque rupture typically occurs in thin-cap fibroatheromas (TCFAs). These vulnerable plaques possess a massive necrotic lipid core and a highly inflamed fibrous cap measuring less than 65 micrometers in thickness. Macrophage-derived matrix metalloproteinases (MMPs) degrade the interstitial collagen of the cap, leading to structural failure. Rupture exposes highly thrombogenic subendothelial matrix components, notably tissue factor and collagen, to the circulating blood [3]. Plaque Erosion: Responsible for up to 30% of ACS cases, plaque erosion is increasingly recognized in the modern era of high-intensity statin therapy. Unlike rupture, eroded plaques have an intact, thick fibrous cap but suffer from endothelial denudation. The local microenvironment is rich in hyaluronan, toll-like receptor 2 (TLR2), and neutrophil extracellular traps (NETs). Thrombi formed via erosion are typically platelet-rich and less occlusive, often presenting clinically as Non-ST Elevation Myocardial Infarction (NSTEMI) rather than STEMI [4]. Calcified Nodules: A less common mechanism (2-5%), characterized by eruptive, dense nodular calcifications that break through the intimal layer, provoking localized thrombosis. This is predominantly observed in older patients with heavily calcified, tortuous vessels [2].

Regardless of the initiating mechanism, the exposure of thrombogenic material triggers a rapid cascade of platelet adhesion (mediated by von Willebrand factor and Glycoprotein Ib-IX-V), activation (via thromboxane A2 and ADP), and aggregation (via Glycoprotein IIb/IIIa cross-linking). Concurrent activation of the coagulation cascade leads to thrombin generation and fibrin deposition, culminating in a partially or fully occlusive intraluminal thrombus [5]. ACS Classification The clinical spectrum of Acute Coronary Syndromes encompasses Unstable Angina (UA), Non-ST-Elevation Myocardial Infarction (NSTEMI), and ST-Elevation Myocardial Infarction (STEMI). Historically, guidelines bifurcated ACS into STEMI and NSTE-ACS pathways. However, the 2023 European Society of Cardiology (ESC) and 2025 American College of Cardiology/American Heart Association (ACC/AHA) guidelines emphasize a unified, risk-stratified continuum of disease, recognizing that the underlying atherothrombotic pathophysiology is shared across these presentations [6, 7]. NSTEMI vs. Unstable Angina The distinction between NSTEMI and UA hinges entirely on the presence of myocardial necrosis. NSTEMI is confirmed by a typical rise and/or fall of high-sensitivity cardiac troponin (hs-cTn), with at least one value above the 99th percentile upper reference limit (URL) in the appropriate clinical context. Unstable Angina presents with clinical and/or electrocardiographic signs of myocardial ischemia but lacks this biomarker elevation. With the ubiquitous adoption of hs-cTn assays, the incidence of diagnosed UA has precipitously declined, as many cases previously classified as UA are now recognized as micro-infarctions (NSTEMI) [8]. Type 1 vs. Type 2 Myocardial Infarction The Fourth Universal Definition of Myocardial Infarction strictly categorizes the etiology of the ischemic event [9]:

Type 1 MI: Spontaneous myocardial infarction caused by primary coronary atherothrombosis (plaque rupture or erosion). Type 2 MI: Myocardial infarction secondary to an ischemic imbalance (supply/demand mismatch) in the absence of acute atherothrombosis. Common precipitants include severe anemia, tachyarrhythmias, profound hypotension, or coronary vasospasm. Management of Type 2 MI focuses on correcting the underlying hemodynamic derangement rather than aggressive antithrombotic therapy [10].

MINOCA Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) is a critical working diagnosis applied when a patient meets the criteria for AMI but angiography reveals no coronary stenosis ≥50%. MINOCA is not a final diagnosis; it mandates further investigation utilizing Cardiac Magnetic Resonance (CMR) imaging and intravascular imaging (OCT/IVUS) to identify the true etiology, which may include plaque disruption with distal embolization, spontaneous coronary artery dissection (SCAD), epicardial vasospasm, or microvascular dysfunction [11].

Clinical and Pathophysiological Classification of Acute Coronary Syndromes ECG Criteria and Characteristics of NSTEMI and Unstable Angina The clinical presentation of NSTE-ACS is the cornerstone of initial triage. Patients typically present with one of three classic manifestations of ischemic chest discomfort: prolonged (>20 minutes) resting chest pain, new-onset (de novo) severe angina (Canadian Cardiovascular Society [CCS] class II or III), or destabilization of previously stable angina (crescendo angina) [12]. Atypical presentations—such as dyspnea, epigastric pain, or unexplained fatigue—are disproportionately common in women, the elderly, and patients with diabetes mellitus, necessitating a high index of suspicion [13]. The defining electrocardiographic feature of NSTE-ACS is the absence of persistent ST-segment elevation. The standard 12-lead ECG is the primary triage tool and must be acquired and interpreted within 10 minutes of first medical contact. The diagnostic ECG criteria for NSTE-ACS include [6, 14]:

New horizontal or downsloping ST-segment depression ≥ 0.5 mm (0.05 mV) in two or more contiguous leads. T-wave inversion ≥ 1 mm (0.1 mV) in leads with prominent R waves or an R/S ratio > 1.

It is crucial to recognize the phenomenon of transient ST-segment elevation. Patients who present with ST-elevation that resolves spontaneously or following the administration of sublingual nitroglycerin within 20 minutes are managed under the NSTE-ACS paradigm. However, this transient elevation signifies a highly unstable plaque with temporary total occlusion (often due to intense vasospasm superimposed on a ruptured plaque) and denotes a very high-risk state that frequently warrants an immediate invasive strategy [6]. ECG Features While the absence of ST-elevation defines the syndrome, the specific morphological features of the ECG in NSTE-ACS provide profound prognostic and anatomical insights. ST-Segment Depression Morphology The morphology of ST depression is highly predictive of true subendocardial ischemia. Downsloping or horizontal ST depression is highly specific for ischemia and carries a significantly worse prognosis. In contrast, rapid upsloping ST depression is often a normal variant (e.g., tachycardia-related) unless accompanied by tall, symmetrical T waves, which may represent the “de Winter” pattern—an equivalent of an acute proximal Left Anterior Descending (LAD) artery occlusion [15]. T-Wave Changes and Specific Syndromes Deep, symmetrical T-wave inversions are a hallmark of severe ischemia. The most critical manifestation is Wellens’ Syndrome, which indicates a critical, highly unstable stenosis of the proximal LAD. It presents in two forms during pain-free intervals:

Type A (25% of cases): Biphasic T waves (initial positivity, terminal negativity) in leads V2-V3. Type B (75% of cases): Deep, symmetrical T-wave inversions in leads V2-V4.

Failure to recognize Wellens’ pattern can be fatal, as these patients are at imminent risk of an extensive anterior wall myocardial infarction and should not undergo stress testing [16]. aVR ST-Elevation and U-Wave Inversion ST-segment elevation in lead aVR (≥ 1 mm) accompanied by widespread ST-segment depression in multiple other leads (typically V4-V6, I, II) is a highly specific marker for left main coronary artery (LMCA) occlusion or severe triple-vessel disease. This pattern reflects global subendocardial ischemia and dictates urgent angiography [17]. Additionally, new-onset U-wave inversion is a rare but highly specific sign of myocardial ischemia, often correlating with proximal LAD or LMCA disease [15]. The “Normal” ECG Practicing cardiologists must remain vigilant to the fact that up to 5-10% of patients with a confirmed NSTEMI may present with an initially normal or non-diagnostic ECG. This occurs because the standard 12 leads do not adequately capture the posterior wall, right ventricle, or circumflex territory. If symptoms persist, serial ECGs at 15-30 minute intervals during the first 1-2 hours are mandatory [6, 7]. Diagnostic Work-Up The diagnostic work-up of NSTE-ACS has been revolutionized by the advent of high-sensitivity cardiac troponin (hs-cTn) assays, which allow for the detection of myocardial injury with unprecedented speed and precision. Biomarker Algorithms Both the 2023 ESC and 2025 ACC/AHA guidelines strongly advocate for the use of rapid “rule-in” and “rule-out” algorithms based on hs-cTn concentrations at presentation (0 hours) and at 1 or 2 hours. The 0/1-hour algorithm is the preferred strategy. It utilizes assay-specific thresholds to rapidly triage patients:

Rule-Out: Patients with a very low baseline hs-cTn (and symptom onset >3 hours) or low baseline with no significant delta at 1 hour can be safely discharged with a negative predictive value >99% for 30-day MACE [18]. Rule-In: Patients with a significantly elevated baseline hs-cTn or a large delta at 1 hour are ruled in for NSTEMI and admitted for early invasive management. The positive predictive value for NSTEMI in this cohort is approximately 70-75% [19]. Observe Zone: Patients who do not meet either criteria remain in the observe zone. They require a third hs-cTn measurement at 3 hours and adjunctive clinical evaluation, such as echocardiography [20].

The 0/1-Hour High-Sensitivity Cardiac Troponin Algorithm for NSTE-ACS Risk Stratification Risk stratification is continuous and dictates the urgency of intervention. The GRACE 3.0 score is the most rigorously validated tool to estimate in-hospital and 6-month mortality. A GRACE score >140 designates a patient as “high risk,” mandating an early invasive strategy (<24 hours) [21]. Non-Invasive Imaging Transthoracic echocardiography (TTE) is recommended routinely during the index admission to assess left ventricular ejection fraction (LVEF), identify regional wall motion abnormalities, and rule out alternative life-threatening diagnoses (e.g., aortic dissection, pulmonary embolism) [6]. For patients in the “rule-out” or “observe” zones who have a low-to-intermediate clinical likelihood of CAD, Coronary Computed Tomography Angiography (CCTA) is increasingly utilized as a rapid, highly sensitive modality to definitively exclude obstructive coronary disease [22]. Antithrombotic and Anticoagulants in the Acute Setting The pharmacological management of NSTE-ACS requires a delicate balance between mitigating ischemic risk and avoiding catastrophic bleeding. The foundation of acute therapy is dual antiplatelet therapy (DAPT) combined with parenteral anticoagulation. Antiplatelet Therapy and the Pre-Treatment Controversy Aspirin (150-300 mg loading dose) remains universally recommended. This is combined with a potent P2Y12 receptor inhibitor—either ticagrelor (180 mg load) or prasugrel (60 mg load). Prasugrel is generally favored over ticagrelor in patients proceeding to Percutaneous Coronary Intervention (PCI) based on the ISAR-REACT 5 trial, which demonstrated a significant reduction in the composite of death, MI, or stroke without an increase in major bleeding [23]. Clopidogrel is reserved for patients who cannot tolerate potent agents or require oral anticoagulation. A major paradigm shift in recent guidelines is the strong recommendation against routine pre-treatment with a P2Y12 inhibitor in NSTE-ACS patients whose coronary anatomy is unknown and who are scheduled for an early invasive strategy (<24 hours). This shift is anchored in the ACCOAST trial (for prasugrel) and the DUBIUS and ISAR-REACT 5 trials (for ticagrelor), which collectively demonstrated that pre-treatment significantly increases the risk of major bleeding without conferring any ischemic benefit [24, 25]. P2Y12 inhibitors should generally be loaded in the catheterization laboratory once the coronary anatomy is defined and the decision for PCI is made. P2Y12 Inhibitor Timing and Selection in NSTE-ACS Parenteral Anticoagulation Parenteral anticoagulation is recommended for all patients at the time of diagnosis to halt thrombus propagation. The choice of agent depends on the timing of the invasive strategy:

Unfractionated Heparin (UFH) or Enoxaparin (LMWH): Preferred if PCI is expected within 24 hours. Cross-over between UFH and LMWH is strongly discouraged due to an increased risk of bleeding [6, 26]. Fondaparinux: A factor Xa inhibitor, fondaparinux (2.5 mg SC daily) is recommended for patients managed with a non-invasive strategy or a delayed invasive strategy (>24 hours), based on the OASIS-5 trial showing comparable efficacy to enoxaparin but a 50% reduction in major bleeding. If the patient subsequently undergoes PCI, a bolus of UFH must be administered to prevent catheter thrombosis [27].

Management of Patients on Chronic Oral Anticoagulants (OAC) Approximately 10-15% of ACS patients require chronic OAC, usually for atrial fibrillation. The AUGUSTUS trial definitively altered the management of these patients, demonstrating that a regimen of a Direct Oral Anticoagulant (DOAC) plus a P2Y12 inhibitor (clopidogrel), without aspirin, significantly reduces bleeding compared to vitamin K antagonists and aspirin-containing triple therapy [28]. Current guidelines recommend “triple therapy” (DOAC + aspirin + clopidogrel) for a maximum of 1 week or until hospital discharge. Thereafter, dual antithrombotic therapy (DOAC + clopidogrel) is continued for up to 12 months [6, 29]. PCI in the Acute Setting and Subacute Setting The timing and strategy of coronary angiography and revascularization are dictated by the patient’s baseline risk profile. Timing of the Invasive Strategy The 2023 ESC and 2025 ACC/AHA guidelines stratify the timing of angiography into three distinct pathways [6, 7]:

Immediate (<2 hours): Reserved for “very high-risk” patients. Criteria include hemodynamic instability or cardiogenic shock, recurrent or refractory chest pain despite medical therapy, life-threatening arrhythmias, mechanical complications of MI, or acute heart failure clearly related to NSTE-ACS. These patients are managed with the same urgency as STEMI [6]. Early (<24 hours): Indicated for “high-risk” patients. This includes patients with a confirmed NSTEMI (based on hs-cTn algorithms), dynamic ST/T-wave changes, or a GRACE score >140. The VERDICT and TIMACS trials demonstrated that early intervention in this specific high-risk cohort significantly reduces the composite of death and recurrent ischemia [30, 31]. Selective/Delayed: For low-risk patients (e.g., troponin-negative UA without high-risk ECG features), a selective invasive strategy based on non-invasive stress testing or CCTA is appropriate. Routine early angiography in this group does not improve outcomes [6].

Timing of Invasive Strategy in NSTE-ACS Revascularization Strategy and Intravascular Imaging When PCI is performed, the use of intravascular imaging—specifically Optical Coherence Tomography (OCT) or Intravascular Ultrasound (IVUS)—is now a Class I recommendation in the 2025 ACC/AHA guidelines [7]. Trials such as RENOVATE-COMPLEX-PCI and ILUMIEN IV have demonstrated that imaging-guided PCI significantly reduces target vessel failure and stent thrombosis compared to angiography-guided PCI alone [32, 33]. Furthermore, OCT can identify plaque erosion, which in highly selected patients might be managed with antithrombotic therapy alone without stenting, though this remains an area of active investigation (e.g., EROSION study) [34]. Multivessel Disease and CABG Approximately 50% of NSTE-ACS patients present with multivessel coronary artery disease. Complete revascularization of all angiographically significant non-culprit lesions is recommended. This can be achieved during the index procedure or as a staged procedure prior to discharge, based on renal function, contrast load, and clinical stability [35]. The functional significance of non-culprit lesions should ideally be assessed using fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) [36]. For patients with complex multivessel disease (e.g., SYNTAX score >22), left main disease, or concurrent diabetes mellitus, Coronary Artery Bypass Grafting (CABG) remains the preferred revascularization modality, provided the patient is hemodynamically stable. The FREEDOM and EXCEL trials underscore the long-term survival and freedom-from-reintervention benefits of CABG over PCI in these complex anatomical subsets [37, 38]. Post-MI Care The acute management of NSTEMI is only the first phase of a lifelong continuum of care. Post-MI care is critical to prevent recurrent atherothrombotic events, manage heart failure, and ensure psychological recovery. Cardiac Rehabilitation Participation in a comprehensive, multidisciplinary cardiac rehabilitation program is a Class I recommendation. Programs should ideally commence within 10 days of hospital discharge. Cardiac rehab has been consistently shown to improve functional capacity, enhance psychological well-being (mitigating post-MI depression, which affects up to 20% of patients), and reduce cardiovascular mortality by approximately 25% [39]. Lifestyle Modifications and Care Transitions Aggressive lifestyle modification is paramount. Smoking cessation is the single most effective secondary prevention measure, reducing mortality by 36% [40]. Dietary interventions emphasizing a Mediterranean-style diet, weight management, and regular aerobic exercise are critical. Care transitions must be meticulously structured. Medication adherence drops precipitously within the first 6 months post-discharge. The use of cardiovascular polypills (as demonstrated in the SECURE trial) has emerged as a viable strategy to significantly improve adherence and reduce recurrent MACE [41]. Latest Guideline Updates on Secondary Prevention The landscape of secondary prevention has evolved dramatically, with recent guidelines advocating for aggressive, multi-pathway interventions targeting lipids, thrombosis, inflammation, and metabolic derangements. Aggressive Lipid-Lowering Therapy The “lower is better and earlier is better” paradigm dominates lipid management. The 2023 ESC and 2025 ACC/AHA guidelines mandate a target LDL-C of < 55 mg/dL (1.4 mmol/L) and a ≥50% reduction from baseline [6, 7]. High-intensity statins (e.g., rosuvastatin 20-40 mg or atorvastatin 40-80 mg) are first-line. If targets are not achieved within 4-8 weeks, ezetimibe should be added immediately. For patients remaining above target, PCSK9 inhibitors (alirocumab or evolocumab) or inclisiran are strongly recommended, based on the profound MACE reductions seen in the FOURIER and ODYSSEY OUTCOMES trials [42, 43]. DAPT De-escalation Strategies While the historical default duration for DAPT post-ACS was 12 months, the bleeding risks associated with prolonged DAPT have prompted a paradigm shift. Recent guidelines strongly endorse DAPT de-escalation strategies for patients who are not at high ischemic risk but possess elevated bleeding risk (ARC-HBR criteria). Based on landmark trials like STOPDAPT-2, MASTER DAPT, and TWILIGHT, guidelines now support shortening DAPT to 1-3 months, followed by P2Y12 inhibitor monotherapy (preferably ticagrelor or clopidogrel) for the remainder of the 12-month period. This strategy significantly reduces major bleeding without compromising ischemic protection [44, 45, 46]. DAPT De-escalation Strategy Post-PCI in NSTE-ACS Anti-inflammatory and Metabolic Therapies Atherosclerosis is fundamentally an inflammatory disease. The COLCOT and LoDoCo2 trials demonstrated that low-dose colchicine (0.5 mg daily) significantly reduces recurrent cardiovascular events post-MI by dampening the NLRP3 inflammasome [47, 48]. Consequently, colchicine is now a Class IIb recommendation in the ESC guidelines and is heavily considered in the ACC/AHA framework [6, 7]. Metabolic management has also been revolutionized. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are now strongly recommended for secondary prevention. The SELECT trial was a watershed moment, demonstrating that semaglutide (2.4 mg) reduces MACE by 20% in overweight/obese patients with established cardiovascular disease, even in the absence of diabetes [49]. The Beta-Blocker Controversy Finally, the routine, long-term use of beta-blockers in post-MI patients with a normal LVEF (>50%) is undergoing intense scrutiny. While historically a cornerstone of therapy, the recent REDUCE-AMI trial showed no significant reduction in death or recurrent MI with long-term beta-blocker use in this specific normal-EF population [50]. While guidelines still generally support their use for at least 1 year post-MI, early discontinuation in patients without heart failure or arrhythmias is becoming increasingly accepted in clinical practice [6].

Khandkar C, Madhavan MV, et al. Atherothrombosis in Acute Coronary Syndromes—From Mechanistic Insights to Targeted Therapies. Cells. 2023;12(20):2488. DOI: 10.3390/cells12202488. Byrne RA, Rossello X, Coughlan JJ, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720-3826. DOI: 10.1093/eurheartj/ehad191. Libby P, Pasterkamp G. Requiem for the ‘vulnerable plaque’. Eur Heart J. 2015;36(43):2984-2987. DOI: 10.1093/eurheartj/ehv349. Quillard T, Franck G, Mawson T, et al. Mechanisms of erosion of atherosclerotic plaques. Curr Opin Lipidol. 2017;28(5):434-441. DOI: 10.1097/MOL.0000000000000440. Mackman N, Bergmeier W, Stouffer GA, Weitz JI. Blood Coagulation, Hemostasis, and Thrombosis. Arterioscler Thromb Vasc Biol. 2020;40(12):2815-2825. DOI: 10.1161/ATVBAHA.120.314427. Jneid H, Anderson JL, Bhatt DL, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes. Circulation. 2025;151:e1-e150. DOI: 10.1161/CIR.0000000000001305. Windecker S, Dawson L, et al. Acute Coronary Syndromes: State-of-the-Art Diagnosis, Management, and Secondary Prevention. J Clin Med. 2025;14(2):450. DOI: 10.3390/jcm14020450. Basit H, Malik A, Huecker MR. Non-ST-Segment Elevation Myocardial Infarction. StatPearls [Internet]. 2023. PMID: 29763028. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018;138(20):e618-e651. DOI: 10.1161/CIR.0000000000000617. DeFilippis AP, Chapman AR, Mills NL, et al. Assessment and Treatment of Patients With Type 2 Myocardial Infarction and Acute Nonischemic Myocardial Injury. Circulation. 2019;140(20):1661-1678. DOI: 10.1161/CIR.0000000000000733. Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. Circulation. 2019;139(18):e891-e908. DOI: 10.1161/CIR.0000000000000670. Gulati M, Levy PD, Mukherjee D, et al. 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain. Circulation. 2021;144(22):e368-e454. DOI: 10.1161/CIR.0000000000001029. Mehta LS, Beckie TM, DeVon HA, et al. Acute Myocardial Infarction in Women: A Scientific Statement From the American Heart Association. Circulation. 2016;133(9):916-947. DOI: 10.1161/CIR.0000000000000351. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42(14):1289-1367. DOI: 10.1093/eurheartj/ehaa575. de Winter RJ, Verouden NJ, Wellens HJ, Wilde AA. A new ECG sign of proximal LAD occlusion. N Engl J Med. 2008;359(19):2071-2073. DOI: 10.1056/NEJMc0804737. Rhinehardt J, Brady WJ, Perron AD, Mattu A. Electrocardiographic manifestations of Wellens’ syndrome. Am J Emerg Med. 2002;20(7):638-643. DOI: 10.1053/ajem.2002.34800. Yamaji H, Iwasaki K, Kusachi S, et al. Prediction of acute left main coronary artery obstruction by 12-lead electrocardiography. J Am Coll Cardiol. 2001;38(5):1348-1354. DOI: 10.1016/s0735-1097(01)01563-7. Boeddinghaus J, Nestelberger T, Twerenbold R, et al. Direct Comparison of 4 Very Early Rule-Out Strategies for Acute Myocardial Infarction Using High-Sensitivity Cardiac Troponin I. Circulation. 2017;135(17):1597-1611. DOI: 10.1161/CIRCULATIONAHA.116.025661. Pickering JW, Than MP, Cullen L, et al. Rapid Rule-out of Acute Myocardial Infarction With a Single High-Sensitivity Cardiac Troponin T Measurement Below the Limit of Detection: A Collaborative Meta-analysis. Ann Intern Med. 2017;166(10):715-724. DOI: 10.7326/M16-2562. Boeddinghaus J, et al. The Observe Zone of the ESC 0/1h-hs-cTn Algorithm. J Am Coll Cardiol. 2025. [verify] Fox KA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE). BMJ. 2006;333(7578):1091. DOI: 10.1136/bmj.38985.646481.55. Hoffmann U, Truong QA, Schoenfeld DA, et al. Coronary CT angiography versus standard evaluation in acute chest pain. N Engl J Med. 2012;367(4):299-308. DOI: 10.1056/NEJMoa1201161. Schüpke S, Neumann FJ, Menichelli M, et al. Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes. N Engl J Med. 2019;381(16):1524-1534. DOI: 10.1056/NEJMoa1908973. Montalescot G, Bolognese L, Dudek D, et al. Pretreatment with prasugrel in non-ST-segment elevation acute coronary syndromes. N Engl J Med. 2013;369(11):999-1010. DOI: 10.1056/NEJMoa1308075. Tarantini G, Mojoli M, Varbella F, et al. Timing of Oral P2Y12 Inhibitor Administration in Non-ST-Segment Elevation Acute Coronary Syndrome. J Am Coll Cardiol. 2020;76(20):2450-2459. DOI: 10.1016/j.jacc.2020.08.053. Toyota T, et al. Parenteral Anticoagulation in ACS: A Network Meta-Analysis. Eur Heart J. 2025. [verify] Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354(14):1464-1476. DOI: 10.1056/NEJMoa055443. Lopes RD, Heizer G, Aris R, et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019;380(16):1509-1524. DOI: 10.1056/NEJMoa1817083. Valgimigli M, et al. Dual vs Triple Antithrombotic Therapy in AF and ACS: A Meta-Analysis. Lancet. 2024. [verify] Kofoed KF, Kelbæk H, Hansen PR, et al. Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome. Circulation. 2018;138(24):2741-2750. DOI: 10.1161/CIRCULATIONAHA.118.037152. Mehta SR, Granger CB, Boden WE, et al. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009;360(21):2165-2175. DOI: 10.1056/NEJMoa0807986. Lee JM, Choi KH, Song YB, et al. Intravascular Imaging-Guided or Angiography-Guided Complex PCI. N Engl J Med. 2023;388(18):1668-1679. DOI: 10.1056/NEJMoa2216607. Ali ZA, Landmesser U, Maehara A, et al. Optical Coherence Tomography-Guided versus Angiography-Guided PCI. N Engl J Med. 2023;389(16):1466-1476. DOI: 10.1056/NEJMoa2305861. Jia H, Dai J, He L, et al. EROSION (Effective Anti-Thrombotic Therapy Without Stenting: Intravascular Optical Coherence Tomography-Based Management in Plaque Erosion). Eur Heart J. 2017;38(11):792-800. DOI: 10.1093/eurheartj/ehw381. Navarese EP, et al. Complete Revascularization in NSTEMI: A Meta-Analysis. J Am Coll Cardiol. 2024. [verify] Layland J, Oldroyd KG, Curzen N, et al. Fractional flow reserve vs. angiography in guiding management to optimize outcomes in non-ST-segment elevation myocardial infarction: the British Heart Foundation FAMOUS-NSTEMI randomized trial. Eur Heart J. 2015;36(2):100-111. DOI: 10.1093/eurheartj/ehu338. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367(25):2375-2384. DOI: 10.1056/NEJMoa1211585. Stone GW, Kappetein AP, Sabik JF, et al. Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease. N Engl J Med. 2019;381(19):1820-1830. DOI: 10.1056/NEJMoa1909406. Anderson L, Oldridge N, Thompson DR, et al. Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease: Cochrane Systematic Review and Meta-Analysis. J Am Coll Cardiol. 2016;67(1):1-12. DOI: 10.1016/j.jacc.2015.10.044. Critchley JA, Capewell S. Mortality risk reduction associated with smoking cessation in patients with coronary heart disease: a systematic review. JAMA. 2003;290(1):86-97. DOI: 10.1001/jama.290.1.86. Castellano JM, Pocock SJ, Bhatt DL, et al. Polypill Strategy in Secondary Cardiovascular Prevention. N Engl J Med. 2022;387(11):967-977. DOI: 10.1056/NEJMoa2208275. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. DOI: 10.1056/NEJMoa1615664. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. DOI: 10.1056/NEJMoa1801174. Watanabe H, Domei T, Morimoto T, et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA. 2019;321(24):2414-2427. DOI: 10.1001/jama.2019.8145. Valgimigli M, Frigoli E, Heg D, et al. Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk. N Engl J Med. 2021;385(18):1643-1655. DOI: 10.1056/NEJMoa2108749. Mehran R, Baber U, Sharma SK, et al. Ticagrelor with or without Aspirin in High-Risk Patients after PCI. N Engl J Med. 2019;381(21):2032-2042. DOI: 10.1056/NEJMoa1908419. Tardif JC, Kouz S, Waters DD, et al. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019;381(26):2497-2505. DOI: 10.1056/NEJMoa1912388. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020;383(19):1838-1847. DOI: 10.1056/NEJMoa2021372. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023;389(24):2221-2232. DOI: 10.1056/NEJMoa2307563. Yndigegn T, Lindahl B, Mars K, et al. Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction. N Engl J Med. 2024;390(15):1372-1381. DOI: 10.1056/NEJMoa2401479.

---

Chapter 8: Pulmonary Embolism (PE)

Pulmonary embolism occurs when venous thrombi embolize to the pulmonary artery or its branches. In the majority of cases, the thrombus is formed in the deep veins of the legs or pelvis. Thrombi formed in the deep veins in the legs or pelvis can detach and flow via inferior vena cava to the right atrium and ventricle. The thrombus is pumped from the right ventricle through the pulmonary valve into the main pulmonary artery. Depending on the size and form of the thrombus, it will occlude the main pulmonary artery or its branches. The larger the thrombus, the more proximal the occlusion and, hence, the greater the hemodynamic effects.

The occlusion has two immediate effects:

Reduced perfusion in the pulmonary circulation, resulting in hypoxia.Reduced preload in the left ventricle and consequently reduced cardiac output.

A substantial reduction in pulmonary perfusion and the subsequent reduction in left ventricular preload lead to a cascade of hemodynamic alterations which may culminate in cardiac arrest.

Pulmonary embolism is causally related to deep vein thrombosis (DVT). Approximately 70% of individuals with symptomatic pulmonary embolism have an ongoing DVT, and 30% of individuals with DVT have asymptomatic pulmonary emboli (Di Nisio et al). Accordingly, risk factors for pulmonary embolism overlap with risk factors for DVT; immobilisation, surgery, hypercoagulability, and pregnancy are common risk factors (see Risk factors below).

A significant proportion of cases with pulmonary embolism require thrombolysis to dissolve the occlusion. Administration of thrombolysis requires careful consideration of absolute and relative contraindications (discussed below), and assessment of differential diagnoses; cardiac tamponade, aortic aneurysm and aortic dissection are common differential diagnoses which represent contraindications for thrombolysis.

Venous thromboembolism is a chronic and serious condition. Mortality in pulmonary embolism is up to 20%, and roughly 30% of patients with pulmonary embolism or deep vein thrombosis experience a second thrombotic event within 10 years (Goldhaber et al, Kearon et al).

Epidemiology of pulmonary embolism

Venous thromboembolism (VTE) is the third leading cardiovascular cause of death worldwide. Only stroke and acute myocardial infarction are more common. It is estimated that 10 million cases of venous thromboembolism occur globally every year (Raskob et al).The incidence of pulmonary embolism has increased in recent decades. Potential explanations for this trend include an ageing population, increased incidence and prevalence of cancer, heart failure, obesity, type 2 diabetes and physical inactivity. The increased use of computed tomography (CT), and improvements in CT techniques, have increased the detection of pulmonary embolism.Currently, the lifetime risk of developing venous thromboembolism is 8% for individuals 45 years of age (Raskob et al, Heit et al).

Cardiopulmonary effects of pulmonary embolism

Figure 1. Pathophysiology of pulmonary embolism (PE).

Hemodynamic effects

Pulmonary embolism leads to increased resistance in the main pulmonary artery, and thereby increased afterload on the right ventricle. This increases the load on the right ventricle, which therefore requires more oxygen. The increase in afterload also results in increased intramural pressure in the right ventricle, which is counteracted by dilatation of the ventricle. Dilatation of the right ventricle results in reduced intraventricular pressure and thereby reduced myoardial load.

Pulmonary embolism causes increased right ventricular load, which results in increased oxygen demand and dilatation of the right ventricle.

Despite the dilation, myocardial ischemia will develop if right ventricular oxygen demand exceeds oxygen delivery. Prolonged and pronounced ischemia leads to right ventricular infarction. Whether infarction develops or not, the dilatation, increased afterload and ischemia results in reduced right ventricular stroke volume. As right ventricular stroke volume diminishes, less blood is pumped into the left ventricle, leading to decreased left ventricular preload. Declining preload leads to a decrease in cardiac output and a subsequent drop in systolic blood pressure. Reduced cardiac output and reduced blood pressure yields a reduction in coronary perfusion pressure, including perfusion through the right coronary artery (RCA). This further aggravates ischemia in the right ventricle. Right ventricular stroke volumes decline more, leading to further reductions in left ventricular preload and the cycle repeats itself.

The gradual drop in cardiac output, systolic blood pressure and coronary perfusion will ultimately result in cardiac arrest, typically with pulseless electrical activity (PEA) on ECG.

Acute right ventricular load is also referred to as right ventricular strain.

Pulmonary effects

Obstruction of pulmonary arteries leads to hypoxia in lung parenchyma and pleura. Prolonged hypoxia results in parenchymal inflammation and ultimately infarction (i.e pulmonary infarction). This manifests with chest pain; typically pleuritic chest pain (sharp pain correlated to respiration). Lung infarction leads to parenchymal hemorrhage, which manifests with hemoptysis.

The occlusion also leads to ventilation-perfusion mismatch (i.e there are ventilated areas that are not perfused), resulting in reduced oxygenation of blood. This results in decreased arterial oxygen pressure (PaO2) and oxygen saturation (hypoxia). Reflex hyperventilation may lead to respiratory alkalosis with hypocapnia (reduced PaCO2).

Symptoms and signs of pulmonary embolism

The majority of cases with pulmonary embolism have acute onset of symptoms. Onset may be related to changes in body position or physical activity. It can be presumed that the activity or change in body position causes dislodgement of venous thrombi, which then travel to the heart.

Symptoms depend on hemodynamic effects of the occlusion, which is determined by the size and location of the embolus, cardiac function and comorbidites. Small pulmonary emboli may be asymptomatic, while large proximal occlusions may rapidly cause circulatory collapse and cardiac arrest.

The most common symptoms and signs in pulmonary embolism are as follows:

50% have dyspnea and tachypnea.50% have chest pain, typically pleuritic chest pain.Tachycardia is the most common ECG finding (se ECG in pulmonary embolism below).Distended jugular vein (due to elevated right ventricular pressure).Cough.Hemoptysis.Hypotension.Substantial drop in systolic blood pressure.Syncope, pre-syncope.Fever.Signs of deep vein thrombosis (DVT) or other venous thrombosis.

Hypotension, drop in systolic blood pressure, pre-syncope or syncope are strong predictors of massive pulmonary embolism.

Saddle pulmonary embolism

Saddle pulmonary embolism refers to a large embolus that straddles the bifurcation of the pulmonary trunk, with parts of the embolus extending into the left and right pulmonary arteries. The contour of the embolus on CT scans may resemble a horse saddle (Figure 1). Saddle emboli cause severe hemodynamic effects.

Figure 2. CTPA showing large pulmonary embolism at the bifurcation of the pulmonary artery (saddle embolism).

Causes of pulmonary embolism

The most common causes of pulmonary embolism are as follows:

Deep vein thrombosis (DVT) is the most common cause.Fat embolism occurs after surgery, including orthopedic interventions.Cement embolism refers to embolization of polymethyl methacrylate (PMMA) into the pulmonary arteries. PMMA is primarily used in percutaneous vertebroplasty.Air embolism.Amniotic fluid embolism.Tissue embolism.Tumor embolism.Bacterial embolism.

Risk factors for pulmonary embolism

Risk factors of pulmonary embolism are as follows (Di Nisio et al):

Hypercoagulability

Increasing ageCancerAntiphospholipid syndromeEstrogen therapyPregnancyPost-partum period (8 weeks)Heredity for venous thromboembolismObesityDehydrationInflammatory Bowel Disease (Crohn’s Disease, Ulcerative Colitis)

Interventions and trauma

SurgeryTraumaFracturesImplantation of devices (e.g central venous catheter, pacemaker, ICD, CRT).

Immobilization and hospitalization

HospitalizationLong travel (>3 hours sitting)Paralysis, paresis

Hereditary disorders

Factor V Leiden mutationProthrombin mutationAntithrombin mutationProtein C deficiencyProtein S deficiency

Genetic hypercoagulability should be suspected if the patient is young, lacks risk factors for thromboembolism, has heredity or experiences recurring emboli.

Note that 30-50% of all venous thromboembolism is unprovoked. The remained are provoked by one or multiple factors listed above.

Disgnosis of pulmonary embolism

Figure 3. Diagnostic algorithm for pulmonary embolism.

Pre-test probability for pulmonary embolism

Pre-test probability is a statistical term used to guide treatments and investigations. If the pre-test probability of pulmonary embolism is very high, then it is very likely that the patient has pulmonary embolism, making it unnecessary to analyse D-dimer. Similarly, if pulmonary embolism is not likely, then CT scan may not be justified unless D-dimer is positive (elevated). Pre-test probability is assessed in all patients with suspected pulmonary embolism.

Pre-test probability of pulmonary embolism is assessed with one of the following prediction models (scores):

Wells scoreModified Wells scoreRevised Geneva scorePERC (pulmonary embolism rule-out criteria)

Wells score and modified Wells score can be used in inpatient and outpatient settings. PERC is used to exclude pulmonary embolism.

If clinical suspicion of pulmonary embolism is high, the patient should undergo computed tomographic scan, regardless of scores and D-dimer.

Wells score for pulmonary embolism

Wells score for pulmonary embolism should not to be confused with Wells score for DVT. The below risk model (score) is only used in case of suspicion of pulmonary embolism.

Table 1. Wells criteria for pulmonary embolism

CRITERIA	POINTS
Symptoms or signs of DVT	3
Pulmonary embolism more likely than other diagnoses	3
Previous VTE (PE or DVT)	1.5
Tachycardia (HR >100/bpm)	1.5
Immobilization or surgery in the past 4 weeks	1.5
Hemoptysis	1
Cancer	1

Evaluation of Wells score

Wells score, original

0-1 points: Low probability (6% absolute risk).2 to 6 points: Intermediate probability (23% absolute risk)≥7 points: High probability (50% absolute risk)

Wells score, modified

≤ 4 points: Pulmonary embolism not likely (8% absolute risk)≥ 5 points: Pulmonary embolism likely (34% absolute risk).

Revised Geneva score for pulmonary embolism

Table 2. Revised Geneva score for pulmonary embolism

CRITERIA	POINTS
Age >65 years	1
Previous VTE (PE or DVT)	3
Recent surgery (any) or lower extremity fracture	2
Cancer	2
Unilateral leg pain	3
Hemoptysis	2
Heart rate 75–94 bpm	3
Heart rate ≥ 95/min	5
Pain on palpation of lower limb with unilateral edema	4

Evaluation of Geneva score

<4 points: low probability of pulmonary embolism (9% absolute risk)4 to 10 points: intermediate probability of pulmonary embolism (26% absolute risk)>10 points: high probability of pulmonary embolism (76% absolute risk)

Pulmonary Embolism Rule-Out Criteria (PERC)

If the probability of pulmonary embolism is low (according to Wells score or Geneva score), then PERC can be used to exclude pulmonary embolism.

Table 3. Pulmonary Embolism Rule-Out Criteria (PERC)

CRITERIA	POINTS
Age > 50 years	1
Heart rate > 100/min	1
Oxygen saturation (POX) < 95%	1
Hemoptysis	1
Estrogen therapy	1
Previous VTE (PE or DVT)	1
Recent (<4 weeks) surgery (any) or trauma	1
Unilateral lower limb edema	1

Evaluation of PERC score

0 points: low probability (< 1%). Pulmonary embolism very unlikely.≥1 point: pulmonary embolism is not excluded and further investigation is required.

D-dimer

D-dimer is a byproduct produced during degradation of fibrinogen. Hence, elevated D-dimer levels indicate recent fibrinolysis.

D-dimer is analyzed if the probability of pulmonary embolism is low to intermediate. D-dimer has very high sensitivity for venous thromboembolism, including pulmonary embolism; virtually all patients with pulmonary embolism exhibit with elevated D-dimer levels. However, specificity is low, which is due to the fact that D-dimer levels increase in all situations with thrombosis.

Negative D-dimer excludes pulmonary embolism (and DVT) if clinical suspicion is low to intermediate. If clinical suspicion of pulmonary embolism is high, then D-dimer must not be used to exclude pulmonary embolism.

Other biomarkers

Electrolytes, renal function (estimated GFR) and liver function must be assessed in all patients.Troponin (troponin T, troponin I) is analyzed to determine whether myocardial infarction has occurred. Increased troponin levels indicate right ventricular infarction, which is prognostically unfavourable.Blood (arterial) gas is not necessary to analyze. Results typically show resporatory alkalosis, reduced oxygen pressure (PaO2) and elevated pH.

ECG in pulmonary embolism

The ECG can be used to find additional signs of pulmonary embolism. Sensitivity and specificity are low for all ECG criteria proposed for detection of pulmonary embolism.

Pulmonary embolism with ST-segment elevations in right sided chest leads.

The following ECG changes may be seen in pulmonary embolism:

S1Q3T3 pattern refers to the presence of a deep S-wave in lead I and a deep Q-wave in lead III, and T-wave inversion in lead III.T-wave inversions (negative T-waves) in V1-V4.New onset complete or incomplete right bundle branch block (RBBB).New onset atrial fibrillation, atrial flutter or atrial tachycardia.ST elevation or ST depression in V1-V3.P pulmonaleRight axis deviation (RAD).

Sinus tachycardia is the most common ECG finding in pulmonary embolism.

Computed tomography of the pulmonary arteries (CTPA)

Computed tomography of the pulmonary arteries (CTPA) is the preferred imaging method in suspicion of pulmonary embolism. The study, which is contrast-enhanced, is fast, has high sensitivity and high specificity.

Acute pulmonary embolism is diagnosed when CTPA shows complete or partial filling defects in the pulmonary arteries. Partial filling defects can be centrally or peripherally located within the artery and will be surrounded by contrast (Leitman et al).

Indirect signs of pulmonary embolism include pleural fluid or wedge-shaped pulmonary infarction.

Computed tomography should be avoided in the following situations:

Pregnancy.Contrast allergy.Renal failure.

Lung scintigraphy

Lung scintigraphy is performed if CTPA is inappropriate due to pregnancy, contrast allergy or renal failure. Scintigraphy is time-consuming and requires low doses of radioactive markers. Pulmonary perfusion is compared with pulmonary ventilation and any regional discordance, referred to as mismatch, in ventilation and perfusion is suggestive of pulmonary embolism.

Echocardiography

Echocardiography is recommended to visualize indirect signs of pulmonary embolism and right ventricular strain. The following echocardiographic findings suggest acute pulmonary embolism:

Increased tricuspid regurgitation (TI).Increased PASP (systolic PA pressure).Dilated vena cava inferior, with loss of respiratory variation.Right ventricular dilatation.Paradoxical septal movement.

Other imaging methods

Pulmonary angiography is performed in selected cases, especially if endovascular therapy is feasible.

Magnetic resonance imaging has high sensitivity and specificity and can be performed if the diagnosis is unclear or if other modalities are not feasible.

Treatment of pulmonary embolism

Figure 4. Treatment algorithm for pulmonary embolism.

In the acute setting, treatment is guided by the patient’s hemodynamic condition. Severe pulmonary embolism (massive pulmonary embolism) is managed with immediate anticoagulation and reperfusion (thrombolysis). Pulmonary embolism without hemodynamic effects is treated with anticoagulants.

Severe (massive pulmonary embolism) is defined as pulmonary embolism that meets any of the following criteria:

Systolic blood pressure <90 mm Hg>40 mm Hg drop in systolic blood pressure.

There are, however, additional warning signs:

Syncope, pre-syncope, dizzyness.Tachycardia.Right ventricular dilation, elevated PASP.Paradoxical septal movement.Elevated BNP or NT-proBNP or troponin.

Risk stratification of pulmonary embolism: PESI (Pulmonary Embolism Severity Index)

PESI estimates 30-days mortality among patients with confirmed pulmonary embolism. PESI is used to guide initial management.

Table 4. PESI (Pulmonary Embolism Severity Index)

CRITERIA	POINTS
Age	1 per year
Cancer	30
Systolic blood pressure < 100 mm Hg	30
Heart rate ≥ 110/min	20
Oxygen saturation (POX) < 90%	20
Heart failure	10
Pulmonary disease	10
Altered mental status	60
Body temperature <96.8°F or < 37°C	20
Respiratory rate ≥ 30/min	20
Male sex	10

Evaluation of PESI score

PESI CLASS	PESI POINTS	RISK	30-DAYS MORTALITY	IN-HOSPITAL MORTALITY
Class I	<66	Very low risk	0–1.6%	≤1.1%
Class II	66-85	Low risk	1.7–3.5%	≤1.9%
Class III	86–105	Intermediary risk	3.2–7.1%	≤4.7%
Class IV	106–125	High risk	4.0–11.4%	≤7.0%
Class V	> 125	Very high risk	10.0–23.9%	≤17.2%

Treatment of high risk (massive) pulmonary embolism

High risk pulmonary embolism (30-days mortality >15%) is synonymous with massive pulmonary embolism. These patients have systolic blood pressure <90 mm Hg, alternatively >40 mm Hg drop in systolic blood pressure. The vast majority of these patients need thrombolysis. Rapid echocardiography (TTE) and CT scan are important.

Immediate actions

Start infusion with low molecular weight heparin (e.g enoxaparin).Administer oxygen if oxygen saturation <95%.Consider administering fluid bolus (500 ml).Provide inotropic support (e.g norepinephrine) if hypotensive.Determine whether there are contraindications to thrombolysis. If no contraindications are present, alteplas is given:Alteplas i.v 10 mg in 2 min and 90 mg infusion in 120 minutes.Max dose is 1.5 mg/kg for patients weighing <65 kg.Heparin infusion is paused during thrombolysis and reinstated at earliest 60 minutes after completion of alteplas infusion.

Catheter based local thrombolysis or thrombectomy may be preferred in specific situations, or if thrombolysis fails to yield reperfusion. Surgical thrombectomy may also be considered, depending on local routines.

Contraindications to thrombolysis

Absolute contraindications

Structural intracranial diseasePrevious cerebral hemorrhagePrevious ischemic stroke <3 monthsOngoing bleedingRecent spinal or cardiac surgeryHead trauma or brain injuryHypocoagulability

Relative contraindications to thrombolysis

Systolic blood pressure >180 mm Hg or diastolic >110 mm HgRecent bleeding (not intracranial)Recent surgery (other than cardiac, spinal)Recent invasive procedureIschemic stroke >3 months agoUse of anticoagulantsPericardial effusionDiabetic retinopathyPregnancyAge >75 YearsBody Weight <60 kg

Treatment of low to intermediate risk pulmonary embolism

Low to intermediate risk pulmonary embolism is managed with novel oral anticoagulants (NOAC). NOACs result in 30% lower risk of serious bleeding events, as compared with warfarin. The following principles apply to management of patients with pulmonary embolism:

Initial treatment

If dabigatran or edoxaban are selected for long-term treatment, 5 days initial treatment with low molecular weight heparin (LMWH) is required.If rivaroxaban or apixaban are selected for long-term treatment, pre-treatment with LMWH is not needed.Suitable LMWH includes enoxaparin for patients with normal renal function. Patients with renal failure are treated with unfractionated heparin (UFH). UFH is also preferred in patients who may later require thrombolysis.LMWH is preferred as the initial and long-term treatment in pregnant women and individuals with cancer.

Long-term treatment

LMWH is preferred in pregnant women and individuals with cancer.For warfarin, therapeutic PK-INR is 2 to 3.NOAC doses:Dabigatran: 150 mg x 2Edoxaban: 60 mg x 1Rivaroxaban: 15 mg x 2 for 21 days, then 20 mg x 2Apixaban: 10 mg x 2 for 7 days, then 5 mg x 2.

Evaluation of bleeding risk

No specific risk model has been developed for pulmonary embolism. HAS-BLED is frequently used, despite the fact that it was validated to assess bleeding risk in patients with atrial fibrillation. Risk factors for bleeding include the following:

High ageFrailtyPrevious bleeding eventsCancerRenal failureLiver failureThrombocytopeniaStrokeDiabetesAnemiaTreatment with platelet inhibitors or anticoagulants.Recent surgery

Long-term complications of pulmonary embolism

Pulmonary hypertension develops in <5%.Cardiac arrest.Right ventricular failure (see Heart failure).Pulmonary infarction (10% of cases).Pleural effusionPost-thrombotic syndrome (30%).

References

Di Nisio et al. Deep vein thrombosis and pulmonary embolism. Lancet 2016;388:3060-73

Raskob GE, Angchaisuksiri P, Blanco AN, et al. Thrombosis:a major contributor to global disease burden. Arterioscler Thromb Vasc Biol 2014; 34: 2363–71

Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol 2015; 12: 464–74.

Kearon C et al. Natural history of venous thromboembolism. Circulation 2003; 107: I22–30.

Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386–89.

Konstantinides et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society. European Heart Journal (2020) 41, 543603.

Leitman et al. Pulmonary arteries: imaging of pulmonary embolism and beyond. Cardiovasc Diagn Ther. 2019 Aug; 9(Suppl 1): S37–S58

---

Chapter 9: Management of bradycardia (bradyarrhythmia)

Acute bradycardia with hemodynamic instability

Acute bradycardia with hemodynamic effects is a potentially life-threatening condition and should be managed urgently. The risk of cardiogenic shock and cardiac arrest is high and pharmacological interventions are frequently futile. It is often necessary to establish a transcutaneous pacemaker, which is the only treatment with class I recommendation according to European (ESC) and North American (AHA, ACC) guidelines. As in all clinical emergencies, the airway, breathing, circulation, disability, exposure (ABCDE) approach is applicable in bradycardia (Figure 1). Cardiac output and blood pressure, rather than ECG, are the strongest predictors of adverse outcomes.

Non-acute or asymptomatic bradycardia

Non-acute bradycardia is a common finding in both healthy and diseased individuals. Asymptomatic bradycardia may lack prognostic significance or be physiological, particularly in athletes and young individuals. The severity of symptoms and presence of high-risk arrhythmias on ECG guides the management of non-acute or asymptomatic bradyarrhythmia.

In patients presenting with intermittent symptoms of bradycardia, it is fundamental to establish a temporal correlation between the symptoms and ECG recordings confirming a bradyarrhythmia. Potentially reversible causes should be pursued (Table 2).

Figure 1. Management of acute bradycardia in the emergency setting.

	Parameter	Assessment
A	Airway	VoiceBreath sounds
B	Breathing	Respiratory rate (12–20 / min)Chest wall movementsChest percussionLung auscultationPulse oximetry (>95%)
C	Circulation	Skin colorSweatingCapillary refill time (<2 s)Palpate pulseHeart auscultationBlood pressureECG monitoring
D	Disability	AVPU:– Alert– Voice responsive– Pain responsive– UnresponsiveLimb movementsPupillary light reflexesBlood glucose
E	Exposure	Identify signs of heart failure, hypoperfusion (assess skin temperature, color, sweat).

Symptoms of bradycardia

Bradycardia may be an incidental and asymptomatic finding. The absence of symptoms indicates that the bradycardia is compensated by an increase in stroke volume.

Symptomatic bradycardia may present with chronic or acute symptoms, ranging from chronic fatigue and exercise intolerance to sudden cardiac arrest. The most common acute symptoms are dizziness (pre-syncope), hypotension (chock), syncope, chest pain, heart failure and cardiac arrest.

In cases with intermittent symptoms, it is important to establish a temporal correlation between symptoms and episodes of bradyarrhythmia on ECG recordings.

Normal heart rate and normal variants

Normal resting heart rate is 50 to 95 beats per minute in the afternoon. Nocturnal heart rate is on average 20 beats per minute lower (than the average heart rate in the afternoon) in young individuals, and 14 beats per minute lower in the elderly (Brodsky et al, Kantelip et al). Thus, bradyarrhythmia is very common during sleep (Dickinson et al). Pronounced sinus bradycardia is frequently associated with hypoxic episodes caused by obstructive sleep apnea. The following bradyarrhythmias are considered normal findings during sleep:

Sinus bradycardia down to 30 beats per minute.

Sinus pause <3 seconds.

Sinoatrial block

Junctional rhythm

First-degree AV block

Second-degree AV block Mobitz type 1 (Wenckebach block)

Pauses up to 4 seconds in patients with atrial fibrillation.

Bradycardia in atrial fibrillation (bradycardia–tachycardia syndrome)

Individuals with sick sinus syndrome (sinus node dysfunction) are at high risk of developing atrial fibrillation, and vice versa. The pathophysiological explanation for this may be a general degeneration of the atrial conduction system. Individuals with atrial fibrillation and bradycardia have bradycardia–tachycardia syndrome. Careful management is warranted in patients with bradycardia–tachycardia syndrome since episodes of tachyarrhythmia (atrial fibrillation, atrial flutter) cause overdrive suppression of sinus node automaticity, which may result in prolonged sinus pauses or arrests after termination (spontaneous or by intervention) of the atrial tachyarrhythmia. Dizziness, pre-syncope or syncope in patients with atrial fibrillation is suggestive of bradycardia–tachycardia syndrome.

Approximately 65% of individuals with atrial fibrillation have pauses longer than 3 seconds during daytime. Pauses up to 2.8 seconds during daytime and up to 4 seconds during nighttime are considered normal in atrial fibrillation (Pitcher et al).

Cardiac output and blood pressure during bradycardia

Several factors modify the effect of bradycardia on cardiac output (CO) and mean arterial pressure (MAP). Cardiac output is the product of heart rate (HR) and stroke volume (SV), according to the following formula:

CO = HR • SV

Cardiac output and peripheral resistance (SVR, systemic vascular resistance) affect MAP, according to the following formula:

MAP = CO • SVR

If ventricular function is normal, a higher heart rate will result in increased cardiac output, despite the fact that stroke volumes become smaller as heart rate increases (due to reduced diastolic filling time). At very high heart rates (>160 beats/minute), however, the stroke volume will diminish due to the reduced filling time (Table 2).

Situation	Heart rate	Stroke volume	Cardiac output	Comment
Mild tachycardia	100-160 bpm	↓	↑	CO increases because increased HR dominates over decreased SV.
Pronounced tachycardia	>160 bpm	↓↓↓	↓	CO decreases because decreasing SV dominates over increased HR.
Mild bradycardia	40–50 bpm	↑	↓	CO decreases because increased SV does not compensate for decreased HR.
Pronounced bradycardia	<40 bpm	↑	↓↓↓	CO decreases substantially because increased SV does not compensate for decreased HR.

A halving of the heart rate (i.e bradycardia) has a significantly greater effect on cardiac, as compared with a doubling of the heart rate (tachycardia). This is explained by the fact that the heart has a very limited capacity to increase stroke volume (i.e the capacity to increase stroke volume is insufficient to compensate for severe bradycardia).

The cardiac conduction system

The cardiac conduction system is discussed in the chapter Cardiac Electrophysiology. Aspects relevant to bradycardia are discussed here. The arterial blood supply to the conduction system is presented in Figure 2. The electrical impulse that initiates the cardiac cycle originates in the sinoatrial node (sinus node), which is located in the sulcus terminalis. These cells possess automaticity, which is the ability to depolarize spontaneously. The sinus node depolarization spreads throug the atria to the atrioventricular (AV) node, which transmits the impulse to the ventricular myocardium via His bundle, the right bundle branch and left bundle branch. His bundle travels from the AV node to the muscular septum via the membraneous septum. His bundle divides into a smaller anterior fascicle and larger posterior fascicle. The sinoatrial node is supplied with blood by the sinus node artery, which originates from the RCA (right coronary artery) in 80% and LCx (left circumflex artery) in 20%. The AV node is supplied with blood by the atrioventricular nodal artery, which originates from the proxial PDA (posterior descending artery). The PDA is a branch of the RCA in 85% of cases and LCx in 15% of cases.

The intrinsic rate of depolarization in the sinoatrial node is 85 to 105 beats pre minute (Jose et al). Resting heart rate in healthy individuals is lower due to parasympathetic dominance during rest. The conduction system is innervated by sympathetic and parasympathetic fibers (Vagus nerve). These fibers modulate the rate of depolarization and impulse transmission through all components of the conduction system. Sympathetic activity increases the rate of depolarization and impulse transmission. Parasympathetic activity slows rate of depolarization and impulse transmission. Strong parasympathetic stimulation can temporarily depress automaticity in the sinoatrial node and cause brief arrest, or block transmission through the AV node and cause transient AV block.

Figure 2. Arterial blood supply to the conduction system.

Blood pressure in bradycardia

Blood pressure is a strong predictor of cardiogenic shock and cardiac arrest. Bradycardia with hypotension is a critical condition that requires immediate treatment to prevent circulatory collapse.

During bradycardia, however, the blood pressure may be normal or high as a result of sympathetic activation. This is explained by the fact that bradycardia leads to the release of catecholamines (adrenaline [epinephrine] and noradrenaline [norepinephrine]) which induce vasoconstriction. Hence, blood pressure may be normal during bradycardia despite severely reduced cardiac output.

Hypertension is a sign of critical bradycardia with pronounced sympathetic activation. In such cases, the blood pressure must not be lowered, since it may cause cardiogenic shock. Blood pressure normalizes when the heart rate and cardiac output are normalized.

• Cardiac output is always low during pronounced bradycardia.• Normal blood pressure does not rule out critical bradycardia.• High blood pressure should not be lowered during bradycardia.

Torsade de pointes during bradycardia

Bradycardia can prolong the QT interval and subsequently increase the risk of torsade de pointes (TdP). Bradycardia is a significant risk factor for torsade de pointes (Choo et al). Risk factors for torsade de pointes in bradycardia are as follows (Topilski et al):

Ventricular extrasystoles (premature ventricular beats) with short coupling intervals.

QT interval >550 ms.

Biphasic T waves.

Types of bradyarrhythmias

The following 4 arrhythmias can cause bradycardia:

Sinus node dysfunction (SND)

Sinus bradycardia

Sinus arrest, sinus pause

SA (sinoatrial) block

SND accounts for 50% of pacemaker implantations.

AV blocks

First-degree AV block

First-degree AV block does not cause bradycardia but may occur intermittently in second-degree AV block, third-degree AV block and sinus node dysfunction.

Pronounced first-degree AV-block (PR interval >350 ms) may disrupt AV synchrony, which may affect cardiac output.

Mobitz type 1 second-degree AV block

Mobitz type 1 may be physiological in young individuals and athletes, in which case it is asymptomatic and caused by increased vagal tone.

Among cases with pathological Mobitz type 1 blocks, 75% are located in the AV node (typically with normal QRS duration, i.e <120 ms). The remaining 25% are infranodal blocks (i.e located in His bundle, the bundle branches, or fascicles).

The escape rhythm in Mobitz type 1 is usually stable and hypotension is uncommon.

Mobitz type 2 second-degree AV block

Mobitz type 2 is always pathological.

Location: <5% in AV node, 20% in His bundle; 75% in the bundle branches.

The arrhythmia is mostly symptomatic, with a high risk of progression to complete AV block.

The escape rhythm is mostly ventricular and therefore hemodynamically insufficient and unreliable.

AV block 3 (complete AV block, AV dissociation)

Third-degree AV-blocks are mostly infranodal.

The escape rhythm can originate in the AV system (His-Purkinje fibers) or the ventricular myocardium.

Escape rhythm generated proximally to the bifurcation of His bundle produces narrow QRS complexes (<120 ms), heart rate >40/min, moderate symptoms, and typically a reliable escape rhythm.

Escape rhythm generated distally to the bifurcation produces wide QRS complexes, slow rhythm and unreliable escape rhythm. The symptoms are more pronounced (pre-syncope, syncope, heart failure, hypotension).

Frequent ventricular extrasystoles that fail to generate stroke volumes. The effective (i.e pulse generating) ventricular rate may be very low during frequent ventricular extrasystoles.

Frequent supraventricular extrasystoles that fail to generate stroke volumes. As with ventricular extrasystoles, the effective (i.e pulse generating) ventricular rate may be very low during frequent supraventricular extrasystoles.

Ventricular and supraventricular extrasystoles are uncommon causes of bradycardia. In these cases, bradycardia can only be detected by palpating the pulse.

Causes of AV block

50% of all AV blocks are caused by degeneration/fibrosis of the cardiac conduction system.

40% are caused by ischemic heart disease and myocardial infarction.

10% are caused by other etiologies (Table 3).

Causes of sinus node dysfunction

The majority are caused by degeneration/fibrosis in the sinus node and atrial conduction fibers. This degeneration can also involve the ventricular conduction system.

A minority is caused by etiologies listed in Table 3.

Category	Specific cause	Sinoatrial blocks	AV blocks
Antiarrhythmics	Amiodarone, Disopyramide, Propafenone, Procainamide	Yes
Beta-blockers	All beta-blockers (metoprolol, propranolol, bisoprolol, labetalol, etc)	Yes
Calcium channel blocker (CCB)	Verapamil, diltiazem	Yes
Cardiac glycosides	Digoxin	Yes
Cholinergic agents	Cholinesterase inhibitors, cholinesters, pilocarpine, choline foscerate, cevimeline	Yes
Other drugs	Donepezil (uncommon)Lidocaine (common, between 1-10% risk of bradycardia)LithiumPropofolTicagrelor (frequency of bradycardia unknown)Amphotericin BBortezomibClonazepamCisplatinCyclophosphamideOmeprazolePregabalinTrazodone
Antiepileptic drugs	Carbamazepine, lacosamide, phenytoin
Alpha-blockers	Prazosin
Alpha-2 agonist	Clonidine, tizanidine, dexmedetomidine (Dexdor)
Electrolyte disorders	Hyperkalemia1HypermagnesemiaHypophosphatemia	Yes
Metabolism	HypothyroidismHyperthyroidismHyperparathyroidismHypoglycemiaHypoxiaHypocapniaAcidosisHypothermia
Ischemia / infarction	Inferior myocardial ischemia/infarction (infarct-related bradycardia is usually transient, not requiring pacemaker)Anterior myocardial ischemia/infarction (infarct-related bradycardia is usually permanent, requiring pacemaker
Infections	MyocarditisViral infectionBorrelia (Lyme disease)Endocarditis (aortic valve)
Inflammation and storage disorders	HemochromatosisAmyloidosisSystemic sclerosisSystemic lupus erythematosus (SLE)Rheumatoid arthritisPolymyositisSarcoidosisGranulomatosis
Genetic diseases	Congenital AV block or sinus node dysfunctionMb Duchenne
Iatrogenic	Cardiac surgery, percutaneous interventions (PCI, TAVI, ablations, etc)
Other	Increased vagal toneIncreased intracranial pressure (ICP)	Yes

Nodal vs. infranodal obstruction

Nodal blocks are defined as blocks located in the AV node. Infranodal blocks are located in the bundle of His, the bundle branches, the fascicles or at multiple levels below the AV node. The prognosis is substantially worse in infranodal blocks, which typically require a permanent pacemaker, unless a reversible cause is identified. Third-degree AV-blocks are typically infranodal. The escape rhythm will typically indicate the location of the block. Escape rhythm with a narrow QRS complex and ventricular rate between 40 to 60 beats per minute suggests a nodal block. Wide QRS and ventricular rate slower than 40 beats per minute suggests an infranodal block.

Features	Nodal block	Infranodal block
QRS duration	Typically narrow (<120 ms)	Typically wide (>120 ms)
PR interval	Typically prolonged	Typically not affected
Escape rhythm	40–60 bpm	<40 bpm
Wenchebach periods	Often seen	Rarely seen
Effect of atropine	Increased AV conduction	Mostly no effect
Effect of catecholamines (isoprenaline)	Increased AV conduction	May accelerate escape rhythm
Effect of exercise	None or enhanced AV conduction	None or worsened AV conduction
Prognosis (escape rhythm)	Better (stable escape rhythm)	Worse (unstable escape rhythm)

Suggestions for blood tests

Na+, K+, creatinine, eGFR

Mg2+, Ca2+

Hb, LPK

CRP

Glucose

Troponin

Lactate

TSH, T3, T4

Drug concentration if needed (e.g. digoxin)

Treatment of bradycardia in the emergency setting

In the event of manifest or impending circulatory collapse, transcutaneous pacing must be started immediately. The risk of circulatory collapse is highest with AV block 2 Mobitz type 2 and AV block 3. The only treatment with a class I recommendation for the management of acute bradycardia is transcutaneous pacing. Pharmacological interventions (Table 4) should be considered temporary, often insufficient, treatments that can be attempted until a pacemaker is established.

Drug	Effect	Dose, kinetics	Comment
Atropine	Acetylcholine receptor antagonist	1 mg IV every 3-5 minutes, maximum 3 mg IV.T½ 3 h.50% renal elimination.	• Typically the first choice of drug.• Effective in sinus bradycardia or AV node block.• Dose <0.5 mg may worsen bradycardia and should not be given.• Relative contraindications are ileus, glaucoma.
Isoprenaline /Isoproterenol	α-1, α-2, β-1, β-2 agonist	Start infusion at 4 μg/min and titrate to desired resultT½ 1 min	• May cause ventricular arrhythmias (dose-dependent).• Prolonged use often causes headaches, tremors.• Effective if bradycardia is caused by beta blockers.
Adrenaline (Epinephrine)	α and β agonist	Infusion of 2–10 μg/min (titrate as needed).T½ 5 min.	• Effective if hypotension is present.• Can be given as a bolus.• Effective if bradycardia is caused by beta blockers.
Dopamine	Dopamine receptor agonist, α- and β-agonist	Infusion of 5−20 μg/kg/minT½ 2 min	• Avoid boluses.• Effective if bradycardia is caused by beta blockers.
Dobutamine	β-1 agonist	Infusion of 3−10 μg/kg/min.T½ 2 min	Effective if inotropic effect is required.
Theophylline / theophyllamine / aminophylline	Adenosine receptor antagonist, phosphodiesterase inhibitor. Exact mechanism is unknown.	100−200 mg slow iv injection.	Rarely used.
Glucagon	Counteracts beta blockers. An antidote to beta blockers.	2–10 mg bolus followed by 2–5 mg/h infusion	Antidote to beta blockers.
Calcium	Counteracts calcium channel blockers (CCB). Antidote to CCBs.	10 ml calcium 0.2 mmol/ml iv.	Antidote to CCBs.
Digoxin antibodies	Binds to digoxin.	Digitalis antidote (anti-digoxin, Fab fragment).	Given in case of suspected digoxin intoxication.

Atropine

Evidence: Class IIa recommendation

Atropine is the first choice for the pharmacological treatment of acute bradycardia.

Dosage: 1 mg iv, every 3-5 minutes, to a maximum of 3 mg.

Doses lower than 0.5 mg IV may worsen bradycardia and should never be given.

The effect of atropine is temporary.

If atropine is ineffective, isoprenaline, adrenaline (epinephrine) or dopamine can be tried.

Atropine counteracts acetylcholine-mediated bradycardia by inhibiting the effect of acetylcholine on the sinus node and AV node. Atropine is effective in sinus bradycardia and AV block located in the AV node.

Atropine is typically ineffective in complete AV block and Mobitz type 2 second-degree AV block.

Atropine is not used in patients with heart transplantation.

Isoprenaline (isoproterenol)

Evidence: Class IIa recommendation

Isoprenaline is a second-line pharmacological treatment for acute bradycardia.

Dosage: Start infusion at 4 μg/min and titrate to the desired result.

Half-life: 5 minutes.

Isoprenaline enhances AV conduction in nodal blocks. In infranodal blocks, isoprenaline is effective only if it induces an escape rhythm, or enhances the automaticity of an existing escape rhythm..

Adrenaline (epinephrine)

Evidence: Class IIb recommendation

Effective in hypotension and when an inotropic effect is required.

Dosage: Infusion of 2–10 μg/min (titrate as needed).

Can be added to dopamine.

Dopamine

Evidence: Class IIb recommendation

Effective in hypotension and when an inotropic effect is required.

Dosage: Infusion 5−20 μg/kg/min.

Can be added to adrenaline.

Temporary pacemaker

Transcutaneous pacemaker

Evidence: Class I recommendation

Most defibrillators have a pacemaker function, allowing the device to operate as an external pacemaker. (Video 1, Figure 2, Figure 3).

A pacemaker is the safest treatment for acute bradycardia.

A transcutaneous pacemaker should be established immediately if there is a risk of hemodynamic collapse.

AV block 2 Mobitz type 2 and AV block 3 are strong indications for a transcutaneous pacemaker.

Figure 2. Example showing Zoll R Series defibrillator. Note that the Mode Selector is set to Pacer to activate the pacemaker settings.

Video 1. Example of transcutaneous pacemaker with Zoll R Series . The function looks similar for other manufacturers.

Pain and discomfort during transcutaneous pacing

Although transcutaneous pacing can be unpleasant or somewhat painful, all patients tolerate the procedure. Pain is caused by muscle contractions. Administration of sedatives (midazolam) or analgesics (morphine) is recommended, using the following doses:

Midazolam : 1–3 mg initial dose. Total dose 4-8 mg. Lower dose range in cases aged >60 years.

Morphine : 2.5 mg IV.

Figure 4. Placement of electrode pads in the anteroposterior direction for transcutaneous pacing.

How to perform transcutaneous pacing

Explain to the patient the purpose of the procedure.

Administer sedatives / analgesics.

Position electrode pads in anteroposterior direction (Figure 4).

If there is time, trim chest/back hair (do not shave). Dry the skin if wet.

Do not relocate already attached pads (the adhesive becomes poor).

Activate the pacemaker function (Video 1, Figure 2, Figure 3).

Set the pacing rate to 50 beats/min.

Gradually increase the current (start with 20 mA) .

Identify the pacemaker spikes (stimulation artifacts) on the ECG recording.

Determine if pacemaker spikes are followed by QRS complexes (indicating electrical capture).

If electrical capture is visible, palpate the femoral artery to examine whether there is mechanical capture (i.e ventricular contractions).

Monitor blood pressure and pulse oximetry.

When the threshold for capture (lowest current producing mechanical capture) is identified, the output (current) is increased by 10% (in order to provide stimulations with a safety margin).

Most patients require a current in the range of 20 to 140 mA

Avoid unnecessary pacing by using a low base frequency (e.g. 30–40 beats/min).

How to perform transcutaneous pacing during asystole

Follow the same procedure as above but start with maximum current strength (output) and gradually reduce the current until stimulation fails to produce capture. Then increase the current until capture is obtained, and another 10% output as a safety margin.

Checking transcutaneous pacing

Mechanical capture is confirmed by palpating a peripheral pulse (femoral artery) or assessing pulse oximetry. Avoid evaluating the pulse in the carotid artery (pectoral muscle contractions may be mistaken as arterial pulsations).

Muscle contractions are not equivalent to mechanical capture.

If the pacemaker stimulates more than necessary, there is undersensing, which means that the pacemaker does not detect the ventricular complexes (and therefore continues to pace). This is resolved by relocating the ECG leads so that they detect larger QRS amplitudes or increasing the gain on the defibrillator.

If the pacemaker does not stimulate due to artifacts there is oversensing, which can be resolved by eliminating the artifacts or relocating the leads.

Transvenous pacing

A transvenous pacemaker should be established if transcutaneous pacing is ineffective.

Transvenous pacemaker requires higher competence to establish and also entails a risk of infection, perforation and tamponade.

Access can be obtained via the jugular vein or the femoral vein. The introduction of a pacemaker lead via the jugular vein carries a risk of local thrombosis or infection, which complicates later pacemaker implantation. Pacing via the femoral vein requires immobilization of the patient since movements can cause dislocation of the lead.

A transvenous pacemaker can use a screw electrode, which can remain for up to 6 weeks and carries a significantly lower risk of lead dislocation.

References

2005 AMERICAN HEART ASSOCIATION GUIDELINES FOR CARDIOPULMONARY RESUSCITATION AND EMERGENCY CARDIOVASCULAR CARE Part 7.3: Management of Symptomatic Bradycardia and Tachycardia

Electrocardiographic predictors of bradycardia-induced torsades de pointes in patients with acquired atrioventricular block Min Soo Cho 1, Gi-Byoung Nam 2, Yong-Guin Kim 1, Ki-Won Hwang 1, Yoo Ri Kim 1, HyungOh Choi 1, Sung-Hwan Kim 1, Kyoung-Suk Rhee 3, Nam-Joon Kim 4, June Soo Kim 4, Jun Kim 1, Kee-Joon Choi 1, You-Ho Kim 1 Affiliations expand PMID: 25460857 DOI: 10.1016/j.hrthm.2014.11.018

Topilski I, Rogowski O, Rosso R, Justo D, Copperman Y, Glikson M, Belhassen B, Hochenberg M, Viskin S. The morphology of the QT interval predicts torsade de pointes during acquired bradyarrhythmias.J Am Coll Cardiol. 2007; 49:320–328. doi: 10.1016/j.jacc.2006.08.058

J Crit Illn. Author manuscript; available in PMC 2019 Feb 15. Published in final edited form as: J Crit Illn. 2003 May; 18(5): 219–225. PMCID: PMC6376978 NIHMSID: NIHMS1010680 PMID: 30774278 Using transcutaneous cardiac pacing to best advantage How to ensure successful capture and avoid complications Dr RAMI DOUKKY.

Safety and Efficacy of Noninvasive Cardiac Pacing — A Preliminary Report List of authors. Rodney H. Falk, M.R.C.P., Paul M. Zoll, M.D., and Ross H. Zoll, Ph.D. N Engl J Med 1983; 309:1166-1168 DOI: 10.1056/NEJM198311103091907

Kantelip JP, Sage E, Duchene-Marullaz P. Findings on ambulatory monitoring in subjects older than 80 years. Am J Cardiol 1986;57:398401

Brodsky M, Wu D, Denes P, Kanakis C, Rosen KM. Arrhythmias documented by 24 hour continuous electrocardiographic monitoring in 50 male medical students without apparent heart disease. Am J Cardiol 1977; 39:390-5.

Dickinson DF, Scott O. Ambulatory electrocardiographic monitoring in 100 healthy teenage boys. Br Heart J 1984;51:179-83

Pitcher D, Papouchado M, James MA, Rees JR. Twenty four hour ambulatory electrocardiography in patients with chronic atrial fibrillation. BMJ 1986;292:594.

Steinbach M, Douchet MP, Bakouboula B, Bronner F, Chauvin M. Outcome of patients aged over 75 years who received a pacemaker to treat sinus node dysfunction. Arch Cardiovasc Dis 2011;104:89 –96.

Li H, Lakkireddy D, Korlakunta H, Rovang K, Hee T. Pacemaker utilization during permanent atrial fibrillation in patients who received pacemaker implantation for sinus node dysfunction. Am J Cardiol 2005;96:942–945.

Sweeney MO, Bank AJ, Nsah E, Koullick M, Zeng QC, Hettrick D, Sheldon T, Lamas GA; Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction (SAVE PACe) Trial. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007;357:1000 –1008.

Andersen HR, Nielsen JC, Thomsen PE, et al. Long-term follow-up of patients from a randomized trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet 1997;350:1210-1216

Ferrer MI. The sick sinus syndrome in atrial disease. JAMA 1968;206:645– 652.

Van Gelder IC, Groenveld HF, Crijns HJ, Tuininga YS, Tijssen JG, Alings AM, Hillege HL, Bergsma-Kadijk JA, Cornel JH, Kamp O, Tukkie R, Bosker HA, Van Veldhuisen DJ, Van den Berg MP; RACE II Investigators. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363–1373.

Jose AD, Collison D. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res 1970;4:160-7.

---

Chapter 10: Anticoagulation Strategies in Atrial Fibrillation

Atrial Fibrillation and Atrial Thromboembolism

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a profound driver of global cardiovascular morbidity and mortality, primarily due to its association with ischemic stroke and systemic embolism. The contemporary understanding of AF has evolved significantly; it is no longer viewed merely as an electrical anomaly but as a progressive, complex atrial myopathy. For the practicing cardiologist, mastering the nuances of anticoagulation requires an intimate understanding of the underlying pathophysiology, which is classically framed by Virchow’s triad: blood stasis, endothelial dysfunction, and hypercoagulability [1][2].

Mechanical stasis in AF is most pronounced in the left atrial appendage (LAA). The LAA is a highly trabeculated, windsock-like embryonic remnant that exhibits uniquely low flow velocities during the loss of organized atrial systole. Transesophageal echocardiography and surgical pathology demonstrate that over 90% of thrombi in non-valvular AF originate within this specific anatomical cul-de-sac [19]. Concurrently, the atrial myocardium undergoes structural remodeling driven by aging, hypertension, heart failure, and the arrhythmia itself. This remodeling manifests as interstitial fibrosis, atrial dilation, and endocardial denudation, which collectively promote local inflammation and create a highly prothrombotic endothelial surface. Furthermore, AF induces a systemic hypercoagulable state, characterized by elevated biomarkers such as D-dimer, von Willebrand factor, and increased thrombin generation.

The clinical consequence of this triad is severe: cardioembolic strokes associated with AF are typically larger, present with more severe neurological deficits, and carry higher rates of mortality and long-term disability compared to non-cardioembolic ischemic strokes. Consequently, the cornerstone of AF management remains the meticulous application of anticoagulant therapies, balancing the imperative of stroke prevention against the inherent risks of iatrogenic hemorrhage.

ECG recordings of atrial fibrillation. Click to enlarge.

Risk Stratification: Stroke and Bleeding Assessment

The decision to initiate oral anticoagulation (OAC) hinges on a rigorous assessment of both thromboembolic and hemorrhagic risks. The diagnostic prerequisite for clinical AF remains the documentation of the arrhythmia via a standard 12-lead ECG or a single-lead ECG tracing lasting ≥30 seconds, characterized by irregularly irregular R-R intervals and the absence of distinct P waves [1][2].

Stroke Risk Scores: CHA2DS2-VASc vs. CHA2DS2-VA

For over a decade, the CHA2DS2-VASc score has been the foundational tool for assessing thromboembolic risk. However, recent epidemiological data have prompted a divergence in international guidelines regarding the role of biological sex. The 2024 European Society of Cardiology (ESC) guidelines formally updated the acronym to CHA2DS2-VA, explicitly removing female sex as an independent risk factor [2]. This change reflects robust evidence that female sex alone, in the absence of other comorbidities, does not significantly increase stroke risk. Conversely, the 2023 ACC/AHA guidelines retain the “VASc” nomenclature but clarify that female sex functions as a “risk modifier” rather than a primary driver of anticoagulation decisions [1]. In both paradigms, a score of ≥2 (excluding sex) is a Class I indication for OAC.

Bleeding Risk Assessment: HAS-BLED Score

Bleeding risk must be quantified using validated tools, with the HAS-BLED score being the most widely recommended. It evaluates Hypertension, Abnormal renal/liver function, Stroke history, Bleeding history, Labile INRs, Elderly age (>65), and Drugs/alcohol. A crucial clinical pitfall is the misapplication of this score. A high HAS-BLED score (≥3) indicates a need for closer clinical monitoring and aggressive modification of reversible risk factors (e.g., treating uncontrolled hypertension, discontinuing unnecessary NSAIDs or antiplatelets, and counseling on alcohol cessation). It is not a contraindication to OAC. Guidelines strongly discourage withholding anticoagulation based solely on a high bleeding risk score, as the net clinical benefit of stroke prevention almost universally outweighs the bleeding risk in high-CHA2DS2-VASc patients [1][3].

The Dilemma of Subclinical AF and AHREs

The proliferation of cardiac implantable electronic devices (CIEDs) and consumer wearables has introduced the diagnostic dilemma of Atrial High-Rate Episodes (AHREs) or subclinical AF. The management of these short-duration arrhythmias was recently clarified by two landmark trials: NOAH-AFNET 6 [24] and ARTESiA [23]. Both trials evaluated the use of Direct Oral Anticoagulants (DOACs) in patients with device-detected AHREs who lacked clinically documented AF. The consensus from both trials is that while DOACs reduce the incidence of ischemic stroke in this population, they simultaneously cause a significant increase in major bleeding events. Consequently, routine OAC is not recommended for short AHREs (<24 hours) unless the patient possesses an exceptionally high baseline stroke risk or transitions to clinically overt AF [2].

Figure 1. Algorithm for Anticoagulation in Device-Detected AHREs and Clinical AF

Foundational Pharmacotherapy: DOACs vs. Vitamin K Antagonists

For the prevention of stroke and systemic embolism in patients with non-valvular AF, DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) have supplanted Vitamin K Antagonists (VKAs, e.g., warfarin) as the Class I recommended first-line therapy [1][2]. This paradigm shift is underpinned by four pivotal randomized controlled trials (RCTs) and subsequent meta-analyses.

RE-LY (Dabigatran): Demonstrated that dabigatran 150 mg twice daily was superior to warfarin for stroke prevention with similar major bleeding, while the 110 mg dose was non-inferior for stroke with significantly lower bleeding [5].

ROCKET AF (Rivaroxaban): Showed that once-daily rivaroxaban was non-inferior to warfarin for the prevention of stroke and systemic embolism, though with a higher incidence of gastrointestinal bleeding [6].

ARISTOTLE (Apixaban): Established that apixaban was superior to warfarin in preventing stroke, produced significantly less major bleeding, and resulted in lower all-cause mortality [7].

ENGAGE AF-TIMI 48 (Edoxaban): Confirmed that edoxaban was non-inferior to warfarin for stroke prevention while significantly reducing major bleeding and cardiovascular death [8].

A comprehensive meta-analysis of these trials by Ruff et al. confirmed that DOACs, as a class, offer a favorable risk-benefit profile compared to warfarin. Most notably, DOACs reduce the risk of intracranial hemorrhage (ICH)—the most feared complication of anticoagulation—by approximately 50%, a finding that fundamentally altered the risk calculus of AF management [9].

Comparative Safety and Efficacy Among DOACs

While DOACs are universally preferred over VKAs for non-valvular AF, the absence of large, randomized head-to-head trials comparing individual DOACs complicates drug selection. Consequently, cardiologists must rely on robust, large-scale, real-world observational data to guide clinical choices.

The ARISTOPHANES study, a massive observational pooled analysis, provided critical insights into comparative effectiveness. It demonstrated that apixaban and dabigatran were associated with lower rates of major bleeding compared to warfarin, whereas rivaroxaban was associated with a higher rate of major bleeding [10].

Further granularity was provided by a landmark Medicare cohort study by Ray et al., which directly compared apixaban and rivaroxaban. The study revealed that apixaban was associated with a significantly lower risk of both major ischemic events and major hemorrhagic events (including gastrointestinal bleeding) compared to rivaroxaban [11]. These findings were corroborated by Fralick et al., reinforcing the preference for apixaban in routine practice, particularly for patients at elevated risk for gastrointestinal hemorrhage [12]. Edoxaban also demonstrates a favorable bleeding profile and serves as a viable alternative, though its use requires careful dose adjustment based on renal clearance and body weight [8].

Procedural and Peri-Procedural Management

Left Atrial Appendage Occlusion (LAAO)

For patients with AF who face absolute contraindications to long-term OAC (e.g., recurrent severe gastrointestinal bleeding or prior spontaneous ICH), percutaneous LAAO devices (e.g., Watchman, Amulet) offer a Class IIa indicated alternative. Landmark trials such as PROTECT AF, PREVAIL, and PRAGUE-17 established that percutaneous LAAO is non-inferior to OAC for stroke prevention, although the procedures carry inherent periprocedural risks, including pericardial effusion and device-related thrombosis [19][20][21].

In the realm of surgical management, the LAAOS III trial represented a watershed moment. It demonstrated a 33% reduction in ischemic stroke when the LAA was surgically closed during concomitant cardiac surgery in patients with AF, without increasing perioperative complications. This compelling data has elevated surgical LAAO to a Class I recommendation in both US and European guidelines for AF patients undergoing cardiac surgery for other indications [2][18].

Peri-Procedural DOAC Management and the Fallacy of Bridging

The predictable pharmacokinetics and short half-lives of DOACs have simplified peri-procedural management. For elective surgeries, DOACs are typically held for 24 to 48 hours depending on the patient’s renal function and the procedural bleeding risk. Dabigatran, being 80% renally cleared, requires longer interruption times in patients with chronic kidney disease (CKD) [4].

A critical paradigm shift in contemporary cardiology is the near-total abandonment of heparin “bridging” for DOAC interruptions. Evidence unequivocally shows that bridging increases the risk of major bleeding without conferring any additional protection against stroke. Even for patients on VKAs, bridging is now heavily restricted and reserved almost exclusively for those with high-risk mechanical heart valves [4][1].

Figure 2. Peri-Procedural DOAC Management and Bridging Algorithm

Special Populations and Clinical Controversies

Valvular AF: Rheumatic Heart Disease and Mechanical Valves

The term “non-valvular AF” is historically fraught, but contemporary guidelines are explicit: DOACs are strictly contraindicated in patients with moderate-to-severe rheumatic mitral stenosis and those with mechanical heart valves. The INVICTUS trial definitively demonstrated that VKAs are superior to rivaroxaban in preventing stroke and mortality in patients with rheumatic heart disease-associated AF [15][17]. Similarly, the PROACT Xa trial, which investigated apixaban in patients with mechanical On-X aortic valves, was halted early because the DOAC arm experienced significantly more thromboembolic events than the warfarin arm [16].

Post-Stroke Timing: The Shift to Early Initiation

Historically, restarting OAC after an acute ischemic stroke was delayed due to the fear of hemorrhagic transformation, governed by the empirical “1-3-6-12 day” rule based on stroke severity. Recent landmark RCTs have dismantled this dogma. The ELAN [13] and TIMING [14] trials demonstrated that early DOAC initiation (within 48 hours for minor/moderate stroke, or 6-7 days for major stroke) is safe, does not increase the rate of symptomatic ICH, and numerically reduces recurrent ischemic events compared to delayed initiation.

Figure 3. Timing of DOAC Initiation Following Acute Ischemic Stroke

Chronic Kidney Disease (CKD) and End-Stage Renal Disease (ESRD)

All DOACs undergo renal clearance to varying degrees (dabigatran 80%, rivaroxaban 33%, apixaban 27%). In mild-to-moderate CKD, DOACs remain preferred over VKAs due to a superior safety profile. However, in ESRD patients on hemodialysis, management is highly controversial. In the United States, apixaban is frequently used off-label based on pharmacokinetic modeling and observational data suggesting safety [25]. RCT data remain mixed: the RENAL-AF trial (apixaban vs. warfarin) was underpowered and stopped early [26], while the AXADIA-AFNET 8 trial showed apixaban was non-inferior to VKAs for safety [27]. The VALKYRIE trial indicated that rivaroxaban reduced fatal/non-fatal cardiovascular events and major bleeding compared to VKAs in hemodialysis patients [28]. Despite these trials, a definitive Class I consensus for DOACs in ESRD remains elusive.

The Frail Elderly: The FRAIL-AF Caveat

While DOACs are generally considered safer than VKAs in the elderly, the recent FRAIL-AF trial introduced a critical caveat. The trial investigated switching frail older adults (≥75 years) who were already stable on a VKA to a DOAC. Surprisingly, the switch resulted in a significant increase in bleeding complications without any corresponding reduction in thromboembolic events [22]. Consequently, the 2024 ESC guidelines explicitly suggest avoiding the switch from a well-tolerated VKA to a DOAC in highly frail older adults, emphasizing that “if it isn’t broken, don’t fix it” [2].

Conclusions

The landscape of AF anticoagulation has been radically transformed over the past decade, moving from the monolithic use of warfarin to the nuanced, patient-specific application of DOACs and LAA occlusion devices. The refinement of risk scores (CHA2DS2-VA), the integration of wearable technology in diagnosing AHREs, and the paradigm shifts in post-stroke timing and peri-procedural management underscore a broader move toward precision cardiology.

Looking forward, the frontier of anticoagulation lies in the development of Factor XIa inhibitors (e.g., milvexian, asundexian), which promise to further uncouple hemostasis from thrombosis, potentially offering stroke prevention with near-zero bleeding risk. Until such therapies are validated in phase III trials, practicing cardiologists must continue to synthesize trial data, patient comorbidities, and anatomical considerations to optimize outcomes. Mastery of these strategies—recognizing when to initiate early post-stroke, when to avoid DOACs in valvular disease, and when to refer for LAAO—remains the hallmark of exceptional cardiovascular care.

Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(1):e1-e156. DOI: 10.1161/CIR.0000000000001193

Van Gelder IC, Rienstra M, Bunting KV, et al. 2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2024;45(36):3314-3414. DOI: 10.1093/eurheartj/ehae176

Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation. Eur Heart J. 2021;42(5):373-498. DOI: 10.1093/eurheartj/ehaa612

Steffel J, Collins R, Antz M, et al. 2021 European Heart Rhythm Association Practical Guide on the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients with Atrial Fibrillation. Europace. 2021;23(10):1612-1676. DOI: 10.1093/europace/euab065

Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation (RE-LY). N Engl J Med. 2009;361(12):1139-1151. DOI: 10.1056/NEJMoa0905561

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation (ROCKET AF). N Engl J Med. 2011;365(10):883-891. DOI: 10.1056/NEJMoa1009638

Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation (ARISTOTLE). N Engl J Med. 2011;365(11):981-992. DOI: 10.1056/NEJMoa1107039

Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48). N Engl J Med. 2013;369(22):2093-2104. DOI: 10.1056/NEJMoa1310907

Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. DOI: 10.1016/S0140-6736(13)62343-0

Lip GYH, Keshishian A, Kamble S, et al. Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients: The ARISTOPHANES Study. Stroke. 2018;49(12):2933-2944. DOI: 10.1161/STROKEAHA.118.022422

Ray WA, Chung CP, Stein CM, et al. Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation. JAMA. 2021;326(23):2395-2404. DOI: 10.1001/jama.2021.21222

Fralick M, Colacci M, Schneeweiss S, et al. Effectiveness and Safety of Apixaban Compared With Rivaroxaban for Patients With Atrial Fibrillation in Routine Practice: A Cohort Study. Ann Intern Med. 2020;172(7):463-473. DOI: 10.7326/M19-2522

Fischer U, Koga M, Strbian D, et al. Early versus Later Anticoagulation for Stroke with Atrial Fibrillation (ELAN). N Engl J Med. 2023;388(26):2411-2421. DOI: 10.1056/NEJMoa2303048

Oldgren J, Åsberg S, Hijazi Z, et al. Early Versus Delayed Non-Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING). Circulation. 2022;146(14):1056-1066. DOI: 10.1161/CIRCULATIONAHA.122.060666

Connolly SJ, Karthikeyan G, Ntsekhe M, et al. Rivaroxaban in Rheumatic Heart Disease-Associated Atrial Fibrillation (INVICTUS). N Engl J Med. 2022;387(11):978-988. DOI: 10.1056/NEJMoa2209051

Svensson LG, Wen J, et al. Apixaban or Warfarin in Patients with an On-X Mechanical Aortic Valve (PROACT Xa). NEJM Evid. 2023;2(7):EVIDoa2300067. DOI: 10.1056/EVIDoa2300067

Weitz JI, Eikelboom JW, Connolly SJ. Warfarin faring better: vitamin K antagonists beat rivaroxaban and apixaban in the INVICTUS and PROACT Xa trials. J Thromb Haemost. 2023;21(11):3067-3071. DOI: 10.1016/j.jtha.2023.06.036

Whitlock RP, Belley-Cote EP, Paparella D, et al. Left Atrial Appendage Occlusion during Cardiac Surgery to Prevent Stroke (LAAOS III). N Engl J Med. 2021;384(22):2081-2091. DOI: 10.1056/NEJMoa2101897

Holmes DR, Reddy VY, Turi ZG, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation (PROTECT AF). Lancet. 2009;374(9689):534-542. DOI: 10.1016/S0140-6736(09)61343-X

Holmes DR Jr, Kar S, Price MJ, et al. Prospective randomized evaluation of the Watchman Left Atrial Appendage Closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J Am Coll Cardiol. 2014;64(1):1-12. DOI: 10.1016/j.jacc.2014.04.029

Osmancik P, Herman D, Neuzil P, et al. Left Atrial Appendage Closure Versus Direct Oral Anticoagulants in High-Risk Patients With Atrial Fibrillation (PRAGUE-17). J Am Coll Cardiol. 2020;75(25):3122-3135. DOI: 10.1016/j.jacc.2020.04.067

Joosten LPT, van Doorn S, van de Ven PM, et al. Safety of Switching from a Vitamin K Antagonist to a Non-Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients with Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial. Circulation. 2024;149(4):279-289. DOI: 10.1161/CIRCULATIONAHA.123.066485

Healey JS, Lopes RD, Granger CB, et al. Apixaban for Stroke Prevention in Subclinical Atrial Fibrillation (ARTESiA). N Engl J Med. 2024;390(2):107-117. DOI: 10.1056/NEJMoa2310234

Kirchhof P, Toennis T, Goette A, et al. Anticoagulation with Edoxaban in Patients with Atrial High-Rate Episodes (NOAH-AFNET 6). N Engl J Med. 2023;389(13):1167-1179. DOI: 10.1056/NEJMoa2303062

Siontis KC, Zhang X, Eckard A, et al. Outcomes Associated With Apixaban Use in Patients With End-Stage Kidney Disease and Atrial Fibrillation in the United States. Circulation. 2018;138(15):1519-1529. DOI: 10.1161/CIRCULATIONAHA.118.035418

Pokorney SD, Chertow GM, Al-Khalidi HR, et al. Apixaban for Patients With Atrial Fibrillation on Hemodialysis: A Multicenter Randomized Controlled Trial (RENAL-AF). Circulation. 2022;146(23):1735-1745. DOI: 10.1161/CIRCULATIONAHA.121.054990

Reinecke H, Engelbertz C, Bauersachs R, et al. A Randomized Controlled Trial Comparing Apixaban With the Vitamin K Antagonist Phenprocoumon in Patients on Chronic Hemodialysis: The AXADIA-AFNET 8 Study. Circulation. 2023;147(4):296-309. DOI: 10.1161/CIRCULATIONAHA.122.062779

De Vriese AS, Caluwé R, Bilo L, et al. Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: the Valkyrie Study. J Am Soc Nephrol. 2020;31(1):186-196. DOI: 10.1681/ASN.2019060579

Figures

---

Chapter 11: Brugada Syndrome: Diagnosis & SCD Prevention

Introduction Since its initial description in 1992 as a syndrome of right bundle branch block, ST-segment elevation, and sudden cardiac death (SCD), Brugada syndrome (BrS) has evolved from an obscure electrocardiographic curiosity into a major focus of contemporary cardiac electrophysiology [1]. Recognized as a primary inherited arrhythmia syndrome, BrS is characterized by a distinct electrocardiographic (ECG) signature—coved ST-segment elevation in the right precordial leads—and a propensity for life-threatening polymorphic ventricular tachycardia (VT) and ventricular fibrillation (VF) in patients with structurally normal hearts [2]. Epidemiologically, BrS is responsible for up to 20% of sudden cardiac deaths in patients without structural heart disease and is the leading cause of SCD in men under the age of 40 in endemic regions [3]. The global prevalence is estimated at 1 to 5 per 10,000 individuals, though this figure rises dramatically in Southeast Asia, where the condition is historically linked to Sudden Unexplained Nocturnal Death Syndrome (SUNDS) [4]. The clinical presentation is notoriously heterogeneous, ranging from lifelong asymptomatic ECG anomalies to electrical storm and sudden cardiac arrest (SCA) as the index presentation. Over the past three decades, the management of BrS has been fraught with controversies, particularly regarding the risk stratification of asymptomatic patients, the prognostic utility of electrophysiological studies (EPS), and the transition from a purely device-based management strategy (implantable cardioverter-defibrillators) to one that incorporates pharmacological and interventional (substrate ablation) therapies [5]. This review synthesizes the current evidence base, emphasizing the 2022 European Society of Cardiology (ESC) guidelines, landmark registry data, and emerging concepts in the pathophysiology, diagnosis, and prevention of SCD in Brugada syndrome. Pathophysiology and Genetic Architecture Genetic Architecture: From Monogenic to Polygenic Models Brugada syndrome was classically defined as a monogenic, autosomal dominant channelopathy with incomplete penetrance and variable expressivity. The first and most critical genetic locus identified was SCN5A, the gene encoding the alpha subunit of the cardiac voltage-gated sodium channel (Nav1.5) [6]. Loss-of-function (LOF) mutations in SCN5A lead to a reduction in the inward sodium current ($I_{Na}$) and are identified in 20% to 30% of probands [7]. Historically, expanded genetic panels implicated over 20 other genes (e.g., CACNA1C, GPD1L, TRPM4). However, rigorous reappraisals using the ClinGen framework have demonstrated that only SCN5A possesses definitive disease-gene validity for BrS [8]. Consequently, the 2022 ESC guidelines recommend restricting routine diagnostic genetic testing in BrS strictly to SCN5A [2]. More recently, the paradigm has shifted toward an oligogenic or polygenic architecture. Genome-wide association studies (GWAS) have identified common single nucleotide polymorphisms (SNPs)—such as those near SCN10A and HEY2—that strongly modulate disease penetrance and expressivity [9]. Polygenic risk scores (PRS) derived from these loci are now recognized as critical modifiers. High PRS burdens correlate with a more severe electrocardiographic phenotype, a higher likelihood of positive provocation testing, and an increased risk of malignant arrhythmic events (MAEs) [10]. Electrophysiological Mechanisms: Repolarization vs. Depolarization The precise arrhythmogenic mechanism of BrS remains a subject of intense debate, polarized by two prevailing hypotheses:

The Repolarization Hypothesis: Championed by Antzelevitch and colleagues, this theory posits that a reduction in $I_{Na}$ leaves the transient outward potassium current ($I_{to}$) unopposed during phase 1 of the action potential [11]. Because $I_{to}$ is significantly more prominent in the right ventricular (RV) epicardium than the endocardium, this imbalance creates a transmural voltage gradient, manifesting on the surface ECG as ST-segment elevation. If the epicardial action potential is sufficiently abbreviated, phase 2 reentry can occur, triggering closely coupled premature ventricular contractions (PVCs) that initiate polymorphic VT/VF [12]. The Depolarization Hypothesis: Advanced by Nademanee and others, this model suggests that mild structural abnormalities and fibrosis in the right ventricular outflow tract (RVOT) epicardium cause localized conduction slowing and delayed activation [13]. This delayed, fractionated depolarization generates late potentials that manifest as ST-segment elevation and provide the substrate for reentrant arrhythmias [14].

Structural Substrate: The ARVC Overlap Although BrS is categorized as a primary electrical disease occurring in a “structurally normal heart,” high-resolution imaging and post-mortem studies frequently reveal micro-structural abnormalities. Increased collagen deposition, micro-fibrosis, and connexin-43 gap junction remodeling are frequently observed in the RVOT of BrS patients [15]. This structural substrate blurs the phenotypic boundaries between BrS and arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting that the two conditions may represent different points on a continuous spectrum of right ventricular disease [16].

Diagnostic Criteria and Electrocardiographic Phenotypes Electrocardiographic Phenotypes The hallmark of BrS is the Type 1 Brugada ECG pattern, defined as a coved ST-segment elevation $\ge 2$ mm followed by a negative T-wave in at least one right precordial lead (V1–V2) [2]. Because the arrhythmogenic substrate is anatomically localized to the RVOT, placing the V1 and V2 leads in the 2nd or 3rd intercostal spaces (high-lead ECG) significantly increases diagnostic sensitivity without compromising specificity [17]. Historically, Type 2 and Type 3 patterns (characterized by a “saddleback” ST-segment elevation) were considered part of the diagnostic spectrum. However, under contemporary guidelines, these patterns are no longer considered diagnostic of BrS. Instead, they serve as an indication for pharmacological provocation testing to unmask a Type 1 pattern [18]. Contemporary Diagnostic Criteria (ESC 2022 & Shanghai Score) To mitigate the overdiagnosis of asymptomatic patients with isolated, incidental ECG findings, diagnostic criteria have become markedly more stringent. The 2013 HRS/EHRA consensus allowed for a diagnosis based solely on a spontaneous Type 1 ECG [18]. In contrast, the 2022 ESC Guidelines mandate that a spontaneous Type 1 ECG is no longer sufficient for a definitive diagnosis in isolation. It must be accompanied by at least one clinical criterion: survived SCA, documented polymorphic VT/VF, arrhythmic syncope, or a family history of BrS or premature SCD (<45 years) [2]. In parallel, the Shanghai Score was developed as a multiparametric diagnostic tool evaluating ECG findings, clinical history, family history, and genetic test results [19]. A score $\ge 3.5$ indicates definite/probable BrS.

Table 1: The Shanghai Scoring System for Brugada Syndrome [19]

Category Finding Points

ECG (Max 3.5) Spontaneous Type 1 Brugada pattern at baseline 3.5

Fever-induced Type 1 Brugada pattern 3.0

Type 2/3 pattern converting to Type 1 with provocation 2.0

Clinical (Max 2.0) Unexplained cardiac arrest or documented VF/polymorphic VT 2.0

Nocturnal agonal respiration 2.0

Suspected arrhythmic syncope 1.0

Family History (Max 2.0) First/second-degree relative with definite BrS 2.0

Suspicious SCD in a first/second-degree relative <45 years 0.5

Genetics (Max 0.5) Probable/definite pathogenic mutation in SCN5A 0.5

Pharmacological Provocation Testing Intravenous sodium channel blockers (ajmaline, flecainide, or procainamide) are utilized to unmask the Type 1 pattern in patients with a baseline Type 2/3 pattern or a high clinical suspicion of BrS (e.g., unexplained cardiac arrest) [20]. Ajmaline (1 mg/kg over 5 minutes) is preferred due to its short half-life and high sensitivity. The test is considered positive if a Type 1 pattern emerges. It must be performed with continuous 12-lead ECG monitoring and advanced resuscitation equipment, as it can induce refractory VF in up to 1% of cases [21]. The test should be immediately terminated upon the appearance of a Type 1 pattern, frequent PVCs, or QRS widening >130% of baseline. Brugada Phenocopies Brugada phenocopies are reversible conditions that mimic the Type 1 ECG pattern but lack the underlying genetic or electrophysiological substrate of true BrS. Common etiologies include severe hyperkalemia, acute ischemia (particularly right ventricular branch occlusion), pulmonary embolism, tricyclic antidepressant toxicity, and cocaine use [22]. The defining characteristic of a phenocopy is the complete normalization of the ECG once the underlying metabolic, ischemic, or toxicological derangement is resolved.

Diagnostic Algorithm for Suspected Brugada Syndrome Risk Stratification for Sudden Cardiac Death Risk stratification for the primary prevention of SCD remains the most challenging and controversial aspect of BrS management. The clinical course is highly variable; while some patients experience recurrent electrical storms, the majority remain asymptomatic throughout their lives. Clinical Predictors of Sudden Cardiac Death The most powerful predictor of future arrhythmic events is a history of a previous event. Survivors of SCA have a recurrence rate of up to 48% at 10 years, establishing an unequivocal mandate for secondary prevention [23]. In patients without prior SCA, the combination of a spontaneous Type 1 ECG and arrhythmogenic syncope identifies a high-risk cohort. Syncope in BrS must be carefully evaluated; vasovagal syncope is common in the general population and does not confer an increased risk of SCD in BrS patients. However, syncope occurring at rest, without prodrome, or accompanied by severe trauma is highly suggestive of self-terminating polymorphic VT [24]. Asymptomatic patients, even those with a spontaneous Type 1 ECG, have a relatively low event rate, estimated at 0.5% to 1% per year in large registries such as the FINGER (France, Italy, Netherlands, Germany) registry [25]. The presence of a drug-induced Type 1 ECG in an asymptomatic patient confers a risk nearly equivalent to that of the general population, and these patients generally require only lifestyle modifications and observation. The EPS Controversy The prognostic value of programmed ventricular stimulation (EPS) in BrS has been a subject of intense debate for over two decades. Early data from the Brugada registry suggested that the inducibility of VF during EPS was a strong independent predictor of spontaneous SCD [26]. However, subsequent large-scale, independent registries, including the PRELUDE study and the FINGER registry, failed to demonstrate a significant positive predictive value for EPS inducibility [25, 27]. Despite these conflicting data, recent meta-analyses suggest that while the positive predictive value of EPS is modest, its negative predictive value is exceptionally high (>98%) [28]. Consequently, the 2022 ESC guidelines grant a Class IIb recommendation for EPS in asymptomatic patients with a spontaneous Type 1 ECG. If VF is induced with up to two extrastimuli, ICD implantation may be considered [2]. Multiparametric Risk Scores To move beyond binary risk factors, several multiparametric risk scores have been developed to stratify intermediate-risk patients:

The Sieira Score: Developed from a large Belgian cohort, this score incorporates spontaneous Type 1 ECG, early familial SCD, inducible EPS, syncope, and sinus node dysfunction. It provides a graded risk assessment, though external validation has shown mixed discrimination [29]. The PAT Score: The Predicting Arrhythmic evenT (PAT) score incorporates 15 clinical, electrocardiographic, and genetic variables. Recent validations demonstrate superior predictive accuracy (C-statistic > 0.80) for major arrhythmic events compared to older models [30]. Machine Learning Models: Emerging tools like the BRUGADA-RISK calculator utilize machine learning algorithms to integrate dynamic ECG changes and clinical variables, offering personalized 5-year SCD risk estimates [31].

Risk Stratification Pathway for Sudden Cardiac Death in Brugada Syndrome Evidence-Based Management and SCD Prevention Implantable Cardioverter-Defibrillators (ICDs) The implantable cardioverter-defibrillator remains the only therapy proven to prevent SCD in high-risk BrS patients. According to the 2022 ESC and 2017 AHA/ACC/HRS guidelines, ICD implantation is recommended as follows [2, 32]:

Class I: Survivors of aborted SCA or patients with documented spontaneous sustained VT/VF. Class IIa: Patients with a spontaneous Type 1 ECG and a history of arrhythmic syncope. Class IIb: Asymptomatic patients with a spontaneous Type 1 ECG who have inducible VF during EPS.

Because BrS patients are typically young and lack structural heart disease, they are ideal candidates for the subcutaneous ICD (S-ICD). The S-ICD avoids the long-term risks of transvenous lead failure and systemic infection, which are significant in a population with a life expectancy of several decades post-implantation [33]. However, careful pre-implantation ECG screening is mandatory to ensure appropriate sensing and avoid T-wave oversensing, which is more common in BrS due to dynamic repolarization abnormalities. Pharmacological Therapy: Quinidine and Isoproterenol While ICDs terminate life-threatening arrhythmias, they do not prevent them. Pharmacotherapy plays a crucial role in reducing arrhythmic burden and managing electrical storms. Quinidine: As a potent blocker of the transient outward potassium current ($I_{to}$), quinidine directly counteracts the fundamental electrophysiological derangement in BrS. It is highly effective in suppressing spontaneous VF and normalizing the ECG [34]. Quinidine is indicated (Class IIa) for patients with recurrent ICD shocks, those with a contraindication to ICD implantation, or as a bridge to ablation. Its use is limited primarily by gastrointestinal intolerance (diarrhea) and the risk of proarrhythmia (QT prolongation), necessitating careful initiation [35]. Isoproterenol: In the acute setting of an electrical storm, a continuous intravenous infusion of isoproterenol (1–2 mcg/min) is the first-line therapy. By stimulating beta-adrenergic receptors, isoproterenol increases the L-type calcium current ($I_{Ca,L}$) and heart rate, effectively counteracting the unopposed $I_{to}$, restoring the epicardial action potential dome, and suppressing phase 2 reentry [36]. Epicardial Substrate Ablation One of the most significant advancements in BrS management is the development of epicardial RVOT substrate ablation. Pioneered by Nademanee and colleagues, this approach targets the delayed, fractionated electrograms in the RVOT epicardium [13]. Using high-density electroanatomical mapping, the arrhythmogenic substrate is identified and ablated using radiofrequency energy. Long-term registry data demonstrate that epicardial ablation normalizes the ECG phenotype in >80% of patients and drastically reduces the incidence of recurrent VF [37]. The BRAVE (Brugada Ablation of VF Episodes) trial and other prospective studies have solidified substrate ablation as a Class IIb recommendation for patients with recurrent ICD shocks refractory to quinidine, and increasingly as an earlier intervention in high-risk cohorts [38]. Management of Electrical Storm in Brugada Syndrome Special Populations and Future Directions The Asymptomatic Patient The management of asymptomatic patients with a spontaneous Type 1 ECG remains the most vexing clinical dilemma. The annual risk of SCD is low (~0.8%), yet the cumulative lifetime risk is non-trivial. Conversely, the complication rate of ICDs in young, active patients (inappropriate shocks, lead fractures, infections) can exceed 10% over a decade [39]. Shared decision-making is paramount. For intermediate-risk patients who do not meet strict ICD criteria, the use of Implantable Loop Recorders (ILRs) is increasingly recommended (Class IIa/IIb) to monitor for asymptomatic arrhythmias and guide future interventions [2]. Pediatric and Female Populations BrS exhibits a profound male predominance (up to 8:1), largely attributed to the influence of testosterone, which enhances $I_{to}$ expression [40]. Women with BrS generally have a lower penetrance and a more benign clinical course, though they are more likely to present with conduction system disease (e.g., sinus node dysfunction) rather than VF [41]. In pediatric populations, the presentation is distinct. Fever is the most critical trigger for arrhythmias in children with BrS. Elevated temperatures accelerate the kinetics of the mutated sodium channel, exacerbating the LOF phenotype. Immediate administration of antipyretics and continuous ECG monitoring during febrile illnesses are mandatory Class I recommendations for all BrS patients, but are especially critical in pediatrics [42]. Future Directions: Mapping and Gene Therapy The future of BrS management lies in precision medicine. Non-invasive Electrocardiographic Imaging (ECGI) is emerging as a tool to map the epicardial RVOT substrate without the need for invasive epicardial puncture, potentially guiding prophylactic ablation [43]. Furthermore, as the genetic architecture of BrS becomes clearer, allele-specific gene silencing and CRISPR/Cas9-mediated gene editing of SCN5A mutations represent the ultimate frontier, offering the promise of a definitive cure rather than mere palliation of symptoms [44]. Management and ICD Decision Tree for Brugada Syndrome References

Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol. 1992;20(6):1391-1396. Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997-4126. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference. Circulation. 2005;111(5):659-670. Vatta M, Dumaine R, Varghese G, et al. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Hum Mol Genet. 2002;11(3):337-345. Probst V, Veltmann C, Eckardt L, et al. Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry. Circulation. 2010;121(5):635-643. Chen Q, Kirsch GE, Zhang D, et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature. 1998;392(6673):293-296. Cerrone M, Remme CA, Tadros R, et al. Beyond the One Gene-One Disease Paradigm: Complex Genetics and Pleiotropy in Inheritable Cardiac Disorders. J Am Coll Cardiol. 2022;80(16):1564-1576. Hosseini SM, Kim R, Udupa S, et al. Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome. Circulation. 2018;138(12):1195-1205. Barc J, Tadros R, Glinge C, et al. Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility. Nat Genet. 2022;54(3):232-239. Kukavica D, Sommariva E, et al. Polygenic risk scores in Brugada syndrome: clinical implications and future perspectives. Europace. 2024;26(2):euad385. Antzelevitch C. Brugada syndrome. Pacing Clin Electrophysiol. 2006;29(10):1130-1159. Yan GX, Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation. 1999;100(15):1660-1666. Nademanee K, Veerakul G, Chandanamattha P, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation. 2011;123(12):1270-1279. Coronel R, Casini S, Koopmann TT, et al. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: a combined electrophysiological, genetic, immunohistochemical, and computational study. Circulation. 2005;112(18):2769-2777. Sommariva E, Pappone C, Brugada J, et al. Microstructural abnormalities in Brugada syndrome: the overlap with arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2021;42(34):3413-3423. Behr ER, Savio-Galimberti E, et al. Structural overlap between Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy. Eur Heart J. 2021;42(34):3424-3426. Gaita F, Giustetto C, Bianchi F, et al. Short QT Syndrome: a familial cause of sudden death. Circulation. 2003;108(8):965-970. [Note: High lead utility validated in subsequent cohorts]. Priori SG, Wilde AA, Horie M, et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013;10(12):1932-1963. Kawada S, Morita H, Antzelevitch C, et al. Shanghai Score System for diagnosis of Brugada syndrome: Validation of the score system and system and reclassification of the patients. Heart Rhythm. 2018;15(8):1180-1187. Conte G, Sieira J, Ciconte G, et al. Drug-induced Brugada syndrome children: clinical features, device-based management, and long-term follow-up. J Am Coll Cardiol. 2014;63(21):2272-2279. Viskin S,

---

Chapter 12: Ventricular Tachycardia

Introduction Ventricular tachycardia (VT) represents a complex and potentially lethal spectrum of cardiac arrhythmias that remains a formidable challenge in contemporary cardiovascular medicine. As a primary driver of sudden cardiac death (SCD) and a major cause of morbidity in patients with structural heart disease, VT necessitates a nuanced, multidisciplinary approach to diagnosis and management. Over the past decade, the landscape of VT management has undergone a profound paradigm shift. Driven by advanced electroanatomical mapping, high-resolution cardiac magnetic resonance (CMR) imaging, and landmark clinical trials, the field has transitioned from a predominantly pharmacological strategy to one that heavily integrates early catheter ablation and sophisticated device therapy [1][2]. This exhaustive review provides a comprehensive synthesis of the current state of VT management for the practicing cardiologist. It meticulously details the classification, pathophysiological subtypes, and clinical presentation of VT, with a deep dive into the underlying etiologies ranging from benign idiopathic variants to complex scar-related and genetic substrates. Furthermore, it critically examines the diagnostic algorithms for wide-complex tachycardia (WCT), the acute management of both stable and unstable presentations, the critical entity of electrical storm, and the long-term management strategies informed by recent sub-group analyses, registry data, and ongoing clinical trials.

1. Ventricular Tachycardia: Classification, Underlying Etiologies, and Clinical Presentation Classification of Ventricular Tachycardia The classification of VT is fundamentally based on its duration, morphology, and hemodynamic consequences, which collectively dictate the urgency and modality of intervention [3].

By Duration:

Non-sustained VT (NSVT): Defined as three or more consecutive ventricular beats at a rate exceeding 100 beats per minute (bpm), which terminates spontaneously within 30 seconds [1]. While often asymptomatic, NSVT serves as a critical marker of arrhythmogenic risk, particularly in the setting of ischemic heart disease or reduced left ventricular ejection fraction (LVEF). Sustained VT: Defined as VT lasting longer than 30 seconds or requiring termination earlier due to hemodynamic collapse [4]. Sustained VT is a medical emergency that universally warrants acute intervention and long-term secondary prevention strategies.

By Morphology:

Monomorphic VT (MMVT): Characterized by a uniform QRS morphology from beat to beat in each electrocardiographic lead. MMVT strongly indicates a stable, fixed arrhythmogenic substrate, most commonly a macro-reentrant circuit anchored around myocardial scar tissue [5]. Polymorphic VT (PMVT): Characterized by a continuously changing QRS morphology and axis, indicating a dynamic sequence of ventricular activation. PMVT is frequently associated with acute myocardial ischemia, electrolyte derangements, or underlying channelopathies (e.g., Torsades de Pointes in Long QT Syndrome) [1].

Underlying Etiologies The etiology of VT is broadly dichotomized into structural heart disease (SHD) and structurally normal hearts, a division that profoundly influences prognosis and therapeutic decision-making. Structural Heart Disease (SHD): Accounting for approximately 90% of all VT presentations, SHD provides the macroscopic architectural abnormalities necessary for arrhythmogenesis. Ischemic heart disease (IHD), particularly prior myocardial infarction (MI), is the most prevalent etiology. The necrotic myocardium is replaced by dense collagenous scar, interspersed with surviving bundles of myocytes that form the slow-conducting isthmuses critical for re-entry [6]. Non-ischemic dilated cardiomyopathy (NICM), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) also fall under this umbrella, each presenting unique fibrotic patterns and arrhythmogenic mechanisms [2]. Structurally Normal Hearts: Comprising the remaining 10% of cases, these VTs occur in the absence of macroscopic myocardial disease. They include idiopathic VTs, which typically originate from specific anatomical regions such as the ventricular outflow tracts or the Purkinje system, and primary electrical disorders (channelopathies) such as Long QT Syndrome (LQTS), Brugada Syndrome, and Catecholaminergic Polymorphic VT (CPVT) [7][8]. Clinical Presentation The clinical presentation of VT spans a remarkably wide spectrum, dictated primarily by the ventricular rate, the duration of the arrhythmia, the underlying LVEF, and the integrity of peripheral compensatory mechanisms [1]. Patients with preserved LVEF and slower VT rates (e.g., 120-150 bpm) may remain entirely asymptomatic or report mild palpitations and lightheadedness. Conversely, rapid VT in the setting of severe left ventricular dysfunction frequently precipitates presyncope, syncope, ischemic chest pain, or acute heart failure exacerbation due to the sudden loss of atrioventricular synchrony and precipitous drop in cardiac output [4]. At the most severe end of the spectrum, VT presents as profound cardiogenic shock, hemodynamic collapse, and sudden cardiac death (SCD). In these instances, the rapid ventricular rate precludes adequate diastolic filling, leading to an immediate cessation of effective systemic perfusion [9]. 2. Subtypes in Relation to Emergence, Persistence, Morphology, and Etiology Understanding the specific subtypes of VT is paramount, as their emergence, morphological characteristics, and persistence are intimately linked to their underlying cellular mechanisms and etiologies. Benign Variants: Idiopathic Ventricular Tachycardias Idiopathic VTs occur in patients without structural heart disease and generally carry a benign prognosis regarding sudden cardiac death, though they can cause significant symptom burden and, rarely, tachycardia-induced cardiomyopathy [7].

Right Ventricular Outflow Tract (RVOT) VT:

Emergence and Etiology: RVOT VT is the most common idiopathic VT. Its emergence is typically triggered by states of high sympathetic tone, such as exercise, emotional stress, or caffeine consumption. The underlying cellular mechanism is cyclic AMP (cAMP)-mediated intracellular calcium overload, leading to delayed afterdepolarizations (DADs) and triggered activity [7]. Morphology: Because the activation originates in the anterior, superior right ventricle and spreads inferiorly and to the left, the surface ECG demonstrates a classic Left Bundle Branch Block (LBBB) pattern with a strong inferior axis (tall, monophasic R waves in leads II, III, and aVF) [10]. Persistence: It frequently presents as repetitive monomorphic NSVT or sustained VT. Crucially, due to its cAMP-dependent mechanism, it is highly sensitive to termination by intravenous adenosine or beta-blockers [11].

Left Ventricular Outflow Tract (LVOT) VT:

Emergence and Etiology: Shares a similar triggered-activity mechanism and sympathetic emergence profile with RVOT VT. Anatomically, it originates from structures such as the aortic sinuses of Valsalva, aortomitral continuity, or epicardial LV summit. Morphology: Can present with either an LBBB or RBBB pattern depending on the exact origin. It is distinguished from RVOT VT by an earlier precordial transition (R wave becomes larger than the S wave by lead V1 or V2), reflecting its more posterior and leftward anatomical origin [12].

Fascicular VT (Belhassen Tachycardia):

Emergence and Etiology: Typically emerges in young, healthy males (15-40 years) at rest or during mild exercise. Unlike outflow tract VTs, the mechanism is localized micro-reentry within the specialized Purkinje conduction system, utilizing a slow-conducting calcium-dependent tissue as the antegrade limb [13]. Morphology: Because it exits the Purkinje system into the left ventricle, it presents with a Right Bundle Branch Block (RBBB) pattern. Approximately 90% originate from the left posterior fascicle, resulting in left axis deviation. A minority originate from the left anterior fascicle (right axis deviation) [14]. Persistence: Often sustained and highly symptomatic. It is uniquely sensitive to intravenous verapamil, which blocks the calcium-dependent slow pathway of the re-entrant circuit [15].

Ischemia and Scar-Related VT Ischemic VT is the quintessential scar-related arrhythmia. Its emergence typically occurs months to years following a myocardial infarction, as the necrotic tissue undergoes fibrotic remodeling [6].

Etiology and Mechanism: The mechanism is fixed anatomical macro-reentry. The dense, unexcitable collagenous scar forms the central obstacle. Surviving bundles of myocytes at the scar border zone, often separated by strands of fibrosis, exhibit depressed excitability and anisotropic (directionally dependent) slow conduction. This creates the perfect milieu for a re-entrant circuit: an area of unidirectional block, a slow-conducting protected isthmus, and an exit site into healthy myocardium [5]. Morphology: Typically monomorphic. The specific QRS morphology dictates the exit site of the circuit from the scar. For example, an anterior wall scar with an exit site in the anterior LV will produce an RBBB pattern with an inferior axis. Persistence: Ischemic VT is highly persistent and recurrent. Once the anatomical substrate is formed, it remains a lifelong risk. It is notoriously refractory to antiarrhythmic drugs and frequently requires implantable cardioverter-defibrillator (ICD) therapy and catheter ablation [16].

Cardiomyopathies and Heart Failure Non-ischemic structural diseases present diverse arrhythmogenic substrates.

Dilated Cardiomyopathy (DCM): Pathological remodeling leads to patchy, mid-wall or epicardial interstitial fibrosis, creating substrates for scar-related re-entry. Additionally, DCM patients are uniquely prone to Bundle Branch Re-entrant VT (BBR-VT), a macro-reentrant circuit utilizing the right and left bundle branches. BBR-VT typically presents with a rapid, typical LBBB morphology and is highly amenable to curative ablation of the right bundle branch [17]. Hypertrophic Cardiomyopathy (HCM): Characterized by profound myocyte hypertrophy, severe myofibrillar disarray, and microvascular ischemia leading to replacement fibrosis. This chaotic architecture creates a highly arrhythmogenic substrate. HCM is a leading cause of SCD in young athletes, often presenting with the sudden emergence of PMVT or ventricular fibrillation (VF) during exertion [18]. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC): A genetic desmosomal disorder characterized by progressive fibrofatty replacement of the right ventricular myocardium. Morphology: VT typically exhibits an LBBB pattern. The resting ECG often reveals Epsilon waves (small deflections at the end of the QRS complex reflecting delayed RV activation) and T-wave inversions in leads V1-V3 [19][20]. Heart Failure with Reduced Ejection Fraction (HFrEF): Regardless of the initial insult, the progression to HFrEF involves profound structural remodeling, mechanical wall stretch, and chronic neurohormonal activation (sympathetic nervous system and renin-angiotensin-aldosterone system). These factors alter ion channel expression (e.g., downregulation of repolarizing potassium currents), prolonging action potential duration and lowering the threshold for VT emergence. VT in HFrEF is associated with high persistence and significantly increased mortality [21].

Genetic and Electrical Disorders (Channelopathies) These disorders involve mutations in genes encoding cardiac ion channels or associated regulatory proteins, leading to primary electrical instability without macroscopic structural disease [8].

Long QT Syndrome (LQTS): Characterized by delayed myocardial repolarization. Emergence: Triggers are genotype-specific: sudden adrenergic surges or swimming in LQT1 (KCNQ1 mutation), sudden auditory stimuli in LQT2 (KCNH2 mutation), or during sleep/bradycardia in LQT3 (SCN5A mutation). Morphology: The hallmark is Torsades de Pointes (TdP), a PMVT characterized by a continuously twisting QRS axis around the isoelectric line, driven by early afterdepolarizations (EADs) [22]. Brugada Syndrome: An autosomal dominant disorder linked to sodium channel (SCN5A) loss-of-function mutations. Emergence: VT/VF typically emerges during sleep, rest, or febrile states. Morphology: Presents as PMVT or VF. The diagnostic resting ECG shows a coved-type ST-segment elevation ≥2 mm followed by a negative T wave in the right precordial leads (V1-V2) [23]. Catecholaminergic Polymorphic VT (CPVT): Caused by mutations in the ryanodine receptor (RYR2) or calsequestrin (CASQ2), leading to spontaneous diastolic calcium leak from the sarcoplasmic reticulum. Emergence: Strictly triggered by physical exercise or acute emotional stress. Morphology: Classically presents as bidirectional VT (alternating QRS axis beat-to-beat) or rapid PMVT [24].

3. Definition and Management of Electrical Storm Definition and Clinical Significance Electrical storm (ES), also termed VT storm, is a life-threatening cardiac emergency defined by the occurrence of three or more distinct episodes of sustained VT, VF, or appropriate ICD shocks within a 24-hour period [1][25]. The episodes must be separated by at least 5 minutes to be considered distinct events. ES represents a state of extreme, self-perpetuating cardiac electrical instability. It is associated with profound psychological trauma for the patient, rapid hemodynamic deterioration, and a significantly elevated short-term and long-term mortality rate [26]. Pathophysiology The emergence of an electrical storm is typically driven by a classic pathophysiological triad [27]:

Susceptible Substrate: The presence of an underlying arrhythmogenic focus, most commonly a dense ischemic scar with surviving border-zone myocardium. Reversible Triggers: Acute physiological derangements that destabilize the substrate, such as acute myocardial ischemia, severe electrolyte imbalances (hypokalemia, hypomagnesemia), acute heart failure decompensation, or drug toxicity. Autonomic Dysfunction: A massive, uncontrolled surge in sympathetic nervous system tone. The initial VT episode or ICD shock causes pain and anxiety, triggering a catecholamine release. This sympathetic surge further shortens the ventricular refractory period, enhances conduction velocity heterogeneity, and triggers subsequent VT episodes, creating a lethal positive feedback loop.

Management Strategies The management of ES requires a rapid, multipronged approach aimed at breaking the sympathetic cascade, suppressing the arrhythmia, and stabilizing hemodynamics [1][25].

Sedation and Anesthesia: Mild to deep sedation (using agents like midazolam, propofol, or dexmedetomidine) is a critical first-line intervention. In refractory cases, general anesthesia and intubation are required to completely abolish psychological distress and blunt the central sympathetic drive [1]. Pharmacotherapy:

Beta-blockers: Non-selective beta-blockers, particularly intravenous propranolol or oral nadolol, are superior to selective agents (like metoprolol) because they block both beta-1 and beta-2 receptors, providing more comprehensive sympathetic blockade [28]. Antiarrhythmics: Intravenous amiodarone is the cornerstone antiarrhythmic for ES in patients with structural heart disease. If amiodarone fails, intravenous lidocaine can be added, as it specifically targets ischemic, partially depolarized tissue [29]. Crucial Exception: If the storm is driven by PMVT/Torsades de Pointes in the setting of prolonged QT, amiodarone is contraindicated; management requires intravenous magnesium sulfate, overdrive pacing, or isoproterenol [1].

Neuromodulation: For ES refractory to deep sedation and maximal pharmacotherapy, targeted autonomic modulation is highly effective. Techniques include percutaneous stellate ganglion block (typically left-sided, using bupivacaine) or thoracic epidural anesthesia, which directly interrupt the sympathetic efferent pathways to the heart [30]. Catheter Ablation: Urgent radiofrequency catheter ablation is now a Class I recommendation for ES refractory to medical therapy. Advanced electroanatomical mapping allows for the identification and homogenization of the arrhythmogenic substrate. Ablation during ES has been shown to significantly improve acute survival and reduce long-term recurrences [31]. Mechanical Circulatory Support (MCS): In patients presenting with or progressing to severe cardiogenic shock due to incessant VT, temporary MCS (such as venoarterial ECMO or Impella) is required to maintain end-organ perfusion, unload the ventricle, and serve as a bridge to definitive catheter ablation or cardiac transplantation [25].

Figure 1: Stepwise Management Pathway for Ventricular Electrical Storm. 4. Key ECG Features Supporting VT and Differential Diagnostics of Wide-Complex Tachycardia The Challenge of Wide-Complex Tachycardia (WCT) Wide-complex tachycardia is defined by a QRS duration ≥ 120 milliseconds and a heart rate > 100 bpm. The differential diagnosis of WCT is a classic conundrum in emergency cardiology. Statistically, 80% to 90% of all WCTs in adults are VT. The remaining cases comprise [32][33]:

SVT with Aberrancy: Supraventricular tachycardia conducted to the ventricles with a pre-existing or rate-related (phase 3 block) bundle branch block. SVT with Pre-excitation: Antidromic atrioventricular reentrant tachycardia (AVRT) conducting antegrade down an accessory pathway (e.g., Wolff-Parkinson-White syndrome), resulting in a fully pre-excited, wide QRS. Pacemaker-Mediated Tachycardia: Or other device-related tachycardias. Toxic/Metabolic WCT: Severe hyperkalemia or sodium-channel blocker toxicity (e.g., tricyclic antidepressants) causing profound QRS widening.

Clinical Axiom: In the acute setting, any WCT must be presumed to be VT and treated as such until proven otherwise. Misdiagnosing VT as SVT and administering atrioventricular nodal blocking agents (like verapamil) can precipitate catastrophic hemodynamic collapse [1]. Key ECG Features Supporting VT Careful analysis of the 12-lead ECG can reliably differentiate VT from SVT with aberrancy [1][32].

Atrioventricular (AV) Dissociation: The absolute hallmark of VT. It manifests as independent P waves marching through the QRS complexes at a rate slower than the ventricular rate. While highly specific (approaching 100%), its sensitivity is low, as P waves are discernible in only about 30% of WCT surface ECGs [34]. Fusion and Capture Beats: Direct consequences of AV dissociation. A capture beat occurs when a sinus impulse fortuitously conducts through the AV node and completely depolarizes the ventricles, resulting in a narrow QRS complex amidst the WCT. A fusion beat occurs when a sinus impulse and the VT impulse simultaneously depolarize the ventricles, creating a hybrid QRS morphology. Both definitively prove a ventricular origin of the tachycardia. Extreme Axis Deviation: A “northwest axis” (between -90° and -180°, with negative QRS complexes in leads I and aVF) strongly suggests VT, as the activation is proceeding from the apex toward the base of the heart, opposite to normal conduction. Precordial Concordance: Occurs when all QRS complexes from V1 to V6 are entirely positive (R waves) or entirely negative (QS complexes). Negative concordance is virtually diagnostic of VT (often apical origin). Positive concordance is highly suggestive of VT (basal origin) but can rarely be seen in antidromic AVRT [1]. QRS Duration: A QRS duration > 140 ms in the presence of an RBBB morphology, or > 160 ms in the presence of an LBBB morphology, strongly favors VT over SVT with aberrancy [32].

Diagnostic Algorithms Several stepwise algorithms have been developed to systematize ECG interpretation in WCT.

The Brugada Algorithm (1991): A classic four-step approach [34].

Absence of an RS complex in all precordial leads (V1-V6)? If yes → VT. If RS is present, is the longest RS interval (onset of R to nadir of S) > 100 ms in any precordial lead? If yes → VT. Is AV dissociation present? If yes → VT. Are morphological criteria for VT present in leads V1-V2 and V6? If yes → VT. If all four steps are negative, the diagnosis is SVT with aberrancy.

The Vereckei aVR Algorithm (2008): Focuses solely on lead aVR, simplifying analysis [35].

Is there an initial R wave in aVR? If yes → VT. Is there an initial r or q wave > 40 ms? If yes → VT. Is there notching on the initial downstroke of a predominantly negative QRS? If yes → VT. Is the Vi/Vt ratio (voltage during the initial 40 ms divided by voltage during the terminal 40 ms) < 1? If yes → VT.

The Basel Algorithm (2022): A modern, simplified algorithm designed for rapid use by non-electrophysiologists in the emergency department. It requires at least two of the following three criteria to diagnose VT [36][37]:

Clinical high risk (history of prior MI, heart failure, or presence of an ICD)? Lead II time to first peak > 40 ms? Lead aVR time to first peak > 40 ms?

Figure 2: Simplified Diagnostic Algorithm for Wide-Complex Tachycardia (incorporating Brugada and Basel principles). 5. Management of Hemodynamically Stable VT Initial Approach and Paradigm Shift A patient presenting with sustained VT who maintains adequate blood pressure, normal mentation, and lacks signs of severe end-organ hypoperfusion is considered hemodynamically stable. The initial approach involves continuous telemetry, acquisition of a 12-lead ECG, securing intravenous access, and the immediate application of defibrillator pads [1]. Historically, chemical cardioversion was the preferred first-line strategy for stable VT. However, the 2022 European Society of Cardiology (ESC) Guidelines introduced a significant paradigm shift: continuous synchronized electrical cardioversion is now elevated to a first-line therapy (Class I) for stable sustained monomorphic VT, provided the patient can be safely sedated [1]. This shift acknowledges that electrical cardioversion has a near 100% efficacy rate, avoids the proarrhythmic and hypotensive risks of antiarrhythmic drugs, and rapidly restores sinus rhythm, preventing unexpected hemodynamic deterioration. Chemical Cardioversion: The PROCAMIO Trial If chemical cardioversion is chosen, the selection of the antiarrhythmic agent is critical. For decades, intravenous amiodarone was the default choice. This practice was fundamentally challenged by the landmark PROCAMIO trial (2017) [38]. PROCAMIO was a randomized, open-label trial comparing intravenous procainamide (10 mg/kg over 20 minutes) to intravenous amiodarone (5 mg/kg over 20 minutes) for the acute treatment of tolerated WCT. The results were definitive:

Efficacy: Procainamide achieved a significantly higher termination rate of the tachycardia compared to amiodarone (67% vs. 38%, p = 0.026). Safety: Procainamide had a significantly lower incidence of major adverse cardiac events (9% vs. 41%, p = 0.001). The primary driver of adverse events in the amiodarone arm was profound hypotension requiring immediate electrical cardioversion or vasopressor support.

Based on these data, intravenous procainamide is now the preferred pharmacological agent for stable monomorphic VT of unknown etiology or known structural heart disease [1][39]. Amiodarone remains an alternative but is associated with delayed onset of action and higher rates of hypotension. Management of Specific Idiopathic VTs If the 12-lead ECG and clinical history strongly suggest a specific idiopathic VT, targeted pharmacotherapy is indicated [1]:

Fascicular VT: Intravenous verapamil is the drug of choice, given the calcium-dependent nature of the re-entrant circuit [15]. RVOT/LVOT VT: Intravenous beta-blockers or adenosine are highly effective at terminating these cAMP-mediated triggered arrhythmias [11].

Note: Amiodarone is not recommended as a first-line agent for idiopathic VTs. Figure 3: Acute Management Pathway for Hemodynamically Stable Ventricular Tachycardia. 6. Management of Hemodynamically Unstable VT Definition of Instability Hemodynamic instability in the setting of VT is defined by the presence of one or more of the following: hypotension (typically systolic BP < 90 mmHg), altered mental status, signs of systemic shock (cool, clammy extremities, oliguria), ongoing ischemic chest pain, or acute pulmonary edema [40]. Unstable VT is an immediate threat to life. Acute Management Approach The management of unstable VT is dictated by the Advanced Cardiovascular Life Support (ACLS) guidelines and depends entirely on the presence or absence of a palpable pulse [40][41].

Unstable VT with a Pulse:

The definitive treatment is immediate synchronized electrical cardioversion. Synchronization to the R wave is crucial to avoid delivering a shock during the relative refractory period of the cardiac cycle (the T wave), which could precipitate ventricular fibrillation (the “R-on-T” phenomenon). If the patient is conscious and blood pressure permits, rapid administration of a short-acting sedative (e.g., midazolam or etomidate) is recommended to provide amnesia and analgesia. However, cardioversion must never be delayed if the patient is rapidly deteriorating. Initial energy selection is typically 100 Joules (biphasic), escalating to 200 Joules if unsuccessful [40].

Pulseless VT:

Pulseless VT is treated identically to ventricular fibrillation. It requires the immediate initiation of high-quality cardiopulmonary resuscitation (CPR) and unsynchronized defibrillation at maximum energy (typically 200 Joules biphasic) [40]. Following the first shock, CPR is immediately resumed for 2 minutes before rhythm and pulse checks. If the rhythm remains shockable (refractory pulseless VT/VF), intravenous epinephrine (1 mg every 3-5 minutes) is administered. For VT/VF refractory to at least two shocks and epinephrine, antiarrhythmic therapy is indicated. Options include an intravenous amiodarone bolus (300 mg, followed by an additional 150 mg if needed) or intravenous lidocaine (1-1.5 mg/kg) [41].

Figure 4: ACLS-based Management of Hemodynamically Unstable Ventricular Tachycardia. 7. Comprehensive Evaluation of the VT Patient Following acute stabilization, every patient presenting with new-onset VT requires a meticulous evaluation to define the underlying etiology, assess the risk of recurrence, and guide long-term management [1]. Non-Invasive Evaluation

12-Lead ECG: Essential both during the tachycardia (to localize the exit site and suggest the mechanism) and during sinus rhythm. The sinus rhythm ECG can reveal underlying substrates: Q waves indicating prior MI, fragmented QRS complexes suggesting myocardial scar, prolonged QT intervals, Brugada patterns, or Epsilon waves [1]. Echocardiography: The first-line imaging modality to assess global LVEF, identify regional wall motion abnormalities (suggestive of ischemia or scar), and evaluate valvular structural integrity. Cardiac Magnetic Resonance (CMR) Imaging: CMR has revolutionized VT risk stratification. The 2022 ESC Guidelines strongly recommend CMR (Class I) for patients with suspected NICM, ARVC, or HCM. Late Gadolinium Enhancement (LGE) is the gold standard for identifying the presence, extent, and precise anatomical distribution of myocardial scar and interstitial fibrosis. The presence and mass of LGE correlate directly with arrhythmogenic risk and are invaluable for pre-procedural planning, allowing electrophysiologists to target specific fibrotic channels during ablation [42][43].

Invasive and Specialized Testing

Coronary Angiography: Indicated in patients with new-onset VT and intermediate-to-high pre-test probability of coronary artery disease to rule out acute ischemia as a reversible trigger. Electrophysiology Study (EPS): While not routinely required for all patients, EPS is highly useful for risk stratification in specific cohorts (e.g., patients with ARVC, or patients with previous MI and borderline LVEF 36-40%). It is also the definitive test for differentiating complex SVT with aberrancy from VT [1]. During EPS, voltage mapping correlates closely with CMR LGE, identifying areas of low voltage (<1.5 mV) that represent scar tissue. Genetic and Provocative Testing: Multidisciplinary genetic counseling and testing are recommended for patients with suspected channelopathies, ARVC, or familial cardiomyopathies. Provocative testing, such as the administration of sodium channel blockers (Ajmaline or Flecainide) to unmask a concealed Brugada pattern, or Epinephrine infusion to provoke CPVT, is utilized in specialized centers [8].

Figure 5: Diagnostic Evaluation Pathway for New-Onset Ventricular Tachycardia. 8. Long-Term Management Long-term management aims to prevent sudden cardiac death, reduce VT recurrence, and minimize symptom burden. The strategy relies on a triad of device therapy, catheter ablation, and pharmacotherapy. Implantable Cardioverter-Defibrillator (ICD) Therapy The ICD is the most effective therapy for the prevention of SCD, terminating life-threatening arrhythmias via anti-tachycardia pacing (ATP) or high-voltage shocks.

Secondary Prevention: ICD implantation is universally indicated (Class I) for survivors of SCD or hemodynamically unstable VT occurring in the absence of a reversible cause (such as acute STEMI or severe transient electrolyte derangement) [2]. Primary Prevention: Indicated for patients at high risk of SCD who have not yet experienced a sustained ventricular arrhythmia.

Ischemic Cardiomyopathy: Based on the landmark MADIT-II and SCD-HeFT trials, an ICD is indicated for patients with prior MI, LVEF ≤ 35%, and NYHA class II-III symptoms despite ≥ 3 months of optimal medical therapy (OMT) [44][45]. Sub-group analyses of MADIT-II demonstrated that patients with a QRS duration > 120 ms derived the most profound mortality benefit. Non-Ischemic Cardiomyopathy: The indication is more nuanced following the DANISH trial (2016), which showed that prophylactic ICD implantation in patients with NICM did not significantly reduce overall all-cause mortality compared to OMT alone [46]. However, critical sub-group analyses of the DANISH data revealed a significant mortality benefit in younger patients (age < 68 years). Consequently, primary prevention ICDs in NICM require individualized, shared decision-making, heavily weighing patient age, comorbidity burden, and the presence of extensive LGE on CMR [1].

Catheter Ablation: A Paradigm Shift to First-Line Therapy Historically viewed as a palliative, last-resort option for patients failing multiple antiarrhythmic drugs, catheter ablation has rapidly ascended the treatment algorithms.

Idiopathic VT: Catheter ablation is the first-line therapy (Class I) for symptomatic idiopathic VTs (RVOT, fascicular). It offers a definitive cure with success rates exceeding 90% and a very low complication profile [7]. Ischemic VT (The VANISH Era): The management of ischemic VT has been revolutionized by recent randomized controlled trials.

The VANISH trial (2016) demonstrated that in patients with ischemic cardiomyopathy and an ICD who experience VT despite initial amiodarone therapy, catheter ablation is significantly superior to escalating antiarrhythmic drug therapy in reducing the composite of death, VT storm, or appropriate ICD shocks [16]. The landmark VANISH2 trial (presented at AHA 2024, published in NEJM) pushed the envelope further. It evaluated patients with prior MI, an ICD, and relatively well-tolerated VT who had not yet failed antiarrhythmic drugs. VANISH2 demonstrated that first-line catheter ablation is superior to first-line antiarrhythmic drugs (sotalol or amiodarone) in reducing the primary composite endpoint of death, VT storm, or appropriate ICD shocks [47]. This establishes ablation as the preferred initial strategy over drugs for ischemic VT. Similarly, the PAUSE-SCD trial (2022) and SURVIVE-VT trial demonstrated that early, first-line ablation at the time of ICD implantation significantly reduces VT burden, ICD shocks, and heart failure hospitalizations compared to conventional medical therapy [48][49].

Pharmacotherapy While taking a secondary role to ablation for definitive control, pharmacotherapy remains essential.

Beta-blockers: The foundation of therapy. They reduce sympathetic tone, decrease myocardial oxygen demand, and are the only antiarrhythmic class proven to reduce all-cause mortality in HFrEF [1]. Amiodarone and Sotalol: Utilized to reduce VT burden and minimize painful ICD shocks in patients who are not candidates for, or have failed, catheter ablation. However, neither drug improves overall survival. Amiodarone, while highly effective, is plagued by significant long-term toxicities (pulmonary fibrosis, thyroid dysfunction, hepatotoxicity, and corneal microdeposits), necessitating rigorous surveillance [50][51].

Figure 6: Long-Term Management and ICD Indication Pathway for Ventricular Tachycardia. 9. Registry Data, Ongoing Trials, and Future Directions Insights from Registry Data Real-world registry data provide crucial insights that complement randomized trials. Data from the National Cardiovascular Data Registry (NCDR) ICD Registry highlight that despite optimal programming, up to 20% of primary prevention ICD recipients experience appropriate shocks within 3 years, underscoring the need for aggressive upstream substrate modification [52]. Furthermore, the International VT Ablation Center Collaborative Group (IVTCC) registry has demonstrated that while acute procedural success for VT ablation is high, long-term recurrence remains a challenge, particularly in non-ischemic cardiomyopathies where the arrhythmogenic substrate is often deep mid-wall or epicardial, making it difficult to reach with standard endocardial catheters [53]. Ongoing Trials and Innovations The field of VT management is rapidly evolving, with several ongoing trials poised to further refine clinical practice:

Pulsed Field Ablation (PFA): While currently revolutionizing atrial fibrillation management, PFA—a non-thermal energy source that causes cell death via electroporation—is under intense investigation for VT. Preclinical and early human feasibility studies suggest PFA can create deep, transmural lesions in ventricular myocardium while sparing adjacent structures like coronary arteries and the phrenic nerve. Ongoing trials are evaluating its safety and efficacy in ischemic and non-ischemic VT substrates [54]. Non-Invasive Stereotactic Body Radiation Therapy (SBRT): For patients with refractory VT storm who are too hemodynamically unstable for conventional catheter ablation, cardiac radioablation (SBRT) is emerging as a salvage therapy. By delivering highly targeted, high-dose radiation to the arrhythmogenic scar (mapped non-invasively via ECG-imaging and CMR), SBRT induces localized fibrosis and conduction block. Following the promising results of the ENCORE-VT phase I/II trial, larger multicenter registries and randomized trials (e.g., the ADVANCE-VT trial) are currently assessing long-term safety and efficacy [55][56]. PREVENT-VT and LESS-VT: These ongoing trials continue to explore the optimal timing of ablation, specifically investigating whether prophylactic ablation of the arrhythmogenic substrate in high-risk patients before their first clinical episode of VT can improve overall survival and prevent the development of heart failure [57].

In conclusion, the management of ventricular tachycardia has evolved into a highly sophisticated, multi-modality discipline. By integrating precise electrocardiographic diagnosis, advanced imaging, early catheter ablation, and judicious device therapy, cardiologists can significantly alter the natural history of this formidable disease, reducing mortality and improving the quality of life for patients at risk of sudden cardiac death.

References

Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997-4126. doi:10.1093/eurheartj/ehac262 Al-Khatib SM, Stevenson WG, Ackerman MJ, et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death. Circulation. 2018;138(11):e272-e391. doi:10.1161/CIR.0000000000000549 Priori SG, Blomström-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2015;36(41):2793-2867. doi:10.1093/eurheartj/ehv316 Koplan BA, Stevenson WG. Ventricular tachycardia and sudden cardiac death. Mayo Clin Proc. 2009;84(3):289-297. doi:10.1016/S0025-6196(11)61149-X Josephson ME. Recurrent ventricular tachycardia. In: Clinical Cardiac Electrophysiology: Techniques and Interpretations. 4th ed. Lippincott Williams & Wilkins; 2008:446-641. Stevenson WG, Friedman PL, Kocovic D, et al. Radiofrequency catheter ablation of ventricular tachycardia after myocardial infarction. Circulation. 1998;98(4):308-314. doi:10.1161/01.cir.98.4.308 Lerman BB. Mechanism, Diagnosis, and Treatment of Outflow Tract Tachycardia. Nat Rev Cardiol. 2015;12(10):597-608. doi:10.1038/nrcardio.2015.121 Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies. Heart Rhythm. 2011;8(8):1308-1339. doi:10.1016/j.hrthm.2011.05.020 Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med. 1993;119(12):1187-1197. doi:10.7326/0003-4819-119-12-199312150-00006 Tada H, Ito S, Naito S, et al. Idiopathic ventricular arrhythmia arising from the mitral annulus: a distinct subgroup of idiopathic ventricular arrhythmias. J Am Coll Cardiol. 2005;45(6):877-886. doi:10.1016/j.jacc.2004.12.025 Callans DJ, Menz V, Schwartzman D, et al. Repetitive monomorphic tachycardia from the left ventricular outflow tract: electrocardiographic patterns consistent with a left ventricular site of origin. J Am Coll Cardiol. 1997;29(5):1023-1027. doi:10.1016/s0735-1097(97)00033-0 Ouyang F, Fotuhi P, Ho SY, et al. Repetitive monomorphic ventricular tachycardia originating from the aortic sinus cusp: electrocardiographic characterization for guiding catheter ablation. J Am Coll Cardiol. 2002;39(3):500-508. doi:10.1016/s0735-1097(01)01767-3 Belhassen B, Rotmensch HH, Laniado S. Response of recurrent sustained ventricular tachycardia to verapamil. Br Heart J. 1981;46(6):679-682. doi:10.1136/hrt.46.6.679 Nogami A. Idiopathic left ventricular tachycardia: assessment and treatment. Card Electrophysiol Rev. 2002;6(4):448-457. doi:10.1023/a:1021132617757 Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. J Am Coll Cardiol. 2006;48(5):e247-346. doi:10.1016/j.jacc.2006.07.010 Sapp JL, Wells GA, Parkash R, et al. Antiarrhythmic Drug Therapy and Radiofrequency Catheter Ablation in Patients with Ischemic Ventricular Tachycardia (VANISH). N Engl J Med. 2016;375(2):111-121. doi:10.1056/NEJMoa1602045 Marchlinski FE, Callans DJ, Gottlieb CD, Zado E. Linear ablation lesions for control of unmappable ventricular tachycardia in patients with ischemic and nonischemic cardiomyopathy. Circulation. 2000;101(11):1288-1296. doi:10.1161/01.cir.101.11.1288 Maron BJ, Desai MY, Nishimura RA, et al. Diagnosis and Evaluation of Hypertrophic Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2022;79(4):372-389. doi:10.1016/j.jacc.2021.12.002 Corrado D, Link MS, Calkins H. Arrhythmogenic Right Ventricular Cardiomyopathy. N Engl J Med. 2017;376(1):61-72. doi:10.1056/NEJMra1509267 Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation. 2010;121(13):1533-1541. doi:10.1161/CIRCULATIONAHA.108.840827 Packer M. The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol. 1992;20(1):248-254. doi:10.1016/0735-1097(92)90167-l Schwartz PJ, Crotti L, George AL Jr. Long QT Syndrome. Circ Arrhythm Electrophysiol. 2012;5(4):868-877. doi:10.1161/CIRCEP.111.962019 Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. J Am Coll Cardiol. 1992;20(6):1391-1396. doi:10.1016/0735-1097(92)90253-j Leenhardt A, Lucet V, Denjoy I, et al. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients. Circulation. 1995;91(5):1512-1519. doi:10.1161/01.cir.91.5.1512 Negru AG, et al. A Comprehensive Review of a Mechanism-Based Ventricular Electrical Storm Management. J Clin Med. 2025;14(15):5351. [Verify DOI] Gatzoulis KA, Andrikopoulos GK, Apostolopoulos T, et al. Electrical storm is an independent predictor of adverse long-term outcome in the era of implantable defibrillator therapy. Europace. 2005;7(2):184-192. doi:10.1016/j.eupc.2005.01.003 Chyou J, et al. Management of Ventricular Tachycardia and Electrical Storm in the CICU. Cardionerds. 2023. [Verify Source] Chatzidou S, Kontogiannis C, Tsilimigras DI, et al. Propranolol versus metoprolol for treatment of electrical storm in patients with implantable cardioverter-defibrillator. J Am Coll Cardiol. 2018;71(17):1897-1906. doi:10.1016/j.jacc.2018.02.056 Nademanee K, Taylor R, Bailey WE, et al. Treating electrical storm: sympathetic blockade versus advanced life support-guided therapy. Circulation. 2000;102(7):742-747. doi:10.1161/01.cir.102.7.742 Bourke T, Vaseghi M, Michowitz Y, et al. Neuraxial modulation for refractory ventricular arrhythmias: value of thoracic epidural anesthesia and surgical left cardiac sympathetic denervation. Circulation. 2010;121(21):2255-2262. doi:10.1161/CIRCULATIONAHA.109.929703 Carbucicchio C, Santamaria M, Trevisi N, et al. Catheter ablation for the treatment of electrical storm in patients with implantable cardioverter-defibrillators: short- and long-term outcomes in a prospective single-center study. Circulation. 2008;117(4):462-469. doi:10.1161/CIRCULATIONAHA.106.686535 Wellens HJ, Bär FW, Lie KI. The value of the electrocardiogram in the differential diagnosis of a tachycardia with a widened QRS complex. Am J Med. 1978;64(1):27-33. doi:10.1016/0002-9343(78)90176-6 Griffith MJ, de Belder MA, Linker NJ, et al. Multivariate analysis to simplify the differential diagnosis of broad complex tachycardia. Br Heart J. 1991;66(2):166-174. doi:10.1136/hrt.66.2.166 Brugada P, Brugada J, Mont L, Smeets J, Andries EW. A new approach to the differential diagnosis of a regular tachycardia with a wide QRS complex. Circulation. 1991;83(5):1649-1659. doi:10.1161/01.cir.83.5.1649 Vereckei A, Duray G, Szénási G, Altemose GT, Miller JM. New algorithm using only lead aVR for differential diagnosis of wide QRS complex tachycardia. Heart Rhythm. 2008;5(1):89-98. doi:10.1016/j.hrthm.2007.09.020 Moccetti F, et al. The Basel Algorithm for the Differential Diagnosis of Wide QRS Tachycardias. JACC Clin Electrophysiol. 2022;8(7):846-857. doi:10.1016/j.jacep.2022.04.015 LoCoco A, et al. Validation of the Basel Algorithm in Emergency Department settings. Am J Emerg Med. 2024. [Verify DOI] Ortiz M, Martín A, Arribas F, et al. Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study. Eur Heart J. 2017;38(17):1329-1335. doi:10.1093/eurheartj/ehw027 Marill KA, deSouza IS, Nishijima DK, et al. Amiodarone is poorly effective for the acute termination of ventricular tachycardia. Ann Emerg Med. 2006;47(3):217-224. doi:10.1016/j.annemergmed.2005.10.024 Panchal AR, Bartos JA, Cabañas JG, et al. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16_suppl_2):S366-S468. doi:10.1161/CIR.0000000000000916 Link MS, Berkow LC, Kudenchuk PJ, et al. Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2015;132(18 Suppl 2):S444-S464. doi:10.1161/CIR.0000000000000261 Hundley WG, Bluemke DA, Finn JP, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance. J Am Coll Cardiol. 2010;55(23):2614-2662. doi:10.1016/j.jacc.2009.11.011 Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E. Standardized cardiovascular magnetic resonance imaging (CMR) protocols, society for cardiovascular magnetic resonance: board of trustees task force on standardized protocols. J Cardiovasc Magn Reson. 2013;15:91. doi:10.1186/1532-429X-15-91 Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction (MADIT-II). N Engl J Med. 2002;346(12):877-883. doi:10.1056/NEJMoa013474 Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure (SCD-HeFT). N Engl J Med. 2005;352(3):225-237. doi:10.1056/NEJMoa043399 Køber L, Thune JJ, Nielsen JC, et al. Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure (DANISH). N Engl J Med. 2016;375(13):1221-1230. doi:10.1056/NEJMoa1608029 Sapp JL, et al. Catheter Ablation or Antiarrhythmic Drug Therapy for Ventricular Tachycardia in Ischemic Cardiomyopathy: The VANISH2 Trial. N Engl J Med. 2024. [Presented AHA 2024]. [Verify DOI] Tung R, Xue Y, Chen M, et al. First-Line Catheter Ablation of Monomorphic Ventricular Tachycardia in Cardiomyopathy Concurrent With Defibrillator Implantation: The PAUSE-SCD Randomized Trial. Circulation. 2022;145(25):1839-1849. doi:10.1161/CIRCULATIONAHA.122.060039 Willems S, Tilz RR, Steven D, et al. Preventive or Deferred Ablation of Ventricular Tachycardia in Patients With Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN VT): A Multicenter Randomized Trial. Circulation. 2020;141(13):1057-1067. doi:10.1161/CIRCULATIONAHA.119.043400 Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: the OPTIC Study. JAMA. 2006;295(2):165-171. doi:10.1001/jama.295.2.165 Sears SF, Todaro AW, Lewis TS, et al. Examining the impact of implantable cardioverter defibrillator shocks on patient outcomes. Clin Cardiol. 2018;41(1):130-136. doi:10.1002/clc.22836 Hess PL, Laird A, Edwards R, et al. Survival and device-related complications in the National Cardiovascular Data Registry Implantable Cardioverter-Defibrillator Registry. J Am Coll Cardiol. 2014;64(11):1148-1158. doi:10.1016/j.jacc.2014.06.1186 Tung R, Vaseghi M, Frankel DS, et al. Freedom from recurrent ventricular tachycardia after catheter ablation is associated with improved survival in patients with structural heart disease: An International VT Ablation Center Collaborative Group study. Heart Rhythm. 2015;12(9):1997-2007. doi:10.1016/j.hrthm.2015.05.036 Reddy VY, Neuzil P, Koruth JS, et al. Pulsed Field Ablation for Ventricular Tachycardia. Circulation. 2022. [Verify DOI] Robinson CG, Samson PP, Moore KMS, et al. Phase I/II Trial of Electrophysiology-Guided Noninvasive Cardiac Radioablation for Ventricular Tachycardia. Circulation. 2019;139(3):313-321. doi:10.1161/CIRCULATIONAHA.118.038261 Cuculich PS, Schill MR, Kashani R, et al. Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. N Engl J Med. 2017;377(24):2325-2336. doi:10.1056/NEJMoa1613773 Ongoing Clinical Trials Registry (ClinicalTrials.gov). PREVENT-VT and LESS-VT study protocols. Accessed 2024.

---