Cardiomyopathies

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Chapter 1: Heart failure: Causes, types, diagnosis, treatments & management

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.

TypeDescriptionEjection fraction (%)
HFREFHeart Failure with Reduced Ejection Fraction<40%
HFmrEFHeart Failure with midrange Ejection Fraction40–49%
HFPEFHeart 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 hospitalizationSurvival (%)
1 year70%
5 year60%

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 ClassPatient Symptoms
INo limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea.
IISlight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea.
IIIMarked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea.
IVUnable 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

BiomarkerThreshold for exclusion of heart failure
Chronic heart failure
NT-proBNP125 pg/mL
BNP35 pg/mL
Acute (decompensated) heart failure
NT-proBNP300 pg/mL
BNP100 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
Furosemide20–4040–240
Bumetanide0.5–1.01–5
Torasemide5–1010–20
TIAZIDES
Hydrochlorothiazide2512.5–100
Metolazone2.52.5–10
lndapamidec2.52.5–5

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, eplerenone12.5–255050100– 200
Amiloride2.555–1010–20
Triamterene2550100200

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)
Captopril6.25 × 350 × 3
Enalapril2.5 × 210–20 × 2
Lisinopril2.5–5.0 × 120–35 × 1
Ramipril2.5 × 110 × 1
Trandolapril0.5 × 14 × 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 blockerInitial dose (mg)Target dose (mg)
Bisoprolol1.25 × 110 × 1
Carvedilol3.125 × 2.25 × 2 d
Metoprolol succinate12.5–25 × 1200 × 1
Nebivolol1.25 × 110 × 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.

ARBsInitial dose (mg)Target dose (mg)
Candesartan4–8 × 132 × 1
Valsartan40 × 2160 × 2
Losartan50 × 1150 × 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)
Eplerenone25 × 150 × 1
Spironolactone25 × 150 × 1

ARNI (Sacubitril-valsartan)

Angiotensin receptor neprilysin inhibitors (ARNI)Initial dose (mg)Target dose (mg)
Sacubitril/valsartan (Entresto)49/51 × 297/103 × 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 kanalblockerareInitial dose (mg)Target dose (mg)
Ivabradine5 × 27.5 × 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 2: Echocardiography in cardiomyopathies: an overview

Definition and types of cardiomyopathies

Cardiomyopathy implies that the myocardium is structurally and functionally altered, and the pathological changes are not explained by coronary heart disease, hypertension, valvular disease or congenital heart disease. Cardiomyopathy leads to impaired cardiac function and heart failure.

There are six main types of cardiomyopathy:

Hypertrophic cardiomyopathy (HCM) — This type of cardiomyopathy is characterized by pronounced hypertrophy of the myocardium. It may also lead to obstruction of the LVOT (Hypertrophic Obstructive Cardiomyopathy, HOCM).Dilated cardiomyopathy (Dilated Cardiomyopathy, DCM).Arrhythmogenic Right Ventricular Cardiomyopathy / Dysplasia (ARVC/ARVD)Restrictive Cardiomyopathy (RCM)Takotsubo cardiomyopathy (broken heart syndrome, apical ballooning syndrome).Non-compaction cardiomyopathy

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Chapter 3: Hypertrophic Cardiomyopathy (HCM) & Hypertrophic Obstructive Cardiomyopathy (HOCM)

Hypertrophic cardiomyopathy (HCM): from pathophysiology to echocardiography

Hypertrophic cardiomyopathy is a genetic disorder that causes left ventricular hypertrophy under normal loading conditions. Hypertrophic cardiomyopathy should not be confused with hypertrophy caused by increased loading conditions. Increased ventricular load is mostly caused by systemic hypertension or aortic stenosis. In hypertension, the increased systemic resistance makes it more difficult for the ventricle to eject blood into the aorta during systole. In aortic stenosis, there is increased resistance in the aortic valve itself, due to the reduced area of the valvular orifice. Both aortic stenosis and hypertension result in increased ventricular load, which the ventricle counteracts by developing hypertrophy.

Hypertrophic cardiomyopathy implies left ventricular hypertrophy under normal loading conditions.

Recommended reading– Ventricular Pressure-Volume Relationship: Preload, Afterload, Stroke Volume, Wall Stress & Frank-Starling’s law– Myocardial Mechanics

It is fundamental to distinguish hypertrophic cardiomyopathy from hypertrophy caused by increased loading conditions. The latter is far more common and the conditions may coexist. A significant percentage of the population has hypertension, and aortic stenosis is also more common than hypertrophic cardiomyopathy (especially among elderly). Patient characteristics and the degree of hypertrophy can be used to distinguish hypertrophic cardiomyopathy from hypertrophy caused by loading conditions. In the presence of increased loading conditions, one should suspect hypertrophic cardiomyopathy if the degree of hypertrophy is disproportional to the load (i.e., if hypertrophy is more pronounced than the load could reasonably explain). The probability of hypertrophic cardiomyopathy is inversely related to age, such that the younger the patient presenting with hypertrophy, the more likely a genetic etiology.

The genetic mechanisms underlying hypertrophic cardiomyopathy are complicated and some gene variants may only cause hypertrophy under certain loading conditions (i.e in the presence of increased load). Thus, some cases of hypertrophic cardiomyopathy may be the result of a disproportionate response to increased ventricular loading.

The presence of systemic hypertension or aortic stenosis does not rule out hypertrophic cardiomyopathy.

Epidemiological aspects of hypertrophic cardiomyopathy (HCM)

Hypertrophic cardiomyopathy is equally common among men and women. The prevalence in a Western population is approximately 0.2%. Hypertrophic cardiomyopathy is one of the most common causes of cardiac arrest and sudden cardiac death (SCD) among young individuals. Among athletes, hypertrophic cardiomyopathy is the most common cause of sudden cardiac death. Therefore, current screening recommendations for athletes emphasize on measures to detect hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is the most common cause of sudden cardiac death among athletes, and one of the most common causes of sudden cardiac death among young individuals.

Echocardiography in hypertrophic cardiomyopathy (HCM)

The hypertrophy is generally asymmetric, i.e its distribution in the left ventricular myocardium varies. Septal hypertrophy, apical hypertrophy and hypertrophy of the left ventricular free wall are common. General hypertrophy is less common.

Hypertrophic cardiomyopathy causes concentric hypertrophy

Hypertrophic cardiomyopathy causes concentric hypertrophy, which means that the generated myocardium allocates space in the ventricular cavity. In concentric hypertrophy, left ventricular volume is reduced, which means that the ejection fraction (EF) must increase to produce sufficient stroke volumes (Figure 1). Although the ventricular volume is reduced by concentric hypertrophy, it may still be normal when compared to reference values.

Figure 1. Types of left ventricular hypertrophy. Left ventricular volume is reduced in concentric hypertrophy. Eccentric hypertrophy results in increased ventricular volume.

The opposite of concentric hypertrophy is eccentric hypertrophy, which is common among athletes. Eccentric hypertrophy is characterized by hypertrophy of the outer myocardial layers, which does not reduce left ventricular volume. Athletes typically exhibit increased ventricular volume and slightly reduced ejection fraction. The athlete’s heart is capable of maintaining cardiac output at lower ejection fractions due to the fact that they generate large stroke volumes.

Definition of hypertrophic cardiomyopathy

To diagnose hypertrophic cardiomyopathy, the following two measurements are made in the parasternal long-axis view (PLAX) or parasternal short-axis view (PSAX):

Septal thickness

Inferolateral wall thickness

If either exceeds 15 mm, there is hypertrophy. If the hypertrophy is not explained adequately by hypertension or aortic stenosis, hypertrophic cardiomyopathy is likely.

Athletes often display pronounced physiological hypertrophy, which can be difficult to differentiate from cardiomyopathy. Likewise, storage disorders and mitochondrial diseases can cause wall thickening, which may be difficult to differentiate from hypertrophic cardiomyopathy. The following features can be used to distinguish cardiomyopathy from the differential diagnoses:

A hyperdynamic left ventricle suggests cardiomyopathy.

Severe septal hypertrophy suggests cardiomyopathy.

Obstruction in LVOT suggests cardiomyopathy.

A small left ventricle suggests cardiomyopathy.

Table 1 presents a comprehensive list of conditions that may mimic HCM/HOCM (adapted from Marian et al [1]).

Table 1. Phenocopy Conditions for Hypertrophic Cardiomyopathy

Phenotype

Phenotypic Clue

AMPK-mediated glycogen storage

Normal or reduced left ventricular systolic function, pre-excitation pattern

Pompe disease

Autosomal recessive, multiorgan disease, pre-excitation pattern

Anderson–Fabry disease

X-linked, multisystem also involving skin, kidney, and peripheral nerves

Danon disease

X-linked dominant, proximal muscle weakness, intellectual disability, short PR on ECG, elevated CK levels

Amyloidosis

Low QRS voltage, other organ involvement, subendothelial LGE

Kearns–Sayre syndrome

Multisystem disease

Friedreich ataxia

Autosomal recessive, neurodegeneration

Myotonic dystrophy

Myotonia, muscular dystrophy, cataract, and frontal baldness

Noonan/LEOPARD syndromes (rasopathies)

Congenital heart defects, lentigines, Café-au-lait spots

Neimann–Pick disease

Autosomal recessive neurodegenerative disease

Refsum disease

Retinitis pigmentosa, peripheral neuropathy, and ataxia

Deafness

Autosomal dominant deafness

CK = creatine kinase; LGE late gadolinium enhancement.

Hypertrophic obstructive cardiomyopathy (HOCM)

In hypertrophic cardiomyopathy, it is important to clarify whether the hypertrophy causes a narrowing of the left ventricular outflow tract (LVOT). Approximately 65% of patients with hypertrophic cardiomyopathy have obstruction in LVOT, a condition referred to as hypertrophic obstructive cardiomyopathy (HOCM).

HOCM with systolic anterior motion (SAM)

The obstruction in LVOT is caused by septal hypertrophy. When the septum bulges into the LVOT, hemodynamics change in the outflow tract, which leads to the anterior leaflet of the mitral valve being sucked into the LVOT. As a result, the outflow tract is obstructed. The motion of the anterior leaflet of the mitral valve is called systolic anterior motion (SAM). Thus, obstruction of the LVOT is due to hypertrophy of the septum and subsequent SAM (Figure 2).

Figure 2. Systolic anterior motion (SAM) of the anterior leaflet of the mitral valve causes obstruction of the LVOT. SAM is typically accompanied by mitral regurgitation (MR), with posteriorly directed jet. CW = continuous wave doppler.

If SAM is pronounced, the anterior leaflet may touch the septum during systole. Subsequently, a pronounced obstruction can lead to closure or flutter of the aortic valve during systole.

Mitral regurgitation is a byproduct of SAM (Figure 2).

Figure 3. Continuous wave (CW) doppler in the LVOT in (A) obstruction due to SAM and septal hypertrophy and (B) aortic stenosis.

Continuous wave (CW) doppler is used to detect obstruction in the LVOT (Figures 2 & 3). The spectral curve is characterized by a slow acceleration, which distinguishes it from the Doppler signal in aortic stenosis (Figure 3).

Note that SAM typically causes the mitral valve regurgitation jet to involve the LVOT. It is important to place the Doppler cursor correctly in the LVOT in order to avoid unintentional recording of the mitral valve regurgitation jet. Video 1 shows HOCM with SAM.

Video 1. HOCM with SAM.

Obstruction in the LVOT is affected by left ventricular filling. The less the filling, the more pronounced the obstruction. This implies that hypovolemia and tachycardia (both lead to diminished ventricular filling) cause increased obstruction in the LVOT. Valsalva maneuver also reduces left ventricular filling (obstruction in LVOT can be provoked by performing Valsalva maneuver).

SAM causes mitral regurgitation (MR)

As mentioned above, hypertrophic cardiomyopathy with SAM is generally accompanied by mitral valve regurgitation (MR) with a posteriorly directed jet.

Apical and midventricular hypertrophy

In midventricular hypertrophy, obstruction may be observed midventricularly, which is detected using continuous wave (CW) Doppler (Figure 4A). In apical hypertrophy, thickened myocardium is seen in the apex. This gives the cavity a pointed appearance, as demonstrated in Figure 4B. Patients with apical hypertrophic cardiomyopathy exhibit T-wave inversion in the precordial leads (V1-V6) on ECG.

Figure 4. Apical and midventricular hypertrophic cardiomyopathy.

ECG 1. ECG in hypertrophic obstructive cardiomyopathy (HCM, HOCM)

Diastolic function in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy leads to impaired diastolic function, i.e the relaxation of the left ventricle is impaired, resulting in prolonged deceleration time (DT) and reduced E/A ratio. The deceleration time is prolonged because it takes longer to equalize the pressure difference between the left atrium and the ventricle. This is explained by the fact that left ventricular compliance is reduced in hypertrophic cardiomyopathy.

Sudden Cardiac Death (SCD) in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is one of the most common causes of sudden cardiac arrest among young people. Cardiac arrest can strike any individual with hypertrophic cardiomyopathy. It should be noted, however, that the incidence of sudden cardiac arrest is very low among people with HCM/HOCM.

Patients with hypertrophic cardiomyopathy who have experienced circulatory arrest or malignant ventricular arrhythmias are unlikely to benefit from beta-blockers or antiarrhythmic drugs. The most effective treatment is an ICD (Implantable Cardioverter Defibrillator). Table 2 shows risk factors for cardiac arrest in hypertrophic cardiomyopathy.

Table 2. Risk factors for sudden cardiac arrest in cardiomyopathy

Known riskfactors
Previous cardiac arrest (“aborted SCD”)
Family history of sudden cardiac arrest
Previous syncope
History of ventricular tachycardia
Severe hypertrophy
Probable riskfactors
LVOT obstruction
Abnormal blood pressure reaction during exercise
Early onset of symptoms

Pitfalls

SAM also occurs in individuals who do not have HOCM. Individuals who have left ventricular hypertrophy may develop SAM in the setting of hypovolemia.

Below follows supplementary material intended for readers interested in the genes causing HCM. Refer to Marian et al for details (1).

Established causal genes for HCM

Established causal gene HCM (large families)

Gene Protein

Function MYH7 β-Myosin heavy chain ATPase activity, force generation MYBPC3 Myosin-binding protein C Cardiac contractionTNNT2 Cardiac troponin T Regulator of actomyosin interaction TNNI3 Cardiac troponin I

Inhibitor of actomyosin interaction TPM1 α-Tropomyosin

Places the troponin complex on cardiac actin ACTC1 Cardiac α-actin

Actomyosin interaction MYL2 Regulatory myosin light chain

Myosin heavy chain 7–binding protein MYL3 Essential myosin light chain

Myosin heavy chain 7–binding protein CSRP3 Cysteine- and glycine-rich protein 3

Muscle LIM protein (MLP), a Z disk protein

Likely causal genes for HCM (small families)

Gene

Protein

Function FHL1 Four-and-a-half LIM domains 1

Muscle development and hypertrophy MYOZ2 Myozenin 2 (calsarcin 1)

Z disk protein PLN Phospholamban

Regulator of sarcoplasmic reticulum calcium TCAP Tcap (telethonin)

Titin capping protein TRIM63 Muscle ring finger protein 1

E3 ligase of proteasome ubiquitin system TTN Titin

Sarcomere function

Genes associated with HCM (small families and sporadic cases)

ACTN2 Actinin, α2

Z disk protein ANKRD1 Ankyrin repeat domain 1

A negative regulator of cardiac genes CASQ2 Calsequestrin 2

Calcium-binding protein CAV3 Caveolin 3

A caveolae protein JPH2 Junctophilin-2

Intracellular calcium signaling LDB3 Lim domain binding 3

Z disk protein MYH6 Myosin heavy chain α

Sarcomere protein expressed at low levels in the adult human heart MYLK2 Myosin light chain kinase 2

Phosphorylate myosin light chain 2 NEXN Nexilin

Z disc protein TNNC1 Cardiac troponin C

Calcium-sensitive regulator of myofilament function VCL Vinculin

Z disk protein

References

Marian et al – Hypertrophic Cardiomyopathy Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy (2017).

Chapter 4: Dilated Cardiomyopathy (DCM): Definition, Types, Diagnostics & Treatment

Dilated cardiomyopathy (DCM)

Dilated cardiomyopathy (DCM) is defined as dilation of one or both ventricles. Dilation of the left ventricle is virtually always accompanied by impaired left ventricular systolic function. It should be noted that several types of cardiomyopathies (e.g ischemic cardiomyopathy, tachycardia-induced cardiomyopathy, diabetic cardiomyopathy, etc.) may ultimately lead to ventricular dilation. However, the term dilated cardiomyopathy (DCM) refers to idiopathic or genetic dilation of the left ventricle. Patients with DCM typically develop heart failure early in life and a family history of heart failure, ventricular arrhythmias or sudden cardiac arrest is common.

The following cardiomyopathies lead to dilation of the ventricle:

Dilated cardiomyopathy (DCM) – Idiopathic or genetic.Ischemic cardiomyopathyAlcoholic cardiomyopathyDiabetic cardiomyopathyTakotsubo cardiomyopathy Tachycardia-induced cardiomyopathyNon-compaction cardiomyopathyPeripartum cardiomyopathyCardiomyopathy secondary to valvular heart disease

Long-term prognosis varies markedly across these conditions. The prognosis in idiopathic dilated cardiomyopathy may be poorer than the prognosis for most cancers, whereas tachycardia-induced cardiomyopathy can be cured completely by restoring sinus rhythm. Dilated cardiomyopathy is currently the most common indication for heart transplantation.

Echocardiography can not distinguish different types of dilated cardiomyopathy. Other causes of ventricular dilation (e.g ischemic cardiomyopathy) must be excluded before establishing a diagnosis of DCM. Patient characteristics, clinical features, family history and genetic testing are important clues in the investigation. Additional examinations (e.g coronary angiography, cardiac MRI) are frequently necessary.

Ischemic cardiomyopathy should be suspected if there is significant stenosis (>75% luminal obstruction) of the left main coronary artery (LAD) or >2 epicardial coronary arteries (Felker et al).

Left ventricular dilation entails a markedly elevated risk of ventricular tachycardia and cardiac arrest, regardless of the underlying cause of the dilation. The only exception to this rule is ventricular dilation secondary to non-compaction cardiomyopathy, which confers only slightly elevated risk of ventricular arrhythmias (Almeida et al).

Genes and DCM

Approximately 40% of all cases of DCM are genetic. Thus, a family history with early onset of heart failure is common among these individuals. The majority of the mutations are inherited in an autosomal dominant manner with variable penetrance and expressivity. Autosomal recessive, X-linked recessive, and mitochondrial forms occur, albeit less frequently (McNally et al).

Screening of family members is justified, including a 12-lead ECG, echocardiography, clinical examination and a pedigree. Studies show that approximately 30% of family members will exhibit signs of dilated cardiomyopathy (Burkett et al).

More than 100 genes have been implicated in dilated cardiomyopathy. The majority of these encode proteins in the sarcomere, Z disk or the cytoskeleton (Herschberger et al). De novo mutations are less common than inherited mutations. Clearly, not all DCM genes have been discovered.

Genetic testing for DCM

Genetic testing of patients with confirmed or likely dilated cardiomyopathy can be recommended. There are several commercially available gene panels, which enables testing of over 100 genes.

Absence of known mutations defines the condition as idiopathic dilated cardiomyopathy.

Echocardiography in dilated cardiomyopathy (DCM)

In dilated cardiomyopathy (DCM), both ventricles are dilated and left ventricular systolic function is impaired (i.e ejection fraction is reduced).Left ventricular diastolic function may be normal or exhibit a restrictive pattern (increased E/A ratio and rapid deceleration time; see Diastolic function). Left ventricular wall thickness may be normal, but since the ventricle is enlarged, the ventricular mass is always increased.Myocardial contractile function is globally impaired (i.e general hypokinesia exists). Regional wall motion abnormality can be seen in the septum in the setting of left bundle branch block.Although the ejection fraction is reduced in DCM, stroke volume may be normal due to the large ventricular volume. Symptoms may, therefore, not manifest until advanced stages of cardiomyopathy, when stroke volume is declining.Ventricular dilation leads to dilation of the mitral annulus and tricuspid annulus, resulting in mitral regurgitation and tricuspid regurgitation. Pronounced ventricular dilation and impaired contractility lead to slow blood flow in the ventricular cavity. This may result in spontaneous echo contrast and the appearance of thrombi in the ventricle.

Stroke volume is generally normal in early stages of DCM. Progressive impairment of contractility leads to gradually diminishing stroke volumes and progression of heart failure symptoms.

ECG in dilated cardiomyopathy (DCM)

The ECG may be completely normal in early stages of DCM. Patients presenting with abnormal ECG during the early stages of the disease may display the following changes:

Signs of left ventricular hypertrophy (LVH)Nonspecific ST-T changesLeft bundle branch block (LBBB)Nonspecific intraventricular conduction delay (IVCD)

Advanced stages of DCM may present with the following ECG changes:

Low voltage (low R wave amplitudes), which indicates widespread myocardial fibrosis and hypokinesia.Pathological Q waves may be due to DCM, but is more likely to be caused by myocardial infarction (i.e ischemic cardiomyopathy).

AV blocks suggest genetic DCM or inflammatory systemic diseases (sarcoidosis, Lyme disease, giant cell myocarditis).

Arrhythmias in DCM

Life-threatening ventricular arrhythmias are common in patients with DCM. Some patients, notably those with LMNA mutations, exhibit a very high risk of ventricular arrhythmias. DCM presenting with syncope, nonsustained ventricular tachycardia, frequent premature ventricular contractions is referred to as arrhythmogenic DCM. The risk of sudden cardiac arrest and sustained ventricular tachycardia is high among these individuals, regardless of the severity of left ventricular dysfunction. Also, a family history of ventricular arrhythmias predicts a high risk of arrhythmogenic DCM.

Patients with evidence of ventricular arrhythmias and confirmed LMNA mutation should receive an ICD according to ESC (Priori et al) and HRS/AHA/ACC guidelines (Kusumoto et al).

Other specific forms of dilated cardiomyopathy

Alcohol cardiomyopathy (cardiomyopathy caused by alcohol)

Regular alcohol consumption >80 g/day for more than 5 years confers a high risk of developing dilated cardiomyopathy (Fauchier et al). High alcohol consumption is presumably a common cause of ventricular dilation. There are large individual variations regarding the amount of alcohol required to cause cardiomyopathy, but in most cases, several years of high consumption is required before overt cardiomyopathy develops.

Alcohol affects multiple mechanisms in the myocardial cell (e.g ATP production, electromechanical coupling, calcium sensitivity, membrane potential, etc.). Alcohol may also directly cause inflammation and apoptosis (Maisch et al).

Alcohol cardiomyopathy causes dilation of both the left and right ventricle, making it difficult to distinguish from dilated cardiomyopathy. As a rule, the ejection fraction is < 45%.

Cardiomyopathy caused by diabetes: Diabetic cardiomyopathy

In recent years, it has become increasingly clear that people with diabetes may develop heart failure in the absence of traditional risk factors for heart failure (hypertension, valvular heart disease, ischemic heart disease, myocardial infarction, etc.). People with type 1 diabetes have up to 10 times increased risk of heart failure (Rawshani et al; Lind et al). Among people with type 2 diabetes, the risk may be up to 5 times, as compared with people without diabetes (Lind et al).

However, the mechanisms causing heart failure in individuals with diabetes remain elusive. Most studies have focused on hyperglycemia and demonstrated strong associations between HbA1c and the risk of heart failure. Interested readers refer to Sattar et al.

Diabetic cardiomyopathy is characterized by myocardial fibrosis, remodeling and diastolic dysfunction. Diastolic dysfunction appears to be the hallmark of the diabetic heart. Approximately 50% of all cases of heart failure among individuals with diabetes consist of heart failure with preserved ejection fraction (HFPEF), and the majority of people with diabetes exhibit diastolic dysfunction. Left ventricular hypertrophy is also common in the early stages of diabetic cardiomyopathy (Jia et al). Systolic dysfunction (i.e reduced ejection fraction) usually develops later, as does ventricular dilation.

Diabetic cardiomyopathy with reduced ejection fraction is managed according to guidelines for heart failure with reduced ejection fraction (HFREF).

There are no evidence-based interventions for diabetic cardiomyopathy with preserved ejection fraction (HFPEF), although multiple clinical trials are underway.

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Chapter 5: Arrhythmogenic Right Ventricular Cardiomyopathy / Dysplasia (ARVC, ARVD)

Arrhythmogenic Right Ventricular Cardiomyopathy / Dysplasia (ARVC, ARVD)

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is considered a genetic cardiomyopathy that predominantly affects the right ventricle. ARVC is defined by the gradual loss of myocardial cells, which are replaced by fat and fibrous tissue. This process begins in the epicardium and gradually moves towards the endocardium. As the fibrofatty replacement progresses, the ventricular wall becomes thinner and the ventricle begins to dilate. Approximately 50% of cases exhibit biventricular cardiomyopathy, although the disease is less pronounced in the left ventricle. Rarely the condition is confined to the left ventricle. ARVC causes ventricular tachycardia and sudden cardiac arrest; the disease is one of the most common causes of sudden cardiac arrest among adolescents and athletes (hypertrophic cardiomyopathy is the most common cause).

Genetic mutations in ARVC

At least 13 genes have been implicated in ARVC. The majority of these are genes encoding desmosomal proteins. The desmosome is a component of the intercalated disc that connects myocardial cells mechanically and electrically. Most mutations are inherited in an autosomal dominant manner, with variable penetrance and expressivity. Recessive forms exist, although they are rare (Naxos disease, Carvajal syndrome). The prevalence of ARVC is between 0.02 and 0.05% in Europe (Corrado et al). ARVC is more malignant in men, the reason for which remains elusive.

Gene mutations can be confirmed in roughly 60% of individuals with ARVC. Mutations in the desmosomal gene PKP2 is the most common. Mutations in non-desmosomal genes are less common. The following genes are associated with ARVC:

CTNNA3

DES

DSC2

DSG2

DSP

JUP

LMNA

PKP2

PLN

RYR2

TGFB3

TMEM43

TTN

Clinical characteristics of ARVC

ARVC is typically concealed (asymptomatic) during childhood and adolescence and becomes symptomatic between the second and fourth decades of life. Likewise, the right ventricle may appear functionally and morphologically normal on echocardiography and cardiac MRI during the first two decades of life.

The most common initial presentation is palpitations or syncope. ARVC can, however, cause ventricular tachycardia, which may degenerate into ventricular fibrillation at any age. Exercise, or any other activity causing adrenergic stimulation, increase the risk of syncope, ventricular arrhythmias and sudden cardiac arrest.

ARVC can cause ventricular tachycardia, ventricular fibrillation and sudden cardiac arrest at any age. Palpitations, syncope or cardiac arrest–particularly during physical activity–in a young adult with T-wave inversions in V1–V4, or other ECG changes (see below) should lead to a suspicion of ARVC.

The gradual loss of myocardium leads to ventricular dilation and right heart failure. Biventricular heart failure is less common.

ECG in ARVC

T-wave inversion in the lead V1 through V4.

Epsilon wave, a late depolarization/potential occurring between the end of the QRS complex and the beginning of the T wave, in leads V1 and V2 (Figure 1).

Terminal activation duration (TAD), defined as the interval between the nadir (lowest point) of the S-wave and the end of the depolarization, is prolonged (>55 ms in V1-V2). Refer to Figure 2.

Epsilon wave and prolonged TAD strongly suggests ARVC.

Low limb lead voltage.

Patients with ARVC display frequent premature ventricular contractions (PVC), which may advance to monomorphic ventricular tachycardia (VT).

Ventricular tachycardia in ARVC has LBBB morphology, with negative T-waves in V1 through V4.

PVCs and ventricular tachycardia can be provoked by physical any adrenergic stimulation, e.g physical activity.

Figure 1. Epsilon wave and TAD on the electrocardiogram.

Echocardiography in ARVC

Echocardiography shows global right ventricular dilation. The left ventricle and the septum are generally spared. Regional wall-motion abnormalities–i.e hypokinesia, dyskinesia and kinesia–may also be seen. With pronounced fibrofatty replacement, ventricular aneurysm develops.

Since echocardiography is insufficient for visualization of the right ventricle, cardiac magnetic resonance imaging (MRI) is the preferred imaging technique. Estimation of the degree of fibrofatty replacement is possible using late gadolinium enhancement.

Differential diagnoses to ARVC

Idiopathic RVOT-VT (ventricular tachycardia originating from RVOT).

Sarcoidosis.

Congenital heart disease with right ventricular load.

Diagnostic criteria for ARVC

The diagnosis is based on clinical data, ECG, genetic analyzes and cardiac MRI. Current criteria (endorsed by ESC, AHA, ACC) use major and minor criteria, divided into 6 categories. Based on the findings, the likelihood of ARVC can be graded as possible, borderline or definitive:

Definitive ARVC: 2 major, or 1 major and 2 minor, or 4 minor from different categories

Borderline ARVC: 1 major and 1 minor, or 3 minor from different categories.

Possible ARVC: 1 major, or 2 minor from different categories

Table 1. Criteria for ARVC

Categories are numbered from 1 to 6.

CATEGORY 1: Global or regional dysfunction and structural alteration†

2D echocardiography

Major criteria: Regional RV akinesia, dyskinesia, or aneurysm and one of the following (end-diastole): PLAX RVOT ≥32 mm (≥19 mm per square meter when corrected for body surface area), PSAX RVOT ≥36 mm (≥21 mm per square meter when corrected for body surface area), or fractional area change of ≤33%.

Minor criteria: Regional RV akinesia or dyskinesia and one of the following (end-diastole): PLAX RVOT 29 to <32 mm (16 to <19 mm per square meter when corrected for body surface area), PSAX RVOT 32 to <36 mm (18 to <21 mm per square meter when corrected for body surface area), or fractional area change of 34 to 40%.

MRI (Magnetic Resonance Imaging)

Major criteria: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following: ratio of RV end-diastolic volume to body surface area ≥110 ml per square meter (male patients) or ≥100 ml per square meter (female patients), or RV ejection fraction ≤40%.

Minor criteria: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and one of the following: ratio of RV end-diastolic volume to body-surface area 100 to <110 ml per square meter (male patients) or 90 to <100 ml per square meter (female patients), or RV ejection fraction 41 to 45%.

Right ventricular angiography

Major criteria: Regional RV akinesia, dyskinesia, or aneurysm.

CATEGORY 2: Tissue characterization

Major criteria: <60% residual myocytes on morphometric analysis (or <50%, if estimated) and fibrous replacement of the RV free-wall myocardium, with or without fatty replacement of tissue, in at least one endomyocardial- biopsy sample.

Minor criteria: 60 to 75% residual myocytes, on morphometric analysis (or 50 to 65%, if estimated) and fibrous replacement of the RV free-wall myocardium, with or without fatty replacement of tissue, in at least one endomyocardial-biopsy sample.

CATEGORY 3: Repolarization abnormalities

Major criteria: Inverted T waves in right precordial leads (V1, V2, and V3) or beyond in patients older than 14 yr of age (in the absence of complete right bundle-branch block, QRS ≥120 msec).

Minor criteria: Inverted T waves in leads V1 and V2 in patients older than 14 yr of age (in the absence of complete right bundle-branch block) or in V4, V5, or V6; inverted T waves in leads V1, V2, V3, and V4 in patients older than 14 yr of age (in the presence of complete right bundle-branch block).

CATEGORY 4: Depolarization & conduction abnormalities

Major criteria: Epsilon wave (reproducible low-amplitude signals from end of QRS complex to onset of the T wave) in the right precordial leads (V1, V2, and V3).

Minor criteria: Late potentials on signal-averaged ECG in at least one of three parameters in the absence of a QRS complex duration of ≥110 msec on the standard ECG; filtered QRS complex duration, ≥114 msec; duration of terminal QRS complex <40 μV (low-amplitude signal duration), ≥38 msec; root-mean-square voltage of terminal 40 msec, ≤20 μV; terminal activation duration of QRS complex, ≥55 msec, measured from the nadir of the S wave to the end of the QRS complex, including R′, in V1, V2, or V3, in the absence of complete right bundle-branch block.

CATEGORY 5: Arrhythmias

Major criteria: Nonsustained or sustained ventricular tachycardia with a left bundle branch block and superior axis pattern (negative or indeterminate QRS complex in leads II, III, and aVF and positive QRS complex in lead aVL).

Minor criteria: Nonsustained or sustained ventricular tachycardia of RV outflow configuration with a left bundle-branch block and inferior axis pattern (positive QRS complex in leads II, III, and aVF and negative QRS complex in lead aVL) or unknown axis, or >500 ventricular extrasystoles per 24 hr (on Holter monitoring).

CATEGORY 6: Family history

Major criteria: ARVC confirmed in a first-degree relative who meets current taskforce criteria, ARVC confirmed pathologically at autopsy or surgery in a first-degree relative, or identification of a pathogenic mutation categorized as associated or probably associated with ARVC in the patient under evaluation‡.

Minor criteria: History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether current task-force criteria are met, premature sudden death (at <35 yr of age) due to suspected ARVC in a first-degree relative, or ARVC confirmed pathologically or by current task-force criteria in a second-degree relative.

Table adapted from Marcus et al.

The diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is considered to be definite if the patient meets two major criteria, one major and two minor criteria, or four minor criteria from different categories; the diagnosis is considered to be borderline if the patient meets one major and one minor criteria or three minor criteria from different categories, and the diagnosis is classified as possible if the patient meets one major or two minor criteria from different categories. ECG denotes electrocardiogram, PLAX parasternal long-axis view, PSAX parasternal short-axis view, RV right ventricular, and RVOT RV outflow tract.

† Hypokinesia is not included in this or subsequent definitions of RV regional wall-motion abnormalities for the proposed modified criteria. ‡ A pathogenic mutation is a DNA alteration associated with ARVC that alters or is expected to alter the encoded protein, is unobserved or rare in a large, non-ARVC control population, and either alters or is predicted to alter the structure or function of the protein or has shown linkage to the disease phenotype in a conclusive pedigree (i.e., a pedigree providing conclusive evidence of a mendelian inheritance of the disease phenotype).

Treatment of ARVC

Treatment of ARVC is primarily focused on preventing sudden cardiac arrest. There are no randomized controlled clinical trials to support the use of antiarrhythmic drugs. Beta-blockers lack antiarrhythmic effects but are still prescribed to most patients with ARVC due to their ability to reduce the effect of adrenergic stimulation in the heart. An ICD should be considered in patients who have experienced syncope, left ventricular dysfunction or risk factors for sudden cardiac arrest. Right heart failure is managed as HFREF (heart failure with reduced ejection fraction).

Chapter 6: Tachycardia induced cardiomyopathy

Cardiomyopathy caused by tachycardia

A prolonged tachycardia can cause cardiomyopathy with left ventricular dilation. This type of cardiomyopathy, referred to as tachycardia-induced cardiomyopathy, can be caused by any tachyarrhythmia leading to prolonged periods of rapid ventricular rate (Table 1). Children and healthy adults may also develop tachycardia-induced cardiomyopathy (Gopinnathair et al). Long-term prognosis is excellent, with the vast majority of patients recovering completely after restoration of sinus rhythm (or any other rhythm with normal ventricular rate and activation). Recovery may, however, take several months.

Table 1. Arrhythmias causing tachycardia-induced cardiomyopathy

SUPRAVENTRICULAR ARRHYTHMIAS
Atrial fibrillation
Atrial flutter
Atrial tachycardia
AV nodal reentrant tachycardia (AVNRT)
AV re-entrant tachycardia (AVRT)
Permanent junctional reciprocating tachycardia (PJRT)
Junctional Ectopic Tachycardia (JET)
VENTRICULAR ARRHYTHMIAS
Ventricular tachycardia
Fascicular tachycardia
FREQUENT ECTOPY
Premature ventricular contractions (PVC)
Premature atrial contractions (PAC)
PACEMAKER RELATED
Pacing with rapid ventricular response rate

The incidence of tachycardia-induced cardiomyopathy is 8–10% among patients with atrial tachycardia (Medi et al, Ju et al). The corresponding figure in children is 28% (Kang et al). The incidence is 10–34% among patients with premature ventricular contractions and/or nonsustained ventricular tachycardia who are referred for electrophysiological evaluation (Hasdemir et al, Kawamura et al, Yokokawa et al).

Tachycardia-induced cardiomyopathy is presumably the main cause of left ventricular dysfunction among patients with atrial fibrillation and other supraventricular tachyarrhythmias. Moreover, ventricular tachyarrhythmias (including recurrent episodes of ventricular tachycardia) can also cause this cardiomyopathy.

The duration of the tachyarrhythmia appears to be a stronger risk factor than the ventricular rate. The longer the duration of the tachyarrhythmia, the greater the risk of cardiomyopathy.

Pathophysiology

Prolonged tachyarrhythmias lead to the following hemodynamic effects:

Tachyarrhythmia results in reduced preload, diminished stroke volume, and subsequently lower blood pressure and reduced organ perfusion.

Left ventricular dilation occurs with ensuing decline in left ventricular ejection fraction (LVEF). This is accompanied by myocardial remodeling.

The remodeling is accompanied by diminishing myocardial contractile function.

Central venous pressure, pulmonary capillary wedge pressure and systemic vascular resistance increases.

Harmful neurohormonal pathways are activated, similar to those seen in heart failure.

A thorough review on the pathophysiology of tachycardia-induced cardiomyopathy is provided by Gopinnathair et al.

All tachyarrhythmias can cause cardiomyopathy. This also applies to frequent premature ventricular contractions (PVC). As a rule, >20000 PVCs/day is required to cause cardiomyopathy.

Management is aimed at restoring normal rhythm. If restoration of sinus rhythm is not possible, attempts must be made to normalize ventricular rate and activation. Elimination of the tachyarrhythmia generally resolves the symptoms and reverses left ventricular dysfunction and dilation. The prognosis is excellent, with the majority of patients recovering fully.

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