Myocardial Ischemia & Infarction

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Chapter 1: Introduction to Coronary Artery Disease (Ischemic Heart Disease)

Coronary artery disease, which is synonymous with ischemic heart disease, is the most common form of cardiovascular disease. It has been the number one killer in Western and high-income countries for more than half a century, causing approximately 20% of all deaths in these regions. Mortality rates and case fatality in coronary artery disease peaked in the 1970s and have declined steadily ever since. The marked decline in death rates and case fatality is most likely explained by successful primary preventive strategies, such as reduced smoking rates, aggressive lowering of blood lipids with statins and sophisticated treatments for hypertension. However, coronary artery disease remains the number one killer in most regions worldwide (Tsao et al.). The New England Journal of Medicine, 1812. Remarks on Angina Pectoris by John Warren The remarkable facts, that the paroxysm, or indeed the disease itself, is excited more especially upon walking up hill, and after a meal; that thus excited, it is accompanied with a sensation, which threatens instant death if the motion is persisted in; and, that on stopping, the distress immediately abates, or altogether subsides; have . . . formed a constituent part of the character of Angina Pectoris. Atherosclerosis: the cause of coronary artery disease The underlying cause is atherosclerosis, which is a chronic inflammatory disease of the arteries. It has become increasingly clear in the past few decades that atherosclerosis is not caused by the passive deposition of lipids into the coronary artery walls; indeed, atherosclerosis is a disease in which the immune system elicits an active inflammation within the artery wall and lipids (particularly LDL cholesterol) plays a key role. As the inflammation and deposition of lipids progress, an atherosclerotic plaque forms in the wall of the artery. Such atherosclerotic plaques start building up early in childhood and by middle age, most persons have some degree of atherosclerosis in the coronary arteries. Advanced atherosclerotic plaques contain inflammatory cells, smooth muscle cells, extracellular matrix, lipids and acellular debris. The interplay between inflammation and risk factors (smoking, hypertension, hyperlipidemia, diabetes, etc) modifies the progression rate in the atherosclerotic plaque. The more inflammation and more risk factors, the more aggressive atherosclerosis. Moreover, inflammation and risk factors also modify the risk of destabilization of the plaque. Atherosclerotic plaques are vulnerable and may disrupt, which may ultimately lead to death (Stone, Libby et al.). As the atherosclerotic plaque increases in size, it bulges into the artery lumen and causes stenosis (reduction of the artery lumen). The reduction of the artery lumen causes limitations to the blood flow. This may cause symptoms in situations with increased cardiac workload (physical exercise) because the increased workload leads to increased oxygen demand but the stenosis limits the volume that can be delivered to the heart muscle supplied by the atherosclerotic artery. Whenever oxygen demand exceeds oxygen (blood) delivery ischemia occurs and this manifests with chest discomfort referred to as angina pectoris. If the physical activity ceases, the myocardial oxygen demand will gradually decline and the symptoms disappear within minutes. Stable coronary plaques cause symptoms at the same level of myocardial workload and the symptoms disappear within minutes after stopping the activity. The greater the stenosis, the lower the level of myocardial workload required to elicit ischemia and symptoms. Angina pectoris: the hallmark of coronary artery disease Angina pectoris is the cardinal symptom of coronary artery disease. It occurs when the myocardium becomes ischemic. It is typically described as a diffuse pain over the anterior chest wall. The pain may be experienced as a pressure, cramp or crushing sensation. The pain may radiate to either arm, neck, back or shoulder. Angina pectoris is often accompanied by shortness of breath (dyspnea). If these symptoms are stable over time, then the condition is classified as stable angina pectoris and this implies that the coronary artery disease is significant but stable. Patients with stable angina pectoris only experience angina (chest pain) in situations with increased myocardial workload, and symptoms subside when the workload returns to normal. The most typical scenario is angina pectoris provoked by physical exercise or mental stress. Both these scenarios increase heart rate and workload which subsequently causes myocardial ischemia. Importantly, in stable angina pectoris, the symptoms subside within minutes after resting or after administration of nitroglycerin. Also, the level of physical activity that elicits angina must be stable during the past few weeks. Please refer to Approach to Patients with Chest Pain for details regarding the evaluation of chest pain patients. The size of coronary plaques tends to increase with time. This leads to increased stenosis (the arterial lumen becomes more narrow) and thus more pronounced symptoms (i.e symptoms at lower myocardial workloads). Notably, research conducted in the past few years has shown that intensive statin treatment may slow, inhibit or even reverse this progression (The JUPITER Study, Ridker et al). Atherosclerotic plaques are frail: damage causes acute coronary syndromes and myocardial infarction The most serious scenario emerges if the atherosclerotic plaque is damaged, either by rupturing or by erosion of the endothelium covering the plaque. This is generally the result of intensive inflammation within the plaque. As mentioned above, the plaque houses inflammatory (immune) cells that maintain a chronic inflammation within the plaque. Chronic inflammation destabilizes the plaque and ultimately results in a rupture or erosion. A damaged plaque exposes thrombogenic substances located within the artery wall (e.g collagen). Such thrombogenic substances will activate thrombocytes and coagulation factors that pass by and this leads to the formation of a thrombus (atherothrombosis; formation of a thrombus within an artery). This process only takes a few minutes, or even less. The thrombus occludes the artery either completely or partially. In either case, the sudden reduction in arterial blood flow will lead to myocardial ischemia. This type of ischemia is typically very severe and causes persisting chest discomfort which is not alleviated by rest and nitroglycerin barely mitigates the pain. This scenario, in which a ruptured/eroded atherosclerotic plaque causes atherothrombosis with ensuing severe myocardial ischemia, is referred to as an acute coronary syndrome. Please refer to Figure 1.

Figure 1. An atherosclerotic plaque that has ruptured and resulted in atherothrombosis. Acute coronary syndrome and myocardial infarction As mentioned above, an acute coronary syndrome occurs when coronary blood flow is reduced suddenly and severely due to atherothrombosis. The myocardial muscle supplied by the occluded artery will immediately become ischemic. If blood flow is not restored rapidly, the ischemic area will undergo infarction (necrosis) which leads to irreversible cell death. The infarction will commence in the most ischemic area and from there it will gradually expand. If the artery is completely occluded (i.e no flow through the artery) all ischemic myocardium will be dead within 2 to 12 hours. The size of the ischemic/necrotic area correlates strongly with the risk of heart failure, malignant ventricular arrhythmias, and other complications. The risk of malignant ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation) is highest in the hyperacute phase (the first hour). Because most patients delay before seeking medical attention, those who die from acute myocardial infarction tend to do so outside of the hospital. This also means that the mere arrival to hospital indicates a good prognosis. It should be noted that the natural course outlined above – i.e the progression from stable coronary artery disease to acute myocardial infarction – is not universal. The majority of patients with coronary artery disease never develop acute coronary syndromes. On the other hand, some develop acute myocardial infarction as their first sign of coronary artery disease. Moreover, the vast majority of middle-aged and older individuals do have some degree of atherosclerosis but only a minority will progress to symptomatic heart disease (more about this below). Risk factors of coronary artery disease and acute myocardial infarction Risk factors of coronary artery disease are some of the most intensively researched areas of medicine. Thousands of studies, ranging from genomics to nationwide epidemiological studies, have elucidated risk factors of coronary artery disease. The INTERHEART study deserves special mention because it was conducted in 52 countries, including all continents. The INTERHEART study showed that more than 90% of the total risk of developing acute myocardial infarction was explained by nine simple modifiable risk factors. This was true for men and women in all 52 countries. It follows that the vast majority of all myocardial infarctions may be prevented by targeting these risk factors. The INTERHEART study brought rather spectacular news, as it was previously believed that only 50% of the risk was modifiable. Virtually all studies have shown that the most important risk factors are high blood lipids (hyperlipidemia), smoking, hypertension, and diabetes. Other significant risk factors are abdominal obesity, psychosocial stress, low levels of physical activity, low intake of fruits and vegetables, etc. Importantly, hyperlipidemia (sometimes referred to as dyslipidemia) and smoking constitute 66% of the risk of myocardial infarction. Table 1: Risk factors for acute myocardial infarction (The INTERHEART Study)

RISK FACTORRELATIVE RISK
High blood lipids3.25
Current smoking2.87
Diabetes2.37
Hypertension1.91
Abdominal obesity1.62
Psychosocial stress2.67
Daily consumption of vegetables and fruit0.7
Physical exercise0.86
Alcohol intake0.91

How to interpret the numbers: e.g., high blood lipids are associated with a relative risk of 3.25, which implies that having high blood lipids, as compared with having normal blood lipids, is associated with 3.25 times as great a risk of acute myocardial infarction. High blood lipids (hyperlipidemia) deserve special mention since the condition is very common and easy to treat. As noted in Table 1 hyperlipidemia is associated with 3.25 times as great a risk of acute myocardial infarction. Actually, all levels of blood lipids are associated with the risk of myocardial infarction. The lower the lipid levels, the lower the risk of myocardial infarction. Note that blood lipids are actually transported in lipoprotein complexes, which are large spheric complexes consisting of lipids and proteins. Lipoproteins are measured to evaluate blood lipid levels. There are numerous types of lipoproteins, such as LDL cholesterol, HDL cholesterol, VLDL cholesterol, etc. LDL (low-density lipoprotein) cholesterol is the most important lipoprotein; the higher the LDL cholesterol, the more aggressive the atherosclerotic process. Body Mass Index (BMI) is not as strongly associated with the risk of acute myocardial infarction, as compared with abdominal obesity. Psychosocial stress (economic stress, workplace stress, depression, domestic stress) are comparable to hypertension and abdominal obesity. Smokers have 2.87 times as great a risk of myocardial infarction, as compared with non-smokers. Smoking one to five cigarettes per day increases the risk of infarction by 40%. Smoking 20 cigarettes per day increase the risk by 400% (i.e. 4 times as great a risk as compared with non-smokers). To conclude, the vast majority of myocardial infarctions may be prevented. More than 90% of the risk is explained by modifiable risk factors. Virtually all risk factors may be treated with evidence-based, cheap and readily available medications. The ECG in ischemic heart disease The ECG is an invaluable tool in acute and chronic myocardial ischemia. Optimal use of the ECG will provide information on diagnosis, prognosis and appropriate treatments. In acute ischemia, the ECG will also provide information on the extension, localization and time course of the ischemia. This is rather remarkable given that an ECG recording costs approximately $10. Because ischemia primarily affects myocardial repolarization, it will cause changes in the ST-segment and T-wave (collectively referred to as ST-T changes). The classical ST-T changes are ST-segment depression, ST-segment elevation, T-wave inversion (i.e. negative T-waves), and flattening of the T-waves or T-waves with increased amplitude.  Note that ST depressions, ST elevations and T-wave inversions are absolutely not specific to myocardial ischemia. However, in the setting of chest discomfort, these ST-T changes strongly suggest myocardial ischemia. Careful examination of the morphology of the ST-T changes usually leads to a definitive diagnosis. Also, note that the ECG may show one or several of these ST-T changes. The localization, time course and extent of ischemia will govern exactly which ECG changes that occur. ECG changes seen in the early phase of ischemia differ from those seen in the late phases. Infarction, on the other hand, affects myocardial depolarization (frankly, dead myocardial cells do not depolarize) which affects the QRS complex. The most characteristic finding is abnormally large Q waves (referred to as pathological Q waves). Other common findings are reduced R-wave amplitude (due to loss of viable myocardium) and fragmented or notched QRS complexes. ECG changes in myocardial ischemia and infarction will be discussed in great detail. Use of ECG to classify stages of coronary artery disease The ECG is utilized in all phases of coronary artery disease to classify the condition. Notably, the ECG is used to guide the management of patients with acute coronary syndromes. ECG characteristics (ST-T changes, QRS changes, criteria, etc) of ischemia and infarction will be discussed in great detail in the subsequent chapters. For now, we will only note the following: Stable coronary artery disease (stable angina pectoris) does not cause any ST-T changes at rest. To reveal ischemic ST-T changes the patient must undergo exercise stress (ECG) testing. The purpose of the exercise stress test is to provoke ischemia (ST-T changes) while performing the ECG. If a person with stable coronary artery disease displays QRS changes (pathological Q-waves, fragmented QRS, reduced R-wave amplitude), it strongly suggests previous myocardial infarction. In the case of acute coronary syndrome, the ECG is used to classify the syndrome into STE-ACS and NSTE-ACS. This subdivision is fundamental because it affects management and immediate treatment. STE-ACS (ST Elevation Acute Coronary Syndrome): acute coronary syndromes with ST elevations on ECG are classified as STE-ACS. Virtually all these patients will develop myocardial infarction, which is then classified as STEMI (ST Elevation Myocardial Infarction). NSTE-ACS (Non-ST Elevation Acute Coronary Syndrome): acute coronary syndromes without ST elevations on ECG are classified as NSTE-ACS. If the patient develops myocardial infarction, then the condition is classified as NSTEMI (Non-ST Elevation Myocardial Infarction). If the patient does not develop infarction, then the condition is classified as unstable angina. The perfect storm scenario Although the majority of adults in high-income countries have some degree of atherosclerosis, the annual incidence of acute coronary syndromes is only 0.2 to 1.0% in individuals aged 40 years or older. Hence, the annual risk of developing acute coronary syndrome is very small. Studies show that the majority of plaque damages (ruptures, erosions) do not lead to acute coronary syndromes, even though they cause thrombosis. Interestingly, plaque damage and ensuing thrombosis appear to be rather common events that mostly pass asymptomatic. Moreover, studies show that these asymptomatic events appear to be a mechanism driving plaque progression (increase in plaque volume). Thus, acute coronary syndromes are fairly uncommon consequences of plaque damage. A large body of science indicates that acute coronary syndromes only occur if the plaque damages coincide with a moment in which pro-thrombogenic factors outweigh pro-thrombolytic factors in the blood. Examples of such factors are thrombocyte levels, thrombocyte reactivity, availability of fibrinogen, degree of systemic inflammation, availability of coagulation factors, etc. These factors vary over the course of the day and they are also modified by external factors such as stress, food, medications, toxins (smoking, air pollution), etc. Studies show that there is a circadian variation in the activity of the coagulation factors and thrombocytes, such that it is higher in the morning hours. It is believed that this explains why the incidence of acute myocardial infarction is higher in the morning hours. To conclude, the balance between pro-thrombogenic and pro-thrombolytic factors varies from one minute to another and they determine whether plaque rupture/erosion will lead to occlusive atherothrombosis. The morphology of atherosclerotic plaques appears to be dynamic. Studies using IVUS (intravascular ultrasound) show that the majority of high-risk plaques (large plaques with thin fibrous caps) tend to revert to more stable plaques over time (within one year) and vice versa (stable plaques tend to progress to more unstable forms). IVUS studies also show that high-intensity statin therapy is very likely to inhibit plaque progression, and even revert it. One may wonder whether the degree of stenosis is a risk factor for acute coronary syndromes. Some studies have shown that large plaques are associated with a greater risk of acute coronary syndromes, while other studies have not been able to confirm this. Other studies show that the majority of acute coronary syndromes occur in plaques with moderate stenosis. Thus, this question remains unanswered. It is, however, very clear that the level of inflammation in the plaque is critical. The greater the inflammation (regardless of plaque volume) the greater the risk of rupture and development of acute coronary syndrome. Of all acute coronary syndromes, plaque ruptures cause 60–75%, whereas plaque erosion causes 35–40%. The level of atherosclerosis varies greatly among people who develop acute coronary syndromes. Approximately 5–10% have left main coronary artery (LMCA) disease (i.e. stenosis); 20% have one-vessel disease; 30% have two-vessel disease and 40% have three-vessel disease. References Arbab-Zadeh et al: Acute Coronary Events; Circulation 2012 Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association. Circulation 2022; 145: e153–639. Stone PH, Libby P, Boden WE. Fundamental Pathobiology of Coronary Atherosclerosis and Clinical Implications for Chronic Ischemic Heart Disease Management—The Plaque Hypothesis: A Narrative Review. JAMA Cardiol 2023; 8: 192.

Chapter 2: Classification of Acute Coronary Syndromes (ACS) & Acute Myocardial Infarction (AMI)

Acute coronary syndromes occur when atherosclerotic plaques disrupt, resulting in the activation of thrombocytes and coagulation factors causing the formation of a thrombus. Such a thrombus can cause occlusion of the artery. The occlusion may be complete or partial, depending on the size of the thrombus and the plaque. The patient will experience severe chest pain due to the abrupt reduction of coronary blood flow. Acute coronary syndromes are subdivided into STE-ACS and NSTE-ACS. STE-ACS is the acronym for ST Elevation Acute Coronary Syndrome. All acute coronary syndromes that exhibit significant ST segment elevations on ECG are classified as STE-ACS. Moreover, STE-ACS is caused by a complete coronary artery occlusion and virtually all these patients will develop myocardial infarction, which is classified as STEMI (ST Elevation Myocardial Infarction). NSTE-ACS is the acronym for Non-ST Elevation Acute Coronary Syndrome. This category includes all acute coronary syndromes without significant ST segment elevations on ECG. NSTE-ACS is caused by partial occlusion of the artery (i.e. coronary blood flow is not completely obstructed). NSTE-ACS typically presents with ST segment depressions and/or T-wave inversions. Most patients with NSTE-ACS will develop acute myocardial infarction, which is then classified as NSTEMI (Non-ST Elevation Myocardial Infarction). Patients with NSTE-ACS who do not develop infarction are classified as unstable angina (UA), which is an imminent precursor to myocardial infarction. NSTEMI and unstable angina have similar pathophysiology and management are also similar. Hence, the difference between STE-ACS and NSTE-ACS is merely the presence of ST segment elevations in the former. Refer to Figure 1, which illustrates the natural course of coronary artery disease, from risk factors to acute coronary syndromes. It also presents a classification of acute coronary syndromes and myocardial infarctions. The reader should study this chart carefully.

Figure 1. Flowchart showing the natural course of coronary artery disease and classification of acute coronary syndromes into STEMI, NSTEMI and unstable angina using ECG criteria. Acute myocardial infarction: a diagnosis based on cardiac troponins A diagnosis of acute myocardial infarction (AMI) is made only after blood analyses confirm elevated levels of myocardial proteins. These proteins are cardiac troponins (henceforth referred to only as troponins). When elevated troponin levels are confirmed in patients with STE-ACS, the condition is classified as STEMI (ST elevation myocardial infarction). When elevated troponin levels are confirmed in patients with NSTE-ACS, the condition is classified as NSTEMI (Non-ST elevation myocardial infarction). If troponin levels are normal in patients with NSTE-ACS, the condition is classified as unstable angina (UA). Please refer to Diagnostic Criteria for Myocardial Infarction for further details. Figure 2 (below) displays ST segment depression, ST segment elevation and T-wave inversion. These ECg changes will be discussed in great detail in the subsequent chapters.

Figure 2. This figure illustrates ST elevations, ST depressions and T-wave inversions. Patients with STEMI (STE-ACS) always display ST elevations but they may also display ST depressions and/or T-wave inversions. Patients with NSTE-ACS (NSTEMI, unstable angina), on the other hand, may only display ST depressions and/or T-wave inversions. STE-ACS (ST Elevation Acute Coronary Syndrome) & STEMI (ST Elevation Myocardial Infarction) Acute coronary syndromes with significant ST segment elevations are classified as STE-ACS. Virtually all cases of STE-ACS lead to myocardial infarction (elevated troponin levels), whereafter the condition is classified as ST Elevation Myocardial Infarction (STEMI). The thrombus causing STE-ACS is located proximally in the coronary artery and it occludes the entire artery lumen (i.e. no blood passes the thrombus). The ensuing ischemia is transmural, implying that it is extensive and stretches from the endocardium to the epicardium (Figures 1 and 2).

Figure 3. STE-ACS (STEMI) is caused by a complete occlusion, which means that there is no flow in the artery. The ischemia will affect all layers of the myocardium, from the endocardium to the epicardium (in the region supplied by the occluded artery). This type of ischemia, which affects all myocardial layers, is referred to as transmural ischemia. ECG characteristics of STE-ACS (STEMI) The ECG leads which display ST segment elevations reflect the ischemic area. This means, for example, that ST segment elevations in leads V3 and V4 (anterior chest leads) reflect transmural anterior ischemia. ST elevations must exist in at least two anatomically contiguous leads in order to fulfill the criteria for STE-ACS. Anatomically contiguous implies that the leads must be anatomically juxtaposed; for example V1 and V2; V5 and V6; V4 and V5; aVF and III and so on. In most cases, the ST segment elevations are accompanied by reciprocal ST segment depressions. Such ST segment depressions occur in leads that detect the ischemic vectors from the opposite angle, compared with the leads showing ST segment elevations. The ST segment elevations are gradually normalized and followed by T-wave inversions. The latter may persist for a month, or even longer.

Figure 4. Two examples of patients with STEMI (ST elevation myocardial infarction). Only limb leads are shown. Pathological Q-waves may appear if the infarct area is large. These Q-waves are abnormally wide and deep. They testify that the heart has suffered a large infarction. Infarctions that leave pathological Q-waves are referred to as Q-wave infarctions. On very rare occasions the thrombus may resolve (either spontaneously or due to fast reperfusion treatment) before the infarction process begins. In this case, the troponin levels are not elevated and the condition is classified as unstable angina (or aborted myocardial infarction). This is, however, rare because virtually all cases of STE-ACS progress to STEMI. Patients with STE-ACS (STEMI) have pronounced symptoms (notably chest pain) and a high risk of ventricular arrhythmias in the acute phase. This is because the ischemic area is extensive. Potentially life-threatening ventricular arrhythmias (ventricular tachycardia and ventricular fibrillation) may occur and such arrhythmias cause virtually all deaths in the acute phase of STEMI (and in acute coronary syndromes in general). Death due to pumping failure (cardiogenic shock) is much less common in the acute phase. STE-ACS (STEMI) is treated with anti-ischemic and antithrombotic medications, as well as immediate coronary angiography with the purpose of performing PCI (percutaneous coronary intervention). Anti-thrombotic medications and PCI reduce mortality markedly by counteracting thrombus formation and restoring coronary blood flow, respectively. NSTE-ACS (Non ST Elevation Acute Coronary Syndrome): NSTEMI (Non-ST Elevation Myocardial Infarction) & Unstable Angina All acute coronary syndromes which do not fulfill the criteria for STE-ACS are automatically classified as NSTE-ACS. The artery occlusion is partial (not complete) and thus some blood flow remains in the artery. The occlusion is typically located proximally (along the epicardial course of the artery). Because the occlusion is partial the ischemia will primarily affect the subendocardium, which has the poorest prerequisites in the case of ischemia. This is explained by the following: The subendocardium is too far away from the blood in the ventricular cavity. Hence, oxygen within the ventricle does not reach the subendocardium (it does, however, reach the endocardium). The oxygen level in the coronary artery reaching the subendocardium is reduced because oxygen is extracted during the passage through the epicardial layers. These two factors explain why the subendocardium has poor prerequisites in the setting of acute coronary syndromes. NSTE-ACS is classified as Non-ST Elevation Myocardial Infarction (Non-STEMI, NSTEMI) if troponin levels are elevated. If cardiac troponin levels are normal, the condition is classified as unstable angina pectoris, which thus can be viewed as an impending myocardial infarction (Figures 1 & 2). ECG characteristics of NSTE-ACS (NSTEMI, unstable angina) The hallmark of NSTE-ACS (NSTEMI) is ST segment depressions which are often accompanied by T-wave changes. The latter may be T-wave inversions or flat T-waves. Importantly, the leads displaying ST segment depressions do not necessarily reflect the ischemic area. This means that ST segment depressions in leads V3–V4 are not necessarily due to anterior wall ischemia. Similarly, ST segment depressions in leads II, aVF and III do not suggest inferior wall ischemia. Hence, ST-segment depressions cannot localize the ischemic area. Please refer to Localization of Acute Myocardial Infarction and Culprit Artery for details on how to localize the ischemia/infarction using ECG.

Figure 5. Example of patient with NSTEMI. This patient displays widespread ST depressions and deep T-wave inversions in the chest leads, as well as aVL and I. Pathological Q-waves usually do not develop, which is explained by the fact that NSTEMI is generally smaller infarctions than STEMI. However, extensive subendocardial infarctions may certainly lead to pathological Q-waves. It is actually a widespread misunderstanding that infarctions must be transmural in order to cause pathological Q-waves. T-wave inversions are also frequently misunderstood. Isolated T-wave inversions, i.e. T-wave inversions without concomitant ST segment deviations, are never indicative of acute (ongoing) ischemia. T-wave inversions that are accompanied by ST segment depressions, however, are indicative of acute (ongoing ischemia), but in that scenario, it is actually the ST segment deviation that reflects the ischemia. Isolated T-wave inversions are post-ischemic, i.e. they occur after the ischemic episode has surmounted. A minority of patients with NSTE-ACS (Non-STEMI) display normal ECG on arrival. It is unusual, however, to display a normal ECG throughout the course; the majority of patients with normal ECG on arrival will develop some ECG changes during the course. Moreover, normal ECGs on arrival cannot be used to rule out myocardial ischemia/infarction. There are infarctions that do not cause ECG changes (typically smaller infarctions) and there are cases in which the thrombus is dynamic in size. The thrombus may become larger or smaller, with minute-to-minute variation, and thus cause varying ECG changes. NSTE-ACS (Non-STEMI) is treated with anti-ischemic, anti-thrombotic medications. Most patients undergo coronary angiography with the purpose of performing PCI. Angiography is performed within 24 hours but sooner if the patient is a high-risk patient. ECG changes, troponin levels, clinical status and comorbidities will dictate if angiography must be performed promptly. Note that immediate angiography (as is done in STE-ACS/STEMI) has not reduced mortality or morbidity in NSTE-ACS (Non-STEMI), which is why guidelines recommend subacute angiography. Last but not least, NSTE-ACS may actually occur due to a proximal and complete occlusion (which usually leads to STE-ACS) if the affected myocardium has extensive collateral circulation. Collateral circulation, which is common among patients with coronary artery disease, implies that the ischemic area obtains blood flow from two coronary arteries (or branches of arteries). This type of circulation arises when ischemic myocardium stimulates surrounding arteries to sprout out vessels to the ischemic area (VEGF [Vascular Endothelial Growth Factor] plays a critical role in the development of collateral circulation). Figure 6 (below) summarizes the classification of acute myocardial infarction and coronary syndromes.

Figure 6. Classification of Acute Coronary Syndromes and Acute Myocardial Infarction. Normalization of ECG changes ST-T changes are normalized within days or weeks. The duration is longer if ischemia results in infarction. QRS changes are mostly permanent, particularly Q-waves. Note that treatment and reperfusion therapy may modify the speed by which the ECG normalizes. Risk stratification in patients presenting with acute coronary syndromes: TIMI and GRACE score Early risk assessment can improve outcomes in patients with acute coronary syndromes. Such risk assessment should address the probability that the syndrome is an acute coronary syndrome and, secondly, the probability of adverse outcomes (myocardial infarction and death). Several validated models (“risk calculators”) have been developed to simplify risk stratification. These models typically include information regarding medical history, ECG findings, presenting features (notably hemodynamic status), and cardiac troponins. The best-validated risk models are FRISC II, TIMI, PURSUIT, and GRACE. These vary concerning the type of risk estimated (short-term, long-term, myocardial infarction, death). TIMI score is the easiest to use but the GRACE score has proven to be the most accurate. Moreover, GRACE is applicable to both NSTEMI and STEMI. TIMI Risk Score for STEMI, NSTEMI and unstable Angina Calculate TIMI Score for NSTEMI, unstable angina and STEMI.

Chapter 3: A New Approach to Acute Coronary Syndromes: Occlusion MI (OMI) vs. Non-Occlusion MI (NOMI)

Introduction The traditional classification of acute coronary syndromes (ACS) into ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina (UA) has guided clinical decision-making for decades but carries several limitations, most notably its reliance on ST-segment elevation as the key trigger for emergent reperfusion therapy. This approach fails to identify a substantial proportion of patients with acute coronary occlusion (ACO) who present without diagnostic ST-elevation, often resulting in delayed treatment. In response to these limitations, a novel classification has been proposed: Occlusion Myocardial Infarction (OMI) versus Non-Occlusion Myocardial Infarction (NOMI). This method focuses on the presence or absence of ACO, rather than rigid ECG thresholds, and incorporates advanced ECG interpretation, clinical context, imaging, biomarkers, and angiographic findings.

OMI is defined by acute coronary artery occlusion causing transmural ischemia and requiring urgent reperfusion, even in the absence of classic ST-elevation. Multiple studies have demonstrated the superior sensitivity of OMI criteria—including subtle and nontraditional ECG patterns such as De Winter T-waves, Wellens syndrome, posterior infarction signs, and terminal QRS distortion—compared to standard STEMI criteria. Observational data suggest that up to 30% of patients initially classified as NSTEMI have an unrecognized OMI, with comparable infarct size and mortality to STEMI patients but significantly delayed treatment. While the OMI/NOMI framework is not yet formally incorporated into major clinical guidelines, it aligns with their emphasis on early angiography in high-risk patients regardless of ECG findings. Thush, it serves as a valuable diagnostic tool and educational model, promoting earlier identification and treatment of high-risk ACS patients. Future randomized trials are needed to validate this paradigm and support its broader adoption.

Figure 1. ECG patterns suggestive of acute coronary occlusion (ACO). Acute Coronary Syndromes The longstanding classification of acute coronary syndromes (ACS) into ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA) has guided diagnosis and management for decades. However, this classification carries significant limitations, particularly the reliance on ST-segment elevation on the electrocardiogram (ECG) as the primary trigger for emergent reperfusion therapy. This approach fails to identify a substantial subset of patients with acute coronary occlusion (ACO) who do not meet the established ECG criteria for STEMI, leading to delays in potentially life-saving interventions. This limitation has been acknowledged in contemporary clinical guidelines (Byrne et al, 2023). A new framework differentiating Occlusion Myocardial Infarction (OMI) from Non-Occlusion Myocardial Infarction (NOMI) was proposed by Smith and colleagues in 2018. This approach seeks to anchor diagnostic and therapeutic decisions in the presence or absence of an acute coronary occlusion, rather than rigid ECG thresholds. Several machine learning models for ECG interpretation have been developed to differentiate between OMI and NOMI, reflecting the growing clinical demand for more accurate and timely identification of acute coronary occlusion (Al-Zaiti et al, 2023). The proposed transition from the traditional STEMI/NSTEMI/UA classification to the OMI/NOMI approach is primarily supported by observational studies and clinical experience. Studies have demonstrated that a significant proportion of patients with acute coronary occlusion (ACO) do not exhibit classic ST-segment elevation on ECG, leading to substantial delays in reperfusion therapy. Advanced ECG interpretation, combined with clinical assessment and imaging modalities, has been shown to improve the identification of these patients. Although current (2025) guidelines continue to utilize the traditional classification, the OMI/NOMI approach has gained traction among clinicians (Al-Zaiti et al, 2023). Therefore, clinicians are encouraged to familiarize themselves with this approach. Interested readers are also referred to the excellent review by Ricci et al. Mechanisms causing acute coronary syndromes Acute coronary syndromes (ACS) are a spectrum of clinical conditions ranging from unstable angina to myocardial infarction, caused by sudden reduction of blood flow in the coronary arteries. Several distinct pathological mechanisms can lead to ACS (Kraler et al, 2025). Plaque rupture is the most common mechanism underlying ACS. It occurs when a thin fibrous cap overlying a lipid-rich atheromatous core ruptures, exposing the highly thrombogenic core contents to the bloodstream. This exposure triggers platelet activation, aggregation, and the coagulation cascade, resulting in thrombus formation that may partially or completely occlude the coronary artery. Plaque rupture accounts for about 60% of STEMI.

Figure 2. Rupture of an atherosclerotic plaque resulting in atherothrombosis. In plaque erosion, the endothelial lining over the plaque becomes denuded without rupture of the fibrous cap. This mechanism is more common in younger individuals, smokers, and women. The exposed subendothelial matrix promotes platelet adhesion and thrombus formation. Plaque erosion contributes to approximately 25-44% of ACS cases and tends to be associated with less lipid-rich plaques compared to plaque rupture. Calcified nodules are less common, accounting for around 5% of ACS events. They occur when dense, eruptive calcium deposits within the plaque disrupt the fibrous cap and protrude into the lumen. These protrusions can cause mechanical damage to the endothelium and promote localized thrombus formation. Coronary vasospasm involves transient, intense constriction of an epicardial coronary artery, which reduces or stops blood flow. This mechanism may cause ischemia or infarction even in the absence of significant atherosclerotic plaque. Vasospasm can be spontaneous or triggered by factors such as stress, cold, certain drugs, or smoking. It is a common mechanism in variant (Prinzmetal’s) angina. Coronary embolism can result in the occlusion of a coronary artery by an embolus, which can originate from various sources such as left atrial thrombi (e.g., due to atrial fibrillation), endocarditic vegetations, or paradoxical emboli via a patent foramen ovale. The embolus lodges in a coronary artery, abruptly blocking blood flow and leading to myocardial infarction. Spontaneous Coronary Artery Dissection (SCAD) is characterized by a spontaneous tear in the coronary arterial wall, creating a false lumen between the intima and media or media and adventitia. Blood entering this false lumen compresses the true lumen, impairing distal blood flow. SCAD is more common in young to middle-aged women and is often associated with fibromuscular dysplasia, peripartum state, or extreme stress. Irrespective of the underlying mechanism, several factors influence the clinical manifestation of the event. These include the location of the occlusion (proximal vs. distal), the presence and adequacy of collateral circulation, the duration of the occlusion, and the dynamic behavior of thrombus formation and lysis. These factors can modulate the extent and intensity of myocardial ischemia, impacting symptom presentation, hemodynamic stability and the electrocardiographic (ECG) changes. For instance, a proximal occlusion with adequate collateral flow may result in few ECG changes and mild symptoms, whereas a proximal occlusion without collateral circulation may result in sudden cardiac arrest. A new approach to classifying acute coronary syndromes The traditional classification of acute coronary syndromes (ACS) into ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA) is based primarily on electrocardiographic (ECG) findings and the presence or absence of cardiac biomarker elevation. In this framework, endorsed by major cardiology societies including the AHA, ACC, and ESC, ST-segment elevation serves as the key determinant for initiating urgent reperfusion therapy. More recent guidelines further simplify this approach into a dichotomy of ST-elevation ACS (STE-ACS) and non-ST-elevation ACS (NSTE-ACS), grouping NSTEMI and UA together. However, studies have shown that this dichotomy fails to detect a substantial proportion of patients with acute coronary occlusion (ACO), as ST-segment elevation is an imperfec, though practical, marker of occlusion. Approximately 30% of ACO cases are missed when relying solely on standard STEMI criteria, leading to delays in reperfusion and worse clinical outcomes. This has prompted calls for a paradigm shift to the concept of Occlusive Myocardial Infarction (OMI), which focuses on identifying ACO regardless of classic ST-segment elevation. The OMI paradigm significantly improves diagnostic sensitivity (78.1% vs. 43.6%) by incorporating more nuanced ECG findings, such as hyperacute T-waves, de Winter T-waves, and posterior infarction patterns, which are often overlooked in the STEMI/NSTEMI model (Ayyad et al). OMI-guided diagnosis facilitates earlier and more appropriate intervention, potentially improving outcomes in high-risk patients who would otherwise be misclassified. Additionally, emerging artificial intelligence (AI) tools show promise in enhancing ECG interpretation and decision-making under the OMI framework. While these findings are compelling, randomized clinical trials are needed to validate the OMI approach and support its integration into routine clinical practice. The Traditional Classification The traditional approach to ACS categorizes patients into three main groups: unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). Unstable angina is defined by myocardial ischemia occurring at rest or with minimal exertion, without evidence of cardiomyocyte necrosis. It typically results from reduced coronary blood flow due to atherosclerosis, often complicated by a non-occlusive thrombus. Clinically, UA may present as new, worsening, or rest angina that is prolonged and unrelieved by nitroglycerin. ECG changes may include ST-segment depression, T-wave inversions, or be normal. NSTEMI is defined by myocardial necrosis due to acute ischemia, confirmed by elevated cardiac biomarkers. It typically results from a partial or transient coronary artery occlusion, causing subendocardial infarction. Symptoms often mirror those of unstable angina but are more severe or prolonged. Diagnosis relies on clinical presentation, ECG changes (e.g., ST depression, T-wave inversion), and elevated troponin levels. Most patients undergo angiography within 24–72 hours, with expedited intervention for those at very high risk. Patients with transient (i.e. <20 minutes) ST segment elevations are also classified as NSTEMI. STEMI is diagnosed based on ischemic symptoms and specific ECG criteria, including persistent ST-segment elevation (i.e. >20 minutes)  in two or more contiguous leads: ≥1 mm in all leads except V2–V3, where the thresholds are ≥2 mm in men ≥40 years, ≥2.5 mm in men <40 years, and ≥1.5 mm in women. New or presumed new left bundle branch block (LBBB), new or presumed new right bundle branch block (RBBB), and posterior infarction patterns may also support the diagnosis. These findings serve as the principal trigger for emergent reperfusion therapy, in the vast majority of cases via primary PCI.

Figure 3. Traditional classification of acute coronary syndromes. STEMI-Negative Occlusion Myocardial Infarction The term STEMI-negative OMI denotes the subset of patients who lack diagnostic ST-segment elevation on ECG and yet have an acutely occluded coronary artery. Several studies and meta-analyses indicate that approximately 25-30% of patients initially classified as NSTEMI have an ACO. Some investigations report this figure to be as high as 47% in certain NSTEMI populations undergoing angiography (Ricci et al, 2025). Herman et al found that conventional STEMI/NSTEMI criteria fail to detect 67.5% of occlusion myocardial infarctions. These missed cases, termed STEMI-negative OMI, represent a significant clinical concern. Among the STEMI-negative OMI patients studied by Herman et al, only 33.9% received revascularization within 2 hours. The clinician’s ability to diagnose STEMI is also a concern. McCabe et al assessed how accurately physicians interpret ECGs for potential STEMI. The key findings were as follows: Physicians showed poor agreement when interpreting potential STEMI ECGs, with a kappa statistic of 0.33. Sensitivity for STEMI was 65% (i.e. the rate of correctly identified true STEMIs). Specificity for STEMI was 79% (i.e. the rate of correctly identified non-STEMIs). Each additional 5 years of clinical experience was associated with a 6% increase in the odds of accurate interpretation. After adjusting for experience, diagnostic accuracy did not differ significantly among emergency physicians, general cardiologists, and interventional cardiologists. Shortcomings of the 12-lead ECG The standard 12-lead ECG is suboptimal for detecting OMI in several scenarios. The sensitivity is poor for OMI affecting the posterior wall of the left ventricle (often supplied by the left circumflex artery or a dominant right coronary artery), the right ventricle and infarctions caused by occlusion of the left circumflex artery. Moreover, some patients exhibit non-specific changes, e.g. new bundle branch block, or ST elevations that are subtle and do not meet the formal voltage criteria. Thus, relying solely on millivolt thresholds for ST-segment elevation oversimplifies the complex and dynamic ECG changes occurring during acute coronary occlusion. A study on 504 patients (Marti et al) with suspected STEMI undergoing systematic primary percutaneous coronary intervention (PCI) found that 20% had only subtle ST-segment elevations (0.1 to 1 mm), which still indicated acute coronary occlusion (ACO). A study on occlusion myocardial infarction cases initially missed by STEMI criteria (Aslanger et al) revealed that three-quarters of these cases could be identified by subtle or evolving ST changes, suggesting dynamic ischemia and warranting urgent reperfusion. A study on 146 patients (Meyers et al) diagnosed earlier by OMI-specific ECG criteria rather than conventional STEMI criteria found that several distinct ECG patterns were more frequently observed, enabling earlier detection of acute coronary occlusion. Khan et al. (2017) conducted a meta-analysis of over 40,000 NSTEMI patients found that approximately 25% had a totally occluded culprit artery on angiography, most commonly in the right coronary and left circumflex arteries. These patients had significantly higher rates of major adverse cardiac events (MACE) and all-cause mortality in both the short and medium-to-long term, compared to NSTEMI patients without total occlusion. The concept of STEMI equivalents (Figure 1), a set of ECG patterns suggestive of OMI, helps address some of the limitations by recognizing additional ECG patterns associated with acute coronary occlusion. However, STEMI equivalents also fall short of offering a comprehensive framework to guide reperfusion strategies. THE OMI vs. NOMI approach provides a comprehensive guide to treatment strategies. Occlusion Myocardial Infarction (OMI) vs. Non-OMI (NOMI) Occlusion Myocardial Infarction (OMI) is defined as an acute myocardial infarction resulting from the acute total or near-total occlusion of a coronary artery, where there is insufficient collateral circulation to prevent ongoing transmural myocardial ischemia and active infarction. Emergent reperfusion therapy is required to limit infarct size and minimize the risk of malignant ventricular arrhythmias. OMI is a pathophysiological and clinical diagnosis, not solely an ECG-defined entity. The diagnosis of OMI integrates the clinical presentation (e.g., characteristic ischemic symptoms, hemodynamic status), comprehensive ECG findings (including subtle signs beyond classic ST-elevation), cardiac biomarker levels, and point-of-care echocardiography. Angiographic evidence of a culprit artery occlusion (e.g., Thrombolysis In Myocardial Infarction (TIMI) flow grade 0, 1, or 2) is a key confirmatory feature. Even TIMI 3 flow on angiography can be consistent with a recently reperfused OMI if associated with very high cardiac troponin levels, indicating a significant preceding ischemic event due to occlusion. The fundament of the OMI approach is that the presence of an ACO is the determinant for emergent reperfusion, regardless of whether traditional STEMI ECG criteria are fulfilled. Non-Occlusion Myocardial Infarction (NOMI) Non-Occlusion Myocardial Infarction (NOMI) encompasses myocardial infarctions where there is no acute, persistent thrombotic occlusion of the culprit coronary artery, or where collateral circulation is sufficient to prevent progressing transmural infarction. This category can include MIs resulting from plaque rupture with a non-occlusive thrombus, instances where spontaneous reperfusion (by means of endogenous thrombolysis) of an occluded artery has occurred prior to presentation, myocardial infarction with non-obstructive coronary arteries (MINOCA) due to various mechanisms (e.g., coronary spasm, microvascular dysfunction, embolism), or Type 2 MI secondary to a profound supply-demand mismatch (e.g., severe anemia, tachyarrhythmia in the setting of stable coronary disease). Patients classified under the NOMI category do not derive benefit from emergent reperfusion strategies (i.e., interventions aiming for reperfusion within <2 hours of presentation) in the same way OMI patients do. However, urgent coronary angiography (e.g., within 24-72 hours) is frequently indicated for NOMI patients based on their overall ischemic risk profile and to definitively characterize their coronary anatomy and underlying pathology. Evidence for the OMI/NOMI approach Several studies have directly compared the diagnostic performance of OMI-focused approach against traditional STEMI criteria in identifying angiographically confirmed ACO. Meyers et al. (2021): A key study by Meyers and colleagues demonstrated that expert ECG interpretation, looking for a broader range of OMI signs beyond just ST-elevation, significantly outperformed standard STEMI criteria in terms of sensitivity for detecting ACO. Sensitivities for OMI detection by expert readers were reported in the range of 80-86%, compared to 36-41% for STEMI criteria, while maintaining comparable or high specificity. This research also highlighted that patients with STEMI-negative OMI had infarct sizes similar to those with STEMI-positive OMI but experienced substantial delays in reperfusion. The OMI-based approach allowed for the diagnosis of ACO a median of 1.5 hours earlier than reliance on STEMI criteria alone. DIFOCCULT Study (Aslanger et al. 2020): The DIFOCCULT study evaluated whether a new classification system based on the presence or absence of acute coronary occlusion (ACO) would more accurately identify patients needing emergent reperfusion, compared to the traditional STEMI/non-STEMI paradigm. Among 3000 patients analyzed, ECG reviewers identified ACO in 28.2% of cases originally classified as non-STEMI. These reclassified patients had significantly higher rates of actual coronary occlusion, greater myocardial injury, and worse in-hospital and long-term mortality. The ACO-based approach outperformed the standard STE/non-STEMI criteria in predicting true occlusion and mortality outcomes. Furthermore, early intervention in patients without ACO findings on ECG was linked to increased long-term mortality, suggesting that overtreatment may be harmful. The study concludes that a shift toward an OMI/NOMI model could improve diagnostic accuracy and clinical outcomes in acute MI care. Koyama et al (2002): In a prospective study, Koyama et al. applied an immediate invasive strategy to all patients with suspected acute coronary syndrome (ACS), including those classified as NSTEMI without requiring biomarker confirmation. Among suspected NSTEMI patients, 63% had coronary flow limitation and 47% had TIMI 0 flow. Despite differing ECG presentations, the rates of in-hospital and 6-month mortality were similar between NSTEMI and STEMI groups, suggesting that early invasive management may equalize outcomes when coronary occlusion is promptly addressed. Diagnosing Occlusion Myocardial Infarction Diagnosing OMI requires a multifaceted approach that integrates advanced ECG interpretation skills, clinical judgment, appropriate use of cardiac biomarkers, and the incorporation of emerging technologies like artificial intelligence (AI) and point-of-care echocardiography. Advanced ECG Interpretation Figure 1. ECG patterns suggestive of acute coronary occlusion (ACO). A cornerstone of the OMI approach is the ability to recognize a spectrum of ECG abnormalities that indicate coronary occlusion, but do not meet traditional STEMI criteria. Below follows a discussion on ECG patterns indicating high or very high risk of occlusion myocardial infarction. De Winter T-Waves

De Winter T-waves (De Winter sign) ECG features Up-sloping ST-segment depression at the J-point in leads V1–V6. Tall, symmetrical T-waves in precordial leads. Possible slight ST elevation in lead aVR. Clinical correlation Indicates acute occlusion of the proximal left anterior descending (LAD) artery. Represents approximately 2% of anterior myocardial infarctions. Requires immediate reperfusion therapy despite absence of classic ST-elevation. Wellens pattern (Wellens syndrome)

Wellens Syndrome (Wellens ECG pattern) ECG features Biphasic or deeply inverted T-waves in leads V2–V3 (may extend to V1–V6). Minimal or no ST-segment elevation. No pathological Q waves; normal R-wave progression. Clinical correlation Signifies critical stenosis of the proximal LAD artery. Typically observed in pain-free state after recent angina. High risk for extensive anterior wall myocardial infarction if left untreated. Posterior Myocardial Infarction

Occlusion of the left circumflex artery or a dominant right coronary artery supplying the posterior wall often does not cause ST-elevation in the standard 12 leads. Indirect (reciprocal) signs in the anterior precordial leads (V1-V4) include horizontal ST-segment depression (especially ≥0.5 mm), prominent and upright T-waves, and tall R waves (an R/S wave ratio >1 in lead V2 is particularly suggestive). ST-segment depression that is maximal in leads V1-V4 is highly specific for OMI. Recording posterior ECG leads (V7-V9) can reveal ST-segment elevation in these cases. Posterior MI signs are also considered STEMI equivalents. ECG features Horizontal ST-segment depression in leads V1–V3. Tall R-waves and upright T-waves in V1–V3. ST elevation in posterior leads V7–V9 if recorded. Clinical correlation Often due to occlusion of the left circumflex artery or right coronary artery. May occur in isolation or with inferior/lateral MI. Easily missed; requires posterior lead placement for confirmation. Bundle branch blocks and paced rhythms

The previous recommendation to manage new or presumed new left bundle branch block (LBBB) or right bundle branch block (BBB) as a STEMI equivalent is no longer suggested. Current guidelines state that the presence of LBBB or RBBB increase the likelihood of an acute coronary occlusion and urgent coronary angigoraphy is warranted if there is a high clinical suspicion of ongoing ischemia (chest pain, arrhythmias, etc.), regardless of whether the BBB is previously known (Byrne et al). The same reasoning is applied to paced rhythms. Sgarbossa Criteria and Smith-Modified Criteria Multiple ECG criteria have been developed to detect ongoing ischemia in patients with LBBB. The Sgarbossa criteria, and the more accurate Smith-Modified Sgarbossa criteria, are the most widely used criteria. Key features include concordant ST-segment elevation (ST elevation in leads with a positive QRS complex) or excessively discordant ST changes (e.g., ST elevation ≥1 mm and ≥25% of the preceding S-wave depth in leads with a negative QRS). ECG features Concordant ST elevation ≥1 mm in leads with positive QRS. Concordant ST depression ≥1 mm in leads V1–V3. Excessively discordant ST elevation: ST/S ratio ≥25%. Clinical correlation Used to detect myocardial infarction in presence of left bundle branch block (LBBB) or ventricular paced rhythm. Smith-modified criteria improve sensitivity and specificity for diagnosing occlusion myocardial infarction. Prompt recognition can lead to timely reperfusion therapy. New RBBB and LAFB

The simultaneous presence of new-onset RBBB and LAFB, known as bifascicular block, is a strong indicator of an acute occlusion in the proximal left anterior descending (LAD) artery (Widimsky et al). This combination suggests extensive involvement of the interventricular septum, as both the right bundle branch and the left anterior fascicle receive blood supply from septal branches of the LAD. This ECG pattern in the context of chest pain is associated with a high risk for third degree AV block, larger infarct size, and increased in-hospital mortality. Subtle ST-Segment Elevation ECG features ST-segment elevation that does not meet standard STEMI criteria (e.g., <1 mm in limb leads or <2 mm in precordial leads). Elevation may appear disproportionately large relative to a low-amplitude QRS complex. Often accompanied by dynamic changes, such as evolving T-wave morphology or reciprocal ST-segment depression. Clinical correlation Commonly associated with acute occlusion of the left anterior descending (LAD) artery. Patients may present with significant myocardial ischemia despite not meeting traditional STEMI criteria. Prompt recognition is crucial, as these patients benefit from immediate reperfusion therapy. Terminal QRS distortion These criteria are applied in suspicion of anterior wall infarction. ECG features Absence of both the S-wave and J-wave in leads V2 and/or V3. In leads with an Rs configuration (e.g., V2–V3), the S-wave is absent. In leads with a qR configuration (e.g., V4–V6), the J-point is elevated to ≥50% of the R-wave amplitude. This pattern is distinct from early repolarization. Clinical correlation Highly specific for acute anterior myocardial infarction, particularly involving proximal left anterior descending (LAD) artery occlusion. Terminal QRS Distortion Pathologic Q waves While often a sign of prior infarction, the development of new pathologic Q waves, which may develop within 2 hours of infarction, can be a sign of OMI requiring reperfusion. Aslanger pattern

Aslanger ECG pattern ECG Features: ST-segment elevation isolated to lead III, without elevation in leads II or aVF. ST-segment depression in leads V4–V6 (but not in V2), accompanied by positive or terminally positive T-waves. ST-segment elevation in lead V1 greater than in lead V2. Clinical Correlation: Suggests acute inferior myocardial infarction, often due to occlusion of the left circumflex artery, in the context of multivessel coronary artery disease. Associated with larger infarct size and higher mortality rates, comparable to those seen in STEMI patients. Northern OMI

ECG Features: ST-segment elevation in leads aVR and aVL, often accompanied by negative T-waves. ST-segment depression in inferior leads (II, III, aVF) and lateral precordial leads (V4–V6), with positive or biphasic T-waves. Clinical Correlation: Suggests acute occlusion of the left main coronary artery or proximal left anterior descending (LAD) artery. Represents a high-risk pattern associated with extensive myocardial ischemia. Precordial swirl

ECG features ST-segment elevation in leads V1 and/or aVR. Reciprocal ST-segment depression in leads V5 and/or V6. Hyperacute or disproportionately tall T-waves in leads V1–V2. Absence of left ventricular hypertrophy (LVH) or wide QRS complexes. Clinical correlation Suggests acute occlusion of the proximal left anterior descending (LAD) artery, typically before the first septal perforator. Associated with septal, anterior wall, and apical myocardial ischemia. Often missed by standard STEMI criteria; early recognition is crucial for timely reperfusion therapy. Occlusion of the left circulfex artery Occlusion of the left circumflex artery (LCx) is challenging to detect using standard 12-lead ECG. This difficulty arises because the LCx supplies the lateral and posterior walls of the left ventricle, areas that are less directly represented in the conventional ECG leads. Consequently, LCx occlusions often lack the classic ST-segment elevation patterns seen with occlusions in LAD and RCA, leading to underdiagnosis and potential delays in treatment. The following should lead to suspicion of occlusion in a left circumflex artery not supplying the inferobasal wall (i.e. not resulting. in posterior wall ECG pattern): ST-segment elevation in lateral leads (I, aVL, V5–V6): Elevation in these leads suggests lateral wall involvement, even if changes are subtle. Reciprocal ST-segment depression in inferior leads (III and aVF): This finding can support the diagnosis of lateral wall ischemia, even if changes are subtle. High clinical suspicion: In patients presenting with severe chest pain and an inconclusive ECG, a high suspicion for LCx occlusion should be maintained. Clinical context The diagnosis of OMI is not made in isolation based on ECG findings. The clinical context is paramount. Persistent ischemic symptoms (e.g., chest pain, dyspnea) that are unresponsive to initial medical therapy (such as nitrates), the presence of hemodynamic instability (hypotension, signs of shock), the development of malignant ventricular arrhythmias, or cardiac arrest occurring in the context of typical ischemic symptoms are all strong indicators of an ongoing OMI. These high-risk clinical features should prompt immediate consideration for reperfusion therapy. Cardiac biomarkers Cardiac troponins (I or T) remain the gold standard for confirming myocardial necrosis and diagnosing MI. Very high levels of troponin (e.g., high-sensitivity cardiac troponin T (hs-cTnT) >1000 ng/L or hs-cTnI >200 times the upper limit of normal) can be indicative of a significant infarction due to a major coronary artery occlusion, even if angiography reveals TIMI 3 flow (normal flow). This scenario might suggest spontaneous reperfusion of a previously occluded artery or occlusion with well-developed collaterals that subsequently failed. Artificial Intelligence (AI) AI is rapidly emerging as a powerful tool to aid in the detection of OMI, particularly in identifying subtle ECG patterns that may be missed by traditional STEMI criteria or by algorithmic (i.e. rule-based) computer algorithms. Rule-based algorithms for ECG interpretation operate using predefined criteria, such as fixed thresholds for ST-segment elevation or specific waveform morphologies. While these systems are transparent and computationally efficient (they can run on any machine), they are limited by their design and fail to capture the varied and nuanced patterns of acute coronary occlusions (ACO). They typically miss cases that fall outside of their built-in definitions. In contrast, machine learning, and deep learning in particular, uses learning algorithms that can automatically learn complex, nuanced and non-linear relationships between ECG patterns and outcomes (e.g. angiographic results, troponin levels, etc.). Deep learning has demonstrated significantly improved sensitivity for OMI detection while maintaining acceptable specificity. Other AI models include gradient boosting, which has also proven efficient for creating AI-enabled ECG interpretation. It is likely that the future of ECG interpretation in patients with chest pain will be fully-automated deep learning models that generate likelihoods for all clinically relevant outcomes. Point-of-care echocardiography Bedside echocardiography can be a valuable adjunct in the assessment of suspected OMI, especially when ECG findings are non-diagnostic or equivocal. The identification of new regional wall motion abnormalities can significantly increase the suspicion for OMI and support the decision for urgent angiography. Coronary CT angiography (CCTA) Coronary CT angiography (CCTA) may have a role in selected patients with acute chest pain, primarily to rule out ACS if initial ECG and biomarker evaluations are inconclusive, particularly in low-to-intermediate risk patients. However, CCTA is generally not the primary diagnostic tool in the setting of a highly suspected acute OMI where the priority is rapid access to invasive angiography. Management of OMI Patients identified as having a STEMI-negative OMI should be considered for emergent reperfusion therapy. The goal should be to achieve door-to-balloon times for percutaneous coronary intervention (PCI) or door-to-needle times for fibrinolysis that match the benchmarks applied to STEMI patients. For many STEMI-negative OMI patients, this approach marks a major shift from the conventional NSTEMI care pathway, which often includes an initial period of medical stabilization, risk stratification, and delayed angiography, typically 24 to 72 hours after presentation. However, existing guidelines from the AHA, ACC, and ESC already acknowledge the majority of these principles: current recommendations state that high-risk NSTEMI or unstable angina (UA) patients should undergo urgent angiography regardless of ECG findings. Thus, the primary contribution of the OMI/NOMI framework is not to replace these guidelines but to provide a more explicit diagnostic lens that emphasizes a comprehensive evaluation using advanced ECG interpretation, imaging, biomarkers (troponin), and clinical context. Thus, while a formal transition to the OMI/NOMI approach may not be adopted by major societies such as the ACC, AHA, or ESC, its educational value is substantial. Training clinicians to recognize subtle ECG patterns and to think beyond traditional STEMI criteria fosters a more skilled approach to managing high-risk patients with acute coronary syndromes.

Chapter 4: Clinical application of ECG in chest pain & acute myocardial infarction

An ECG must be performed on all patients seeking medical attention due to chest discomfort or other symptoms that may be caused by myocardial ischemia. Other symptoms include dyspnea, pain radiating to the left arm/shoulder/throat, palpitations, back pain and selected cases of upper abdominal pain. An ECG recording costs approximately $10 (10€) and may reduce morbidity and mortality substantially in patients with acute coronary syndromes. Importantly, the ECG findings dictate the management of acute coronary syndromes. Hence, an ECG must be performed and interpreted within 10 minutes of arrival to the care facility (typically the emergency room [ER]). It is recommended that the 12-lead ECG (conventional ECG) be used for interpretation of ischemia. All available ECG criteria for acute myocardial infarction and ischemia are based on conventional 12-lead ECG. Established ECG criteria do not apply to mathematically derived 12-lead ECGs (e.g EASI, Frank’s leads etc). Note that in some situations it is appropriate to connect additional electrodes in order to detect right ventricular infarction (leads V3R, V4R, V5R, V6R) and posterolateral infarction (leads V7, V8, V9). Criteria for ischemia/infarction have been established for these leads (please refer to ECG leads or Additional leads in acute myocardial infarction). Importance of performing ECG during ongoing chest pain It is of paramount importance to record the ECG during ongoing chest pain if the opportunity is given. An ECG without ischemic ST-T changes when recording during chest pain is not consistent with myocardial ischemia. In other words, chest pain caused by ischemia will always result in ischemic ST-T changes. This is acknowledged in the latest recommendation issued by the International Society for Holter and Non-Invasive Electrocardiology, where it is stated that it is extremely uncommon to have a non-ischemic ECG (absence of ST-T changes) during chest pain caused by myocardial ischemia. This is corroborated by millions of exercise stress tests, where ischemic ECG changes always precede symptoms of ischemia. In summary, if an ECG recorded during chest pain does not display ischemia, then the chest pain is not caused by myocardial ischemia. The ischemic cascade explains why subjective symptoms (chest pain) always occur after ECG changes during myocardial ischemia. Comparison with previous ECG recordings The ECG must be compared to previous ECG recordings if such are available. ST-T changes are extremely common in every population. For example, almost 80% of men display ST segment elevations that are not caused by ischemia and a significant proportion have ST-T changes caused by other pathological conditions (such as bundle branch blocks). Comparing the ECG recordings may reveal if the ST-T segments differ; any difference may be suggestive of myocardial ischemia. It is also important to control the placement of electrodes. Incorrect placement of electrodes, or varying placement between repeated recordings, may cause significant variations in the ECG waveforms. Importance of repeated ECG recordings Acute coronary syndromes are dynamic processes. Factors that promote thrombosis (pro-thrombogenic factors) are constantly in a struggle with factors striving to lysate the thrombus (pro-thrombolytic factors). The balance between pro-thrombogenic and pro-thrombolytic factors varies from one minute to another, which may cause variations in the size of the thrombus. This means that a patient who experienced chest pain at home may be asymptomatic during the assessment in the ER, only to develop severe chest pain and magnificent ST elevations a few minutes later. It is important to note that a traditional 12-lead ECG only presents a few seconds of myocardial electrical activity and there is a chance that ischemic episodes are missed. Indeed, studies (with continuous ST segment monitoring) show that 60% to 75% of ischemic episodes during acute coronary syndromes are asymptomatic. Therefore, it is recommended that repeated 12-lead ECGs be performed in the ER as well as in the ward. Patients at high risk of acute coronary syndromes should be observed with continuous ECG (ST segment) monitoring. Continuous assessment of ST-T changes increases the probability of discovering ischemic ECG changes. The ECG in stable coronary artery disease: angina pectoris Stable angina pectoris occurs when an atherosclerotic plaque causes at least 70% stenosis of the coronary artery. Plaques causing less than 70% stenosis rarely cause stable angina pectoris. Although 70% may appear as much, it is not sufficient to cause ischemic ST-T changes at rest (i.e on resting 12-lead ECG). An exercise stress test with treadmill or bicycle is needed to reveal ischemic ECG changes in patients with stable angina pectoris. The increased myocardial workload during exercise can provoke ischemia and thus ischemic ST-T changes (ST depressions and T-wave inversions). In summary, stable coronary artery disease (angina pectoris) cannot be diagnosed with resting 12-lead ECG. The prehospital ECG The ECG is invaluable in the prehospital setting. It is used to diagnose, risk stratify and guide treatment in patients with acute coronary syndromes. The 12-lead ECG, with conventional electrode placement, should be used in the prehospital setting. Occasionally, prehospital personnel places the limb electrodes on the torso (i.e Mason-Likar electrode placement). This results in an almost identical ECG as the conventional 12-lead ECG, but only almost. The Mason-Likar electrode placement is not approved for interpretation of ischemia on the initial recording (because amplitudes and intervals may differ from conventional 12-lead ECG). However, Mason-Likar electrode placement may be used for ECG monitoring (which is discussed later). Studies have shown that paramedics are excellent interpreters of the ECG. It is, however, common that the paramedic transmits the ECG recording to the nearest hospital so that it can be assessed by a physician, preferably a cardiologist. Advantages of the prehospital ECG The ECG is perhaps the most integral part of the prehospital assessment in acute coronary syndromes because it guides the subsequent treatments and interventions. The prehospital ECG has the following advantages: A diagnosis of myocardial infarction/ischemia can be made already in the prehospital setting. Time to interventions is reduced because the diagnosis is established earlier. The coronary care unit or catheterization laboratory may be prepared early. Time to reperfusion therapy (thrombolysis or PCI) is reduced. Time to administration of evidence-based medications (beta-blockers, statins, aspirin, ticagrelor, clopidogrel, etc) is reduced. It is highly likely that mortality is reduced. The prehospital ECG is also an excellent reference ECG to which future recording (for example in the ER) may be compared. It should be noted that mortality among patients using the EMS (emergency medical system) is usually higher than those capable of transporting themselves to the ER. This is explained by the fact that those utilizing the EMS are older and have more comorbidities. In some studies from the US, almost 50% of patients who called the EMS due to chest pain have ischemic ECG changes. Continuous ischemia ECG monitoring (ST segment monitoring) As discussed above, acute coronary syndromes are dynamic processes and the coronary blood flow may change rapidly. Changes in coronary blood flow have an immediate effect on myocardial membrane potential and thus the ECG. Continuous ECG monitoring allows for uninterrupted assessment of myocardial perfusion. The size of the thrombus, and thus the extent of ischemia, is reflected primarily on the ST-segment. Any deviations in the position of the ST-segment (either ST-segment elevation or ST-segment depression) is suggestive of myocardial ischemia. Continuous ECG monitoring is superior to repeated 12-lead ECGs, which only present a few seconds of myocardial activity. The probability of detecting asymptomatic ischemic episodes (which may constitute 60–75% of all ischemic episodes in patients with acute coronary syndromes) is markedly increased by using continuous ECG surveillance. However, in patients with marked secondary St-T changes due to other conditions (e.g left bundle branch block) the utility of continuous ECG monitoring is much lower and it is usually not performed. ST segment monitoring is done either by means of 12-lead ECG (with limb electrodes placed on the torso according to Mason-Likar) or vectorcardiography (VCG). It was mentioned above that interpretation of ischemia is not recommended on any lead system but the 12-lead ECG. This is true with respect to establishing a diagnosis on the initial recording. For monitoring purposes, however, the initial recording is not interesting, only the changes over time, which is why Mason-Likars electrode placement is suitable. Placement of limb electrodes on the torso results in fewer artifacts from limb muscles. Besides VCG and Mason-Likar 12-lead ECG, there are other lead systems for monitoring (e.g EASI and TruST). Patients with ST elevation myocardial infarction (STEMI / STE-ACS) Patients with STE-ACS must be monitored for at least 25 hours. All patients with STE-ACS who are treated with reperfusion should display rapid normalization of ST segment elevations; this verifies that the reperfusion was successful. In patients receiving thrombolysis, the ST segment elevation must be reduced by 50% within 60 minutes, otherwise rescue-PCI should be considered. The more rapid the normalization of ST segment elevations the better the prognosis. Patients with NSTEMI and unstable angina (NSTE-ACS) Patients with NSTE-ACS should be monitored until 24 hours after the last ischemic episode. The number, magnitude and duration of ischemic episodes must be noted in patients waiting for angiography. The more the ischemia, the faster the angiography is needed. In patients with unstable angina pectoris, the absence of ischemic episodes during 12 hours suggests that the condition has stabilized.

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Chapter 5: Diagnostic Criteria for Acute Myocardial Infarction: Cardiac troponins, ECG & Symptoms

Acute myocardial infarction is the most severe complication of coronary artery disease. The most common initiating mechanism is rupture or erosion of a vulnerable (unstable) atherosclerotic coronary plaque. Upon such damage, the plaque exposes highly thrombogenic materials which activate circulating platelets and coagulation factors, which results in thrombus formation (Figure 1). Disruption of an atherosclerotic plaque may also release atherosclerotic debris downstream, causing microvascular embolization (i.e occluding smaller vessels downstream). The thrombosis causes occlusion of the artery; blood flow may be partially or completely obstructed. Consequently, the myocardium supplied by the occluded artery becomes ischemic. Ultimately this results in myocardial necrosis (death of myocytes) which can be detected by elevated levels of cardiac proteins in the blood. Diagnostic criteria for acute myocardial infarction A diagnosis of myocardial infarction is based on the following three components: Cardiac troponins – Elevation of cardiac troponins in peripheral blood is mandatory to establish a diagnosis of myocardial infarction. ECG – ST elevations, ST depressions, T-wave inversions and pathological Q-waves may be used to diagnose myocardial ischemia and infarction. Symptoms – Patients with acute myocardial infarction may present with typical ischemic chest pain, or with dyspnea, nausea, unexplained weakness, or a combination of these symptoms. The diagnosis requires elevated levels of cardiac troponins. In addition to elevated troponins, the patient must display either symptoms or ECG changes consistent with myocardial infarction/ischemia. Most patients, however, display both ECG changes and symptoms. Troponins and other biomarkers of myocardial necrosis (infarction) Myocardium can endure 20 to 30 minutes of complete ischemia. After this period the cells die and the cell membranes collapse whereby cellular proteins are released into the circulation. It is possible to detect elevated levels of myocardial proteins in blood within 2 to 3 hours after the onset of myocardial infarction. Cardiac troponin T and troponin I have emerged as the preferred biomarkers because they are extremely sensitive and specific for myocardial injury. Elevated levels of cardiac troponins is firm evidence of myocardial necrosis (i.e infarction). This is explained by the fact that there is no (or very little) turnover of myocardial cells and therefore myocardial troponins should not be detected in the blood. It should be noted, however, that current troponin assays are extremely sensitive. These assays, referred to as high-sensitive cardiac troponin, may actually detect the presence of troponins in most normal persons. In 2017 it was possible to detect myocardial infarctions 100 times smaller than what was possible to detect in year 2000. This explains why there has been a 20% increase in NSTEMI and a corresponding decrease in unstable angina in the past two decades (many of those who would previously have been classified as unstable angina are now classified as NSTEMI due to the sensitive troponin assays). Interested readers are referred to E. Braunwald: Unstable angina: is it time for a requiem? Circulation, 2013. Nevertheless, cardiac troponin (T or I) has almost 100% specificity for myocardial cells and is the preferred biomarker according to North American (ACC, AHA) and European (ESC) guidelines. Reference limit for troponins Regardless of how sensitive troponin assays are, it is always possible to define an upper reference limit. Any value above the upper reference limit is considered elevated (abnormal) and thus indicates myocardial necrosis. The upper reference limit is currently the 99th percentile in a healthy population. Troponin levels higher than the 99th percentile of a normal population are considered elevated (abnormal). Criteria for elevated troponins: serial measurements with a rising or falling pattern and at least one value above the upper reference limit A diagnosis of myocardial infarction requires at least two troponin samples. One of these must be elevated (above the upper reference limit) and there should be a change between the two samples, such that troponin levels either rise or fall between the samples. This pattern (with falling or rising troponin) is required to differentiate acutely elevated troponin levels (i.e acute myocardial infarction) from chronically elevated troponin levels (e.g. chronic kidney disease, which leads to reduced renal elimination of troponins from blood). In clinical practice, it is conventional to draw the first troponin sample directly upon arrival to the hospital and then repeat the test after 6 hours. If the first two analyses are negative (i.e troponin levels are normal) but suspicion of infarction persists, a third test may be done after 12 to 24 hours. Troponin levels increase within 2 to 3 hours after the onset of myocardial necrosis. Levels are normalized within 7 days (Figure 2, below). The slow normalization is due to the slow ongoing leakage of troponin from necrotic cells. A negative (i.e normal) troponin 6 hours after the last episode of symptoms rules out myocardial infarction (it does not rule out unstable angina). With high-sensitive troponin assays, it is possible to rule out myocardial infarction after 3 hours. Troponin levels at 24 hours after onset of symptoms may be used to estimate the size of the infarction. Although cardiac troponins are highly specific to myocardial cells, elevated levels do not tell the cause of the elevation. Any condition causing damage to myocardial cells may lead to elevated troponin levels. A common cause of steadily elevated troponin levels is chronic kidney disease (CKD). Individuals with reduced glomerular filtration rate will eliminate troponin slower, which leads to higher baseline levels of troponins. It is wise to analyze troponin I in patients with chronic kidney disease because troponin I is less affected by glomerular filtration. Nevertheless, even in individuals with chronic kidney disease it is possible to analyze any type of cardiac troponin because if the individual has suffered a myocardial infarction, the troponin levels will display dynamics (i.e a rise or fall between two samples). There are numerous causes of elevated troponin levels. A rather comprehensive list follows: Myocardial infarction Chronic and acute kidney failure Cardiac contusion or trauma Acute or chronic heart failure Electrical cardioversion Takotsubo cardiomyopathy Pericarditis and myocarditis (perimyocarditis) Ablation procedures Supraventricular tachyarrhythmia Ventricular tachyarrhythmia Bradyarrhythmia Stroke, subarachnoidal hemorrhage Sepsis (septic shock) Intoxication Extreme physical exercise Aortic dissection Rhabdomyolysis with myocardial damage Pulmonary embolism Severe pulmonary hypertension Amyloidosis Burn injury Severely ill patients Other biomarkers of myocardial necrosis Besides troponins it is possible to analyze CK-MB, total CK and MB but these biomarkers have much lower specificity than cardiac troponins (CK-MB, CK and MB are abundant in skeletal muscle). Figure 2 shows how blood levels of these proteins change during the course of myocardial infarction.

Figure 2. Levels of myocardial proteins in the circulation following myocardial infarction. Note that cardiac troponins peak after 24 to 28 hours after initiation of infarction. CK-MB and MB CK-MB (Creatinin-Kinase MB) is the best alternative if troponin assays are not available. The upper reference limit (99th percentile) and decision process is identical to troponin. CK-MB is, however, less specific than troponin because it is abundant in skeletal muscle. CK-MB has two advantages over troponin: CK-MB is released into the circulation faster (can be detected earlier) and it is normalized earlier (which makes it useful for diagnosing re-infarctions). Refer to Figure 2. MB (myoglobin) is even less specific but can be detected even earlier than CK-MB. Normal MB levels 3 to 4 hours after the last episode of symptoms rule out myocardial infarction. ECG criteria for ischemia & infarction ECG in myocardial ischemia Acute myocardial ischemia manifests on ECG as ST deviation (ST elevation or ST depression) and T-wave changes. ST deviation and T-wave changes are collectively referred to as ST-T changes. ST deviation indicates acute (ongoing) ischemia. In most cases, ST deviations are accompanied by T-wave changes. The latter manifests as T-wave inversions (negative T-waves), flat T-waves (T-waves with low amplitude), or hyperacute T-waves (very large T-waves). As for the T-waves, the following must be noted: Isolated T-wave inversion is never a sign of acute (ongoing) ischemia. Isolated T-wave inversion occurs after the ischemic episode. These T-wave changes are referred to as post-ischemic T-wave inversions. The same is true for flat T-waves. Hyperacute T-waves may, however, be an isolated sign of myocardial ischemia. These T-waves are very broad and very high. ECG in myocardial infarction Myocardial infarction manifests as pathological Q-waves, reduced R-wave amplitude or fragmented QRS complexes. Risk stratification using the ECG Among patients with chest discomfort the ECG correlates strongly with the risk of acute myocardial infarction and 30-days mortality. Table 1 below presents 7 variants of ECG changes; the risk of infarction and 30-days mortality increase gradually from 1 to 7. Table 1. Risk stratification using ECG

ECGCLASSIFICATION OF INFARCTION
1Normal or inconclusive ECGNSTEMI
2Isolated T-wave inversionsNSTEMI
3ST depressionsNSTEMI
4ST depression and T-wave inversionNSTEMI
5Left bundle branch block (LBBB) on presentationPatients with left bundle branch block (LBBB) on presentation pose a special challenge. In the presence of LBBB, the ECG diagnosis of ischemia/infarction is difficult. For years it was recommended that patients with new (or presumably new) LBBB be managed as patients with acute STEMI. However, in 2017 the European Society for Cardiology revised their recommendations; it is now recommended that all patients with a clinical suspicion of ongoing myocardial ischemia and LBBB should be managed similar to acute STEMI patients, regardless of whether the LBBB is previously known or not. This is discussed in detail in LBBB and Acute Myocardial Infarction. With respect to the current discussion, LBBB is associated with a worse prognosis than ST depressions, but a slightly better prognosis than ST elevations.
6ST elevationSTEMI
7ST elevation and ST depressionSTEMI

In patients with acute coronary syndromes, the association between ECG changes and mortality has been examined in several studies. Figure 3 shows results from the legendary GUSTO-II study. As seen in Figure 2, isolated T-wave inversions carry the lowest mortality. Short-term mortality is higher in STEMI than non-STEMI, but long-term mortality is higher in the non-STEMI group which is usually explained by the fact that patients with Non-STEMI are older and have more comorbidities. As seen in Figure 3, roughly 7% of patients with STEMI die within 30 days, as compared with 3–5 % of patients with non-STEMI.

Figure 3. The GUSTO-II study. ECG in guidelines Current guidelines include ECG criteria for ST deviation, T-wave inversion, Q-waves, and R-waves. Hyperacute T-waves and fragmented QRS complexes are not included as criteria for myocardial infarction. The reason for this will be discussed later. ECG criteria for ischemia/infarction must always be evident in at least two anatomically contiguous (i.e neighboring) leads. This is required because it is unlikely that ischemia/infarction will be localized to just one ECG lead. ECG changes in ischemia and infarction will be discussed in great detail in subsequent chapters. Symptoms of acute myocardial infarction and ischemia Angina pectoris is the hallmark of myocardial ischemia. It is described as a retrosternal chest discomfort (pressure, heaviness, squeezing, burning or choking sensation). It is commonly accompanied by radiation of pain to the left shoulder and/or arm. Pain localized in the epigastrium, back, jaw, or neck is also common. Autonomic symptoms such as paleness, cold sweat, anxiety, vomiting are also common. Dyspnea is very common and actually equally common as chest discomfort in older patients (particularly women). The pain lasts longer than 20 minutes in myocardial infarction. Shorter durations are usually episodes of unstable angina. As compared with stable angina pectoris, the symptoms during acute coronary syndromes are more pronounced, present at rest, and do not respond to nitroglycerin. Differential diagnoses Chest discomfort may be explained by a wide range of conditions which must be included as differential diagnoses. In patients presenting with chest discomfort, the following differential diagnoses must be considered: Cardiac: Stable angina pectoris. Acute coronary syndromes. Perimyocarditis. Aortic dissection. Arrhythmias. Valvular disease. Prinzmetal’s angina (vasospasm). Syndrome X (angina without vasospasm but with normal coronary arteries). Pulmonary: Pneumonia. Pleuritis. Pneumothorax. Pulmonary embolism. Pulmonary infarction. Gastrointestinal: Ventricular ulcer. Esophageal reflux. Esophageal rupture. Esophageal spasm. Pancreatitis. Cholecystitis. Musculoskeletal: Tietze’s syndrom. Rib fracture. Trauma/contusion. Post-thoracotomy. Neurogenic pain. Psychiatric: Acute/chronic stress. Anxiety. Depression. Other: Herpes Zoster. Anemia with secondary ischemia. Classification of myocardial infarction according to the ESC The discussion so far has been devoted to myocardial infarction due to coronary atherothrombosis, which is indeed the most common cause of myocardial infarction. However, there are other types of myocardial infarction. Currently, the ACC, AHA and ESC all recommend the following classification of myocardial infarction: Classification of myocardial infarction Type 1: Spontaneous myocardial infarction – Spontaneous myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries leading to decreased myocardial blood flow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe CAD but on occasion non-obstructive or no CAD. Type 2: Myocardial infarction secondary to an ischaemic imbalance – In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between myocardial oxygen supply and/or demand, e.g. coronary endothelial dysfunction, coronary artery spasm, coronary embolism, tachy-/brady-arrhythmias, anaemia, respiratory failure, hypotension, and hypertension with or without LVH. Type 3: Myocardial infarction resulting in death when biomarker values are unavailable – Cardiac death with symptoms suggestive of myocardial ischaemia and presumed new ischaemic ECG changes or new LBBB, but death occurring before blood samples could be obtained, before cardiac biomarker could rise, or in rare cases cardiac biomarkers were not collected. Type 4a: Myocardial infarction related to percutaneous coronary intervention (PCI): Myocardial infarction associated with PCI is arbitrarily defined by elevation of cTn values >5 x 99th percentile URL in patients with normal baseline values (≤99th percentile URL) or a rise of cTn values >20% if the baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischaemia, or (ii) new ischaemic ECG changes or new LBBB, or (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolization, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required. Type 4b: Myocardial infarction related to stent thrombosis – Myocardial infarction associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischaemia and with a rise and/ or fall of cardiac biomarkers values with at least one value above the 99th percentile URL. Type 5: Myocardial infarction related to coronary artery bypass grafting (CABG) – Myocardial infarction associated with CABG is arbitrarily defined by elevation of cardiac biomarker values >10 x 99th percentile URL in patients with normal baseline cTn values (≤99th percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographic documented new graft or new native coronary artery occlusion, or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.

Figures

Chapter 6: Cardiac troponin I (TnI) and T (TnT): Interpretation and evaluation in acute coronary syndromes

Troponin is a protein complex expressed in cardiac and skeletal muscle. The complex consists of troponin I (TnI), troponin C (TnC) and troponin T (TnT), which enable the interaction between actin and myosin and are therefore fundamental to muscle contraction. There are cardiac-specific isoforms of troponin and these are abbreviated cTnI, cTnT, and cTnC. The isoforms cTnI and cTnT are specific to cardiac muscle cells. Cardiac troponin levels are extremely low in healthy subjects; the 99th percentile is less than a few nanograms per liter of blood (typically <5 ng/L). This is explained by the low turnover of cardiac muscle cells (Parmacek et al). Cardiac troponin levels rise within a few hours after the onset of myocardial infarction. This is utilized in clinical practice by detecting troponins in patients with suspected acute coronary syndromes. Several manufacturers have developed highly sensitive troponin assays for troponin I (cTnI) and troponin T (cTNT). The following differences exist between troponin I and T: An increase in troponin I (cTnI) is only seen in myocardial injury. Hence, cTnI is the most cardiac-specific biomarker. Troponin T (cTnT) is cardiac specific but the cTnT assays also detect proteins released from skeletal muscle. Consequently, skeletal muscle damage or inflammation may result in elevated cTnT levels. Although both troponin T and I may be chronically elevated in patients with renal failure, this is more pronounced for troponin T (Seng et al). Troponin I rises faster than troponin T in acute myocardial infarction. Troponin I levels are substantially higher than troponin T levels in acute myocardial infarction. Troponin I levels may be up to 100 times higher than troponin T in the same individual. Hence, higher troponin levels should be expected when converting from troponin T to troponin I assays. No conversion formula (between troponin I and T) has been validated. The risk of interference with antibodies in the blood is higher for troponin I (cTnI). Antibody interference is a rare phenomenon that occurs when troponin forms complexes with immunoglobulins, leading to higher levels of troponin being detected with conventional assays. False positive elevations of troponin are rarely explained by such interference (Bularga et al). Age, sex and renal function affect baseline troponin levels. Troponin levels are up to 3-fold higher in healthy elderly compared with healthy young individuals. Similarly, subjects with severely reduced glomerular filtration rate (GFR) have up to 3-fold higher troponin levels, as compared with individuals with normal GFR. Men have approximately twice as high troponin, as compared with women (Mueller et al, Boeddinghaus et al, Miller-Hodges et al, Twerenbold et al) Kinetics Troponin T (cTnT) and troponin I (cTnI) increase 2-3 hours after the onset of acute myocardial infarction. The maximum troponin value is observed in 12–48 hours. Troponin may be elevated for up to 2 weeks after a heart attack. The larger the infarction, the higher the troponin level and the longer the duration of elevated troponin levels. Differences in absolute concentrations of troponin I and T during acute myocardial infarction As noted above, cardiac troponin I (cTnI) concentrations tend to increase to higher levels than cTnT during acute myocardial infarction. cTnI and cTnT have different molecular structures, which may affect their release into the blood as well as their clearance. cTnI has a smaller molecular weight (35 kDa) than cTnT (37 kDa), and a faster release kinetics. This may explain higher peak levels of cTnI compared with cTnT. Normal values (reference values) URL (upper reference limit): The URL is the upper normal limit of troponin in a normal (healthy) population. It is defined as the 99th percentile in healthy subjects. The 99th percentile varies among different assays (see Table 1), with values between 10 ng/L and 20 ng/L being most common. Elevated troponin: A value above the URL (99th percentile) is considered elevated. The type of assay and algorithm used to rule out or rule in acute myocardial infarction varies across regions and nations. Currently, the 0h / 1h and 0h / 2h algorithms are the most widely used algorithms (discussed below). Fundamental to the diagnosis of acute myocardial infarction is the confirmation of rising and/or falling troponin levels. The changing (i.e rising or falling) levels differentiate acute myocardial infarction from chronic elevations (e.g due to heart failure, renal failure, etc). High-sensitivity troponin (hs-troponin) High-sensitivity troponin (hs-troponin) assays have been adopted in most hospitals. The definition of high-sensitivity assays is that it is able to detect troponin in healthy subjects without myocardial injury (i.e a few nanograms of troponin per liter blood). Thus, high-sensitivity troponin assays can detect troponin in healthy individuals. Values above the 99th percentile for healthy subjects are considered abnormal. High-sensitivity troponin is approximately 1000 times more sensitive than the previous generation of troponin assays. The introduction of high-sensitivity troponin, therefore, resulted in a substantial proportion (approximately 20%) of patients with unstable angina being re-classified as NSTEMI (Braunwald et al, Collet et al, Mueller et al). High-sensitivity troponins have several advantages over previous assays, namely: Hs-troponin assays detect troponin elevations earlier than previous assays. The negative predictive value (NPV) for hs-troponin is higher than in previous assays. A substantial proportion (~20%) of cases previously classified as unstable angina can be correctly classified as NSTEMI. The positive predictive value (PPV) for troponin levels elevated 5-fold the URL is 90% for type 1 myocardial infarction. Troponin in acute myocardial infarction A diagnosis of acute myocardial infarction is made when troponin levels are elevated (with rising or falling levels) and the patient exhibits at least one of the following: ECG changes consistent with myocardial ischemia. Imaging evidence of myocardial infarction (CMR, SPECT, echocardiography). Symptoms consistent with myocardial infarction. Interpretation of elevated troponin levels Myocardial injury (infarction) requires at least one troponin value above the 99th percentile. In acute myocardial injury (including infarction) the troponin level should rise or fall during repeated sampling. To rule in or rule out acute myocardial infarction ≥2 analyses of troponin are obtained. The following algorithms exist (discussed below): The 0 h / 1 h algorithm: Troponin is analyzed immediately on arrival (0 h) and after 1 hour. The 0 h / 2 h algorithm: Troponin is analyzed immediately on arrival (0 h) and after 2 hours. The 0 h / 3 h algorithm: Troponin is analyzed immediately on arrival (0 h) and after 3 hours. In chronic myocardial injury the troponin elevation is typically persistent, without significant dynamics during repeated sampling. Pitfalls, caveats and confounders in interpreting troponin levels Patients with unstable angina pectoris do not have elevated troponin levels. Unstable angina is an acute coronary syndrome (ACS). In the late course and very late course of myocardial infarction (Figure 1), troponin levels may remain relatively unchanged between two measurements (taken at short intervals), thus not allowing for the detection of a clear rise or fall in troponin. The 0 h / 1 h and 0 h / 2 h algorithms apply to all patients in the emergency room, regardless of chest pain onset. However, only a minority of patients in the validation studies presented within 1 hour, which causes some uncertainty in patients presenting very early. Additional measurements of troponin should be considered in patients presenting very early (<1 h after chest pain onset). In less than 1% of cases of myocardial infarction, troponin release is slower than normal, causing a delay in troponin elevation. If suspicion of myocardial infarction remains high, additional troponin measurements should be considered. Causes of elevated troponin levels A long range of conditions can lead to elevated cardiac troponin levels. The magnitude or course of the elevation does not clarify the cause of the injury. The most likely cause of the troponin elevation is indicated by the clinical context. Below follows a list of causes of troponin elevation. Acute myocardial infarction (STEMI, NSTEMI) Cardiac contusion/trauma Acute heart failure or chronic heart failure Takotsubo cardiomyopathy Perimyocarditis (myocarditis, pericarditis) Cardiac procedures CABG PCI Ablation Implantation of pacemaker, ICD or CRT Electrical cardioversion Myocardial biopsy Supraventricular tachyarrhythmia (e.g atrial fibrillation) Ventricular tachyarrhythmia (e.g. ventricular tachycardia) Hypertensive crisis Stroke or subarachnoid hemorrhage Intoxication Extreme physical exertion Aortic dissection Valvular heart disease (e.g aortic stenosis, aortic insufficiency) Rhabdomyolysis with cardiac injury Pulmonary embolism Severe pulmonary hypertension Renal failure Critically ill patients (e.g sepsis, burns, etc) Hypothyroidism Hyperthyroidism Amyloidosis Hemochromatosis Sarcoidosis Scleroderma Cardiotoxic drugs (doxorubicin, 5-fluorouracil, herceptin) Rule in and rule out algorithms The ESC (European Society for Cardiology) advocates the use of early rule out and rule in algorithms. These algorithms have been extensively validated in prospective studies and randomized clinical trials, with all major troponin assays. The algorithms are used in the emergency room to rule in or rule out myocardial infarction. The ESC currently recommends the 0 h / 1 h algorithm, which is currently used in the majority of North America, European and Asian hospitals. The algorithms have very high sensitivity for acute myocardial infarction. Troponin algorithms are not used in patients presenting with ST-segment elevation on ECG. These patients are managed with a primary PCI strategy, meaning that they undergo urgent angiography with readiness to perform PCI. Nurses should obtain troponin measurements immediately on patient arrival (t = 0 h) and after 1 h (± 10 minutes), regardless of patient characteristics. The decisions in the algorithms are based on whether the troponin level is very low, low, high, or if a change (Δ) occurs during repeated measurements after 1, 2 or 3 hours. Each assay has defined the cut-offs for these values, as visible in Table 1. Table 1. Assay-specific cut-offs for troponin levels 0 h/1 h algorithm Very lowLowNo 1 h change (1hΔ) High 1hΔ hs-cTn T (Elecsys; Roche) <5 <12 <3 ≥52 ≥5 hs-cTn I (Architect; Abbott) <4 <5 <2 ≥64 ≥6 hs-cTn I (Centaur; Siemens) <3 <6 <3 ≥120 ≥12 hs-cTn I (Access; Beckman Coulter) <4 <5 <4 ≥50 ≥15 hs-cTn I (Clarity; Singulex) <1 <2 <1 ≥30 ≥6 hs-cTn I (Vitros; Clinical Diagnostics) <1 <2 <1 ≥40 ≥4 hs-cTn I (Pathfast; LSI Medience) <3 <4 <3 ≥90 ≥20 hs-cTn I (TriageTrue; Quidel)<4 <5 <3 ≥60 ≥8 0 h/2 h algorithm Very lowLow No 2 h change (2hΔ) High2hΔ hs-cTn T (Elecsys; Roche) <5 <14 <4 ≥52 ≥10 hs-cTn I (Architect; Abbott) <4 <6 <2 ≥64 ≥15 hs-cTn I (Centaur; Siemens) <3 <8 <7 ≥120 ≥20 hs-cTn I (Access; Beckman Coulter) <4 <5 <5 ≥50 ≥20 hs-cTn I (Clarity; Singulex) <1 TBD TBD≥30 TBDhs-cTn I (Vitros; Clinical Diagnostics) <1 TBD TBD≥40 TBDhs-cTn I (Pathfast; LSI Medience) <3 TBD TBD≥90 TBDhs-cTn I (TriageTrue; Quidel) <4 TBD TBD≥60 TBDCollet et al. TBD = to be determined. 0 h / 1 h algorithm

The flowchart below shows how the 0 h / 1 h algorithm. Troponin is analyzed at 0 h (on arrival) and at 1 h. According to the ESC, this is the best method and it should be preferred over the 0 h / 2 h and 0 h / 3 h algorithms (Wildi et al). The same principle is applied for the 0 h / 2 h algorithm, but with different cut-offs according to Table 1. Cardiac troponin in sudden cardiac arrest Cardiac-specific Troponin T (TnT) and Troponin I (TnI) are often analyzed in cases of out-of-hospital cardiac arrest to determine whether the cardiac arrest was caused by an acute myocardial infarction. The rationale behind this is that myocardial necrosis commences after 20 minutes of complete myocardial anoxia. Thus, cardiac arrests due to causes other than acute myocardial infarction should present with low levels of troponins, as opposed to infarction-caused cardiac arrests, which should result in high troponin levels. However, it is questionable whether troponin can be used for this purpose. In a study of 145 patients who regained circulation after cardiac arrest and underwent serial troponin measurements and echocardiographic examinations, all individuals had elevated troponin levels. Therefore, troponin levels could not be used to distinguish infarction-related cardiac arrest from other causes. Troponin levels also did not correlate with survival or left ventricular function (Agusala et al.). References 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) Jean-Philippe Collet, Holger Thiele, Emanuele Barbato, Olivier Barthélémy, Johann Bauersachs, Deepak L Bhatt, Paul Dendale, Maria Dorobantu, Thor Edvardsen, Thierry Folliguet et al. European Heart Journal (2020). Rubini Gimenez M, Twerenbold R, Reichlin T, et al. Direct comparison of high-sensitivity-cardiac troponin I vs. T for the early diagnosis of acute myocardial infarction. Eur Heart J. 2014 Sep 7;35(34):2303-11. Gore MO, Seliger SL, Defilippi CR, et al. Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay. J Am Coll Cardiol. 2014 Apr 15;63(14):1441-8. Lee KK, Ferry AV, Anand A, et al; High-STEACS Investigators. Sex-Specific Thresholds of High-Sensitivity Troponin in Patients With Suspected Acute Coronary Syndrome. J Am Coll Cardiol.2019 Oct 22;74(16):2032-2043. Mueller T, Egger M, Peer E, et al. Evaluation of sex-specificcut-off values of high-sensitivity cardiac troponin I and T assays in an emergency department setting – Results from the Linz Troponin (LITROP) study. Clin Chim Acta. 2018 Dec;487:66-74. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J 2019;40:237-69. Shah ASV , Anand A , Strachan FE , Ferry AV , Lee KK , Chapman AR , Sandeman D , Stables CL , Adamson PD , Andrews JPM , Anwar MS , Hung J , Moss AJ , O’Brien R , Berry C , Findlay I , Walker S , Cruickshank A , Reid A , Gray A , Collinson PO , Apple FS , McAllister DA , Maguire D , Fox KAA , Newby DE , Tuck C , Harkess R , Parker RA , Keerie C , Weir CJ , Mills NL , High-STEACS investigators. High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial. Lancet 2018;392:919–928. Wildi K, Nelles B, Twerenbold R, Rubini Gimenez M, Reichlin T, Singeisen H, Druey S, Haaf P, Sabti Z, Hillinger P, Jaeger C, Campodarve I, Kreutzinger P, Puelacher C, Moreno Weidmann Z, Gugala M, Pretre G, Doerflinger S, Wagener M, Stallone F, Freese M, Stelzig C, Rentsch K, Bassetti S, Bingisser R, Osswald S, Mueller C. Safety and efficacy of the 0 h/3 h protocol for rapid rule out of myocardial infarction. Am Heart J 2016;181:16–25. Unstable angina: is it time for a requiem? Eugene Braunwald, David A Morrow. Circulation . 2013 Jun 18;127(24):2452-7. doi: 10.1161/CIRCULATIONAHA.113.001258.

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Chapter 7: Myocardial Ischemia & infarction: Cellular changes, ECG and symptoms

Like all other cells in the human body, cardiac myocytes use ATP (adenosine triphosphate) as the primary energy source. ATP is produced by metabolizing carbohydrates (glucose), fats or proteins, whichever is available. ATP fuels all cellular functions, such as contraction and relaxation. Increasing cardiac workload by increasing heart rate and contractility (i.e contractile force), results in increased metabolism. Cardiac cells are highly capable of matching the supply and demand of ATP; increased cardiac workload results in increased ATP production and vice versa. Importantly, cardiac myocytes require aerobic metabolism (oxygen) to produce sufficient quantities of ATP. This implies that the heart requires continuous blood flow to maintain cellular function.

Myocardial ischemia occurs when there is insufficient oxygen available. Insufficient oxygen supply results in diminished ATP production and subsequently disruption of cellular metabolism. In case of ischemia, cardiac myocytes protect themselves by switching to anaerobic metabolism. This is possible because cardiac myocytes store glycogen (a storage form of glucose) which can be used to produce ATP in absence of oxygen. Unfortunately, glycogen yields only small amounts of ATP and glycogen supplies are limited. In order to reduce oxygen demands, cardiac myocytes stop contracting under anaerobic conditions (i.e during ischemia). These two measures – i.e switching to anaerobic metabolism and discontinuing the contractions – enables the myocardium to endure 20 to 30 minutes of severe ischemia. If myocardial perfusion (blood flow) in the ischemic zone is not restored before that time limit, the cell will die.

Figure 1. Myocardial cells require a continuous oxygen supply in order to maintain normal metabolism. If oxygen supply is less than oxygen demand, ischemia develops. Myocardial cells can switch to anaerobic metabolism and discontinue contractions in order to alleviate the ischemia. This enables the cell to endure up to 30 minutes of severe ischemia. If blood flow is not restored before 30 minutes, the cell will die. Death of myocardial cells is referred to as myocardial infarction.

Myocardial ischemia in clinical practice: coronary artery disease

In clinical practice, myocardial ischemia occurs in numerous situations. In stable angina pectoris, there are atherosclerotic plaques which limit coronary blood flow and cause symptoms during increased myocardial workload (exercise). The more severe the stenosis, the more pronounced the symptoms. Stable angina pectoris is diagnosed by means of exercise stress testing (exercise ECG). The purpose of the stress test is to increase the myocardial workload (and thus the oxygen demand) in order to provoke ischemia in myocardium supplied by atherosclerotic arteries. This engenders the typical ECG changes as well. In acute coronary syndromes, however, symptoms and ECG changes are manifest at rest because of the severe reduction of coronary flow caused by acute atherothrombosis.

Table 1: Myocardial and ECG reaction in various settings with ischemia or increased workload

STATUS OF CORONARY ARTERYSETTINGEFFECTECG REACTION
Normal coronary artery (no atherosclerosis)At restOxygen supply is adequate and ischemia cannot occur.No changes on resting ECG.
Increased myocardial workload (exercise)Oxygen supply increases in parallel with increased oxygen consumption during exercise. Thus, supply and demand are balanced and no ischemia occurs. (Some individuals display a benign form of ischemia located in the subendocardium during exercise; this manifests with ST-segment depressions with upsloping ST-segment during exercise but the person is asymptomatic).No changes on resting ECG.Benign ST-segment depression has an upsloping ST-segment during exercise stress testing.
Stable coronary artery disease (atherosclerotic plaque causing 70% stenosis or more)At restNo symptoms.No changes on resting ECG.
Increased myocardial workload (exercise)Oxygen demand increases with workload but the stenosis (atherosclerotic plaque) limits the needed increase in blood flow, which results in myocardial ischemia. The ischemia manifests as chest pain. This type of ischemia (induced by increased workload) is located in the subendocardial muscle layer. It is reversible and will resolve when the exercise is stopped. Only on rare occasions (if the ischemia is severe and prolonged) does this result in troponin leakage (i.e cell death).Exercise stress testing is used to provoke the same ischemic process and this may reveal ST segment depressions, diminished T-wave amplitude and, on rare occasions, ST-segment elevations.
Stable but severe coronary artery disease (atherosclerotic plaque causing 90% stenosis or more)At restOxygen supply increases in parallel with increased oxygen consumption during exercise. Thus, supply and demand is balanced and no ischemia occurs. (Some individuals display a benign form of ischemia located in the subendocardium during exercise; this manifests with ST-segment depressions with upsloping ST-segment during exercise but the person is asymptomatic).Resting ECG may show ST-deviation and/or T-wave changes.
Plaque rupture/erosion with ensuing acute coronary syndromeAny timeTransmural ischemia causes ST-segment elevation. Subendocardial ischemia causes ST-segment depressions. Symptoms are pronounced (particularly in transmural ischemia) and are not alleviated by resting or administering nitroglycerin.Resting ECG shows ST-deviation, T-wave changes and occasionally QRS changes
Any status of coronary arteryCoronary artery vasospasmSevere atherosclerosis may cause ischemia already at rest. This is a serious condition that lies between stable atherosclerosis and acute coronary syndrome.Resting ECG usually shows ST-segment elevations which indicates that the ischemia is transmural

Time is muscle: 30 minutes from myocardial ischemia to infarction

The duration of ischemia is crucial when an occlusion has occurred. Myocardium supplied by the occluded artery immediately becomes ischemic and ceases to contract. As mentioned above, the cells revert to anaerobic metabolism to maintain viability. This enables the cell to endure 20–30 minutes of ischemia. If coronary flow is restored within that period, all ischemic myocardium will recover (after a brief period of contractile dysfunction [called stunned myocardium]). If coronary flow is not restored, infarction will commence and the necrosis will spread like a wavefront in water, starting in the most ischemic area, which is the subendocardium. From there the infarction will spread towards the epicardium. Refer to Figure 2.

Figure 2. The natural course in total occlusions (transmural ischemia).

The time it takes for all ischemic myocardium to become infarcted is of great interest. In the literature it is traditionally suggested that the infarction is completed within 4 to 6 hours but this is questioned by newer studies which suggest longer durations. Recent studies actually suggest that the infarction may be completed anywhere between 2 to 12 hours after onset of symptoms. This wide time range is due to factors that modify the natural course. One such factor is the presence of collateral coronary circulation.

Total occlusions (which result in acute STEMI) are generally persistent until virtually all ischemic myocardium is infarcted (unless reperfusion therapy is successful). One-third of all total occlusions are recanalized spontaneously within 12–24 hours (the coronary arteries have a thrombolytic system that handles the thrombus, albeit too late). It should be noted, however, that although the vast majority of the affected myocardium will be necrotic by the time the artery is recanalized, restoration of blood flow may improve contractile function and prognosis. This is because there may be hibernating myocardium in or near the affected area. Hibernating myocardium is severely ischemic but viable and may recover fully if blood flow is restored. Moreover, restoration of blood flow improves healing of the infarct area (which yields a stronger scar) and slows ventricular remodeling (which leads to heart failure).

Figure 3 illustrates how the infarction spreads from the subendocardium towards the epicardium. The reason why the infarction starts in the subendocardium is simply because it has the poorest prerequisites in case of ischemia. The subendocardium is located too far away from the ventricular cavity in order to enjoy oxygen from the cavity. Moreover, it receives blood which has already been extracted of much of its oxygen as it has passed through the bulk of the ventricular wall (coronary blood flow is directed from the epicardium to the endocardium (Figure 3).

Figure 3. Coronary blood flow.

Chapter 8: The left ventricle in myocardial ischemia and infarction

Acute myocardial infarction (AMI) always affects the left ventricle

Myocardial infarction is virtually synonymous with left ventricular infarction. All myocardial infarctions affect the left ventricle. Right ventricular infarction is uncommon but may occur if there is a proximal occlusion in the right coronary artery (RCA). Nevertheless, if the right ventricle is affected, then the left ventricle is virtually always affected due to the coronary anatomy (refer to the chapter Coronary Arteries and Localization of Infarction & Ischemia). Figure 1 shows a detailed view of the coronary arteries.

Figure 1. The right ventricle is supplied by the right marginal artery (r. marginalis dx), which originates from the right coronary artery (RCA). The RCA also supplies the inferior left ventricular wall in over 90% of all individuals. Hence, a proximal occlusion (in the RCA) which cuts off blood flow to the right ventricle, will also affect the inferior wall of the left ventricle in 90% of the cases.

As compared with the right ventricle, the left ventricle contracts against much greater resistance (i.e. the pressure in the systemic circulation), and therefore it faces the highest workload; for the same reason, the left ventricle has the highest oxygen demand. The right ventricle and the atria work against much lower resistances and therefore have lower oxygen demands. The wall thickness is considerably thinner in the atria and right ventricle, as compared with the left ventricle. Indeed, the atrial myocardium consists of such a thick layer that much of it may receive oxygen directly from the blood within the atrial cavity. The left ventricle is considerably thicker and – except the endocardium – it cannot utilize the oxygen from within the ventricular cavity.

The location of acute myocardial infarction refers to the area of the left ventricle

When specifying the location of myocardial infarction, reference is being made to the left ventricle. For this purpose, the left ventricle is subdivided into 4 walls: inferior, anterior, lateral and septal wall (Figure 2 below). An inferior myocardial infarction refers to an infarction located in the inferior wall of the left ventricle. An anterior myocardial infarction refers to an infarction located in the anterior wall of the left ventricle and so on.

Figure 2. The anatomy of the left ventricle.

As mentioned before, the subendocardium of the left ventricle has the poorest prerequisites in case of ischemia. The infarction process starts in the subendocardium from where it spreads to the epicardium. Purkinje fibers often manage to survive ischemia. This is probably explained by the fact that the Purkinje fibers run through the endocardium. It is likely that conduction defects would have been more common in myocardial ischemia otherwise.

Chapter 9: Factors that modify the natural course in acute myocardial infarction (AMI)

The traditional distinction between NSTE-ACS (NSTEMI, Non-STEMI) and STE-ACS (STEMI) is slightly simplified. In reality, the course in acute myocardial infarction (AMI) is modified by several factors. The most important of these, and their implications, are as follows:

The size of the thrombus (i.e the degree of artery obstruction): The greater the obstruction the more extensive the ischemia/infarction.

The location of the thrombus in the artery: a proximally located thrombus will cut off blood flow to more branches, and thus more myocardium, as compared with a distally located thrombus.

The duration of the ischemia: the longer the duration of the ischemia, the more extensive the infarction.

These three are the most important determinants of infarct size. However, there are additional factors that deserve mention.

Collateral circulation: connected coronary arteries

Coronary collateral circulation may be extremely important. Collateral circulation develops in ischemic myocardium because longstanding ischemia causes the myocardium to secrete growth factors (particularly VEGF [vascular endothelial growth factor]) which stimulate nearby arteries to grow new vessels into the ischemic zone. Newly formed vessels, which may originate from other branches of the same coronary artery or another coronary artery, will alleviate the ischemia, improve myocardial function and increase resistance to episodes of more severe myocardial ischemia.

Collateral circulation may be very effective in reducing ischemia. Indeed, it may be so efficient that a total occlusion in the main artery may not lead to infarction due to the collaterals. Occasionally, patients with total and proximal occlusions may present without ST-segment elevations (which they should exhibit) due to rich collateral circulation in the ischemic area. Moreover, intensive collateral circulation may also prevent ischemia from occurring during exercise stress testing, which leads to false negative stress tests. Studies have shown that if the myocardium obtains 30% of its resting perfusion from collaterals, it may survive for 60 minutes in the case of a total occlusion or >5 hours in the case of a partial occlusion.

Coronary artery anatomy

There is individual variation in the coronary artery anatomy. These details will be discussed in later chapters. As for now, it is sufficient to note that the more myocardium supplied by an artery, the greater the ischemic area in case of occlusion.

Ischemic preconditioning: preparing for ischemia

The concept of ischemic preconditioning was developed two decades ago. In experiments conducted in the canine heart, it was shown that applying a 5-minute occlusion-reflow cycle repeatedly to the circumflex artery before a 60-minute occlusion of the left anterior descending coronary artery (LAD) would reduce the infarct size by 60%, as compared with directly occluding the LAD. Hence it was believed that the muscle could be preconditioned (acclimatized, adapted) to ischemia from a distance. It was, and still is, suggested that ischemic myocardium secretes protective substances that affect and precondition the metabolism of myocardial cells.

Researchers have pushed the notion that repeated cycles of transient ischemia induce the protective effect. Some studies (including randomized clinical trials) have suggested the benefit of ischemic preconditioning, while other studies have failed to establish such a relation. The most cited study to date, Botker et al, reported that remote ischaemic conditioning increases myocardial salvage. The reason why this is highly relevant is that the identification of a protective factor could guide the development of a pharmacological agent that can alleviate ischemia by inducing the same effect. Nevertheless, the mechanisms underlying ischemic preconditioning, and whether the phenomenon actually exists, remain elusive. Several studies (Hausenloy et al.) have failed to show any effect of remote ischemic conditioning.

Cardioprotective medications

Beta-blockers have a negative chronotropic and inotropic effect which means that they slow the heart rate and diminish contractility. This reduces myocardial metabolism and thus ischemia. Studies performed in the 1980s and 1990s showed that the administration of beta-blockers could limit infarct size (Yusuf et al, Swedberg et al, Herlitz et al).

Aspirin, if administered early, is highly effective in reducing infarct size. Early studies conducted decades ago showed that aspirin may reduce the risk of death by 50% in STE-ACS (STEMI) and 20–30% in NSTE-ACS (Non-STEMI).

Statins do not affect the risk of infarction/mortality in the short-term, but certainly in the long term. Statins lower LDL cholesterol, which results in lower risk of acute myocardial infarction, stroke and cardiovascular mortality.

Interestingly, studies show that the more cardioprotective medications in use, the lower the risk of developing STE-ACS in the case of acute coronary syndromes. Hence, these evidence-based medications may reduce the risk of developing total and proximal occlusions.

Circulatory stress: tachycardia, anemia and hypotension

Tachycardia, anemia and hypotension aggravate the situation in acute coronary syndromes and lead to larger infarctions if left untreated.

(none)

Chapter 10: ECG in myocardial ischemia: ischemic changes in the ST segment & T-wave

This chapter discusses typical and atypical changes in the ST segment and the T-wave during myocardial ischemia. A thorough discussion of the electrophysiological principles, ECG changes and clinical implications is provided. The reader should already be familiar with the classification of acute coronary syndromes. Subsequent chapters will deal with ST segment elevation myocardial infarction (STEMI) and non ST segment elevation myocardial infarction (Non-STEMI, NSTEMI) in detail. Although myocardial ischemia may affect every aspect of the ECG – from heart rhythm to QTc interval – the most prominent and reliable ECG changes occur in the ST segment and the T-wave. This chapter focuses mainly on ST segment deviations (ST segment depression, ST segment elevation) and T-wave changes.

The reader may wish to view the video lecture on The ST segment, J point, J 60 point and T-wave to facilitate understanding of this chapter.

The normal ST segment and T-wave

The ST segment

The ST segment represents the plateau phase (phase 2) of the cardiac action potential. It stretches from the J point to the onset of the T-wave (Figure 1 A). The plateau phase has a long duration which enables the majority of the ventricular myocardium to contract simultaneously. Since the membrane potential is relatively unchanged during the plateau phase, the potential differences in the myocardium will be small during this phase. Therefore, the ST segment should be isoelectric, which means that it should be flat and on the same level as the baseline (recall that the baseline is the level of the PR segment). Refer to Figure 1 B.

Figure 1. (A) The relation between the action potential and the ECG curve. Myocardial ischemia primarily affects repolarization, which is reflected in ST-T changes on the ECG. (B) Note that the reference level for measuring deviation (elevation or depression) of the ST segment is the PR segment (the terminal portion of the PR interval). (C) and (D) Shows how to measure the magnitude of ST segment elevation and ST segment depression. The J 60 point is located 60 ms after the J point.

The T-wave

The transition from the ST segment to the T-wave is smooth, as is the transition between phases 2 and 3 of the action potential (Figure 1 A). The T-wave represents the rapid repolarization phase (phase 3). The T-wave is normally concordant with the QRS complex, which means that a net positive QRS complex should be followed by a positive T-wave and vice versa (a net negative QRS complex is normally followed by a negative T-wave).

Normal findings regarding the direction of the T-wave

Lead I, II, –aVR, V5 and V6 should display positive T-waves in adults.

Lead aVR normally displays a negative T-wave.

Lead III may occasionally display an isolated T-wave inversion. This is considered normal if the neighboring lead (aVF) does not display T-wave inversion.

Lead aVL may also occasionally display an isolated T-wave inversion.

Lead aVF: positive T-wave, but occasionally flat.

Lead V1: Inverted or flat T-wave is rather common, particularly in women. The T-wave inversion is concordant with the QRS complex.

Leas V7–V9: should display a positive T-wave.

ST segment changes are typically accompanied by T-wave changes

Because phase 2 and phase 3 are electrophysiologically related, changes in the ST segment are typically accompanied by T-wave changes on the ECG. The term ST-T changes is commonly used in clinical practice to refer to changes occurring on the ST-T segment (from the J point to the end of the T-wave).

Ischemic ST-T changes

Ischemia affects the plateau phase (phase 2) and the rapid repolarization phase (phase 3), which is why ischemia causes changes to the ST segment and T-wave (ST-T changes). The ST segment may be either elevated or depressed. The T-wave may diminish in amplitude (flat T-waves), become negative (T-wave inversion) or even increase markedly in amplitude (hyperacute T-wave).

Which of these ST-T changes occur depends on the localization, extension and timing of the ischemia. For example, ST-T changes early in ischemia differ from those in later phases. Moreover, a wide range of other conditions may cause similar ST-T changes and every clinician must be able to differentiate between ischemic and non-ischemic ST-T changes.

Myocardial ischemia causes changes to the ST segment and T-wave (ST-T changes).

The ST segment may be either elevated or depressed (in relation to the PR segment). This is referred to as ST segment elevation and ST segment depression.

The T-wave may diminish in amplitude (flat T-waves), become negative (T-wave inversion) or even increase markedly in amplitude (hyperacute T-wave).

Measuring ST segment elevation and depression on ECG

In the case of ST segment elevation or ST segment depression, the magnitude of the elevation or depression must be measured. ST segment elevation is measured from the baseline (i.e. the reference level, which is the level of the PR segment) to the J point. The J point is the point where the QRS complex ends and the ST segment starts (J stands for junction). ST segment depression is also measured from the same baseline to the J point. Refer to Figure 1 panels B, C and D. Hence, ST segment depression implies that the J point is located below the baseline and ST segment elevation implies that the J point is located above the baseline. Refer to Figure 2. If the PR segment is difficult to discern, one may use the TP segment (the line between the T-wave and the P-wave) as the reference level, but this is rarely needed.

Figure 2. Examples of measuring ST segment elevation and ST segment depression. Myoardial ischemia is very likely if these ECG changes are accompanied by chest discomfort or other symptoms suggestive of ischemia.

Electrophysiological explanations to ischemic ST-T changes: injury currents

The electrophysiological explanations for ischemic ST-T changes have been debated since year 1909 when Eppinger and Rothberger first described ischemic ECG changes. There is no robust theory as to why ischemia induces ST-T changes. However, it is generally acknowledged that ischemia primarily affects the repolarization (phase 2 and phase 3) but it also affects the resting membrane potential (phase 4), by making it less negative. Ischemia also reduces the duration of the action potential. Hence, the action potential in ischemic myocardium will differ from that of non-ischemic myocardium. Differences in the action potential lead to electrical potential differences between normal and ischemic myocardium. These potential differences will result in electrical currents – referred to as injury currents – between normal and ischemic myocardium during systole (due to changed action potential) and diastole (due to changed resting membrane potential). It is generally accepted that these injury currents explain the emergence of ST segment elevations and depression, as well as T-wave changes.

The two main types of ischemia are transmural and subendocardial ischemia. Transmural ischemia implies that the entire wall thickness – from endocardium to epicardium – is affected in the area supplied by the occluded coronary artery. In subendocardial ischemia, only the subendocardium is affected.

Transmural ischemia: ST segment elevation myocardial infarction (STEMI, STE-ACS)

The injury currents in transmural ischemia (which manifests as STE-ACS and leads to STEMI) redirect the ST vector such that it becomes directed from the endocardium to the epicardium in the ischemic area (Figure 3). This leads to ST segment elevations in the leads which observe the ischemic area. For example, ST segment elevations in V3–V4 indicate ongoing transmural ischemia located in the anterior wall of the left ventricle. The more intensive the ischemia, the greater the ST segment elevation. Similarly, the larger the affected area, the more ECG leads will display ST segment elevation.

Although ST-segment elevations are the hallmark of transmural ischemia, they are actually preceded by hyperacute T-waves. These T-waves are symmetric, broad-based and have high amplitude. They occur immediately (within seconds) following occlusion of the coronary artery. It is believed that hyperacute T-waves are caused by increased concentrations of potassium (along with changes in repolarization) in the ischemic area. Hyperacute T-waves have a short duration and they diminish within a few minutes, after which the ST segment becomes elevated.

Since hyperacute T-waves are of very short duration and they arise the moment that the occlusion occurs, it is uncommon to spot these in clinical practice. However, clinicians who regularly see patients with chest discomfort will certainly encounter hyperacute T-waves every now and then (ischemia is a highly dynamic process and some patients will develop a complete occlusion while monitored). Also, note that high T-waves (but not hyperacute) may persist for a few hours following the occlusion.

It should also be noted that ECG leads whose exploring electrode is angled approximately opposite to the leads showing ST-segment elevations may show ST segment depressions. This is simply because these leads record the same ST-vector, but from the opposite direction. Such ST-segment depressions are referred to as reciprocal ST-segment depressions.

Figure 3. Injury currents in transmural myocardial ischemia. Note that ST segment elevation myocardial infarction (STEMI/STE-ACS) usually also causes ST-segment depressions in leads that are opposite to the leads displaying the ST segment elevations. However, the primary ECG change in STEMI/STE-ACS is the ST segment elevations.

Subendocardial ischemia: Non ST segment elevation myocardial infarction (Non-STEMI/NSTEMI, NSTE-ACS)

The injury currents in subendocardial ischemia (which manifests as NSTE-ACS) redirect the ST-vector such that it becomes directed from the epicardium to the endocardium and the back (Figure 4). This results in ST-segment depressions and T-wave inversions. However, the leads displaying these ECG changes are not necessarily indicative of the ischemic area. In other words, ST-segment depressions or T-wave inversions in leads V3–V4 do not indicate that the ischemia is located anteriorly. It follows that ST-segment depressions and T-wave inversions cannot localize the ischemic area.

Figure 4. Injury currents in subendocardial ischemia. These are the hallmarks of non-ST segment elevation myocardial infarction (NSTEMI/Non-STEMI).

Chapter 11: ST segment depression in myocardial ischemia and differential diagnoses

ST segment depression due to acute myocardial ischemia

ST segment depressions caused by ischemia are characterized by a horizontal or downsloping ST segment. Indeed, North American and European guidelines assert that the ST segment must be either downsloping or horizontal. Otherwise, ischemia is unlikely to be the cause of the ST segment depression. The horizontal ST segment depression is more specific than the downsloping depression. Refer to Figure 1.

Figure 1. Characteristics of ischemic ST segment depressions on ECG.

Current guideline criteria for ischemic ST segment depression:

New horizontal or downsloping ST segment depressions ≥0,5 mm in at least two anatomically contiguous leads.

The transition from ST segment to T-wave is more abrupt in ischemia (the transition is normally smooth). Refer to Figure 2.

Figure 2. Transition from ST segment to T-wave in ischemia.

Ischemic ST segment depressions occur in both NSTE-ACS (NSTEMI and unstable angina pectoris) and STE-ACS (STEM). However, the significance of the ST segment depression differs markedly in NSTE-ACS and STE-ACS. In NSTE-ACS the ST segment depressions are the primary ischemic ECG changes. ST segment depressions in NSTE-ACS are frequently accompanied by T-wave inversions (or flat T-waves), but the primary ECG finding is the ST segment depressions. In STE-ACS, on the other hand, the ST segment depressions are secondary findings and the primary findings are the ST segment elevations. As explained in the previous article, ST segment depressions in STE-ACS are actually reciprocal (mirror images) to ST segment elevations.

ST segment depressions with upsloping ST segment are rarely caused by ischemia, with one notable exception. Occurrence of upsloping ST segment depressions with prominent T-waves in the majority of the chest leads may indicate an acute occlusion in the LAD (left anterior descending artery). This ECG pattern is referred to as de Winter’s ECG.

Figure 3 provides all clinically relevant differential diagnoses, and their ECG appearance, to ischemic ECG changes. This figure must be studied carefully.

Figure 3. Differential diagnoses in ST-segment depressions.

Differential diagnoses in ST segment depressions

Please refer to Figure 3 for examples.

Normal (physiological) ST segment depressions

Normal (physiological) ST segment depressions occur during physical exercise. These ST segment depressions have an upsloping ST segment. The depression in the J 60 point is usually <1 mm and it resolves rapidly once the exercise is stopped. Some experts believe that these ST segment depressions represent a benign form of subendocardial ischemia. Refer to Exercise Stress Testing for details.

Hyperventilation

Hyperventilation causes ST segment depressions very similar to those normally seen during physical exercise.

Left ventricular hypertrophy (LVH), right ventricular hypertrophy (RVH), left bundle branch block (LBBB), right bundle branch block (RBBB) and pre-excitation

Left ventricular hypertrophy (LVH), right ventricular hypertrophy (RVH), left bundle branch block (LBBB), right bundle branch block (RBBB) and pre-excitation (WPW syndrome) may all cause ST segment depressions. These are all common conditions in which an abnormal depolarization (QRS complex) causes abnormalities in the repolarization (ST-T-segment). For example, a block in the left bundle branch (i.e left bundle branch block) means that the left ventricle will not be depolarized via the Purkinje network, but rather via spread of the depolarization from the right ventricle. The abnormal ventricular depolarization will cause an abnormal repolarization. For this reason, these ST-T changes are referred to as secondary ST-T changes. It is actually expected that these conditions display such secondary ST-T changes; the absence of such changes should lead to suspicion of ischemia (if the patient has symptoms consistent with ischemia). The same is true for artificial pacemakers (virtually all pacemakers stimulate the ventricles in the right ventricular apex). Thus, it is expected to observe secondary ST-T changes during pacemaker rhythm.

Digoxin

Digoxin (digitalis, digitoxin) causes downsloping ST depression with a characteristic “sagging” appearance.

Sympathetic stimulation and hypokalemia

Sympathetic stimulation and hypokalemia cause non-specific ST segment changes.

Heart failure

Heart failure may cause ST segment depressions in left-sided leads (V5, V6, I and aVL). These depressions are horizontal or downsloping.

Supraventricular tachycardia

Supraventricular tachycardia may also cause ST segment depressions. These depressions are usually horizontal or upsloping and tend to be most evident in leads V4–V6. these ST segment depressions resolve rapidly once the tachycardia has resolved.

A novel cardiac syndrome with concave-upward ST-segment depressions

In November 2018 researchers from Denmark, Netherlands and United Kingdom reported a novel ECG syndrome characterized by widespread ST-segment depressions  and an increased risk of sudden cardiac arrest. The researchers identified five unrelated families with features that represent a previously unrecognized autosomal dominant syndrome (Figure 4). The ECG is characterized by deep and persistent, concave-upward ST-segment depression in multiple limb and chest leads. ECG changes are stable over time and accentuated during exercise. Patients present with syncopal episodes, ventricular tachycardia (including torsade de pointes), ventricular fibrillation and sudden cardiac arrest.

Figure 4. 12-lead ECG (presented according to Cabrera), recorded at 63 years of age, demonstrates concave-upward ST-segment depression in leads I, II, aVL, aVF, and V2 through V6; and ST-segment elevation in lead aVR (which corresponds to an identical ST-segment depression in the inverted lead -aVR). A notch is evident in the ascending part of the ST segment.

Chapter 12: ST segment elevation in acute myocardial ischemia and differential diagnoses

ST segment elevation in acute myocardial ischemiaContents1. Male/female pattern (“Normal ST segment elevation”).2. Early repolarization3. Left ventricular hypertrophy (LVH)4. Left bundle branch block (LBBB)5. Acute perimyocarditis (myocarditis)6. Hyperkalemia7. Brugada syndrome8. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D)9. Pre-excitation & WPW (Wolff-Parkinson-White syndrome)10. Electrical cardioversion11. Takotsubo cardiomyopathy (broken-heart syndrome, apical ballooning syndrome, stress-induced cardiomyopathy)12. Prinzmetal’s angina (variant angina, coronary artery vasospasm)13. Pulmonary embolism14. Hypothermia & hypercalcemia15. Proximal aortic dissection16. Left ventricular aneurysm

ST segment elevations with straight (horizontal, upsloping, or downsloping) or convex ST segment strongly suggest acute transmural ischemia (Figure 1 A). Concave ST segment elevations, on the other hand, are much less likely to be caused by ischemia (Figure 1 B). This is noted in both North American and European guidelines. However, a concave ST segment does not rule out ischemia, it merely reduces the probability of ischemia as the underlying cause. Concave ST segment elevations are very common in the population (discussed below). Study Figure 1 carefully.

Figure 1. Types of ST segment elevations on ECG.

Current guideline criteria for ischemic ST segment elevation:New ST segment elevations in at least two anatomically contiguous leads:• Men age ≥40 years: ≥2 mm in V2-V3 and ≥1 mm in all other leads.• Men age <40 years: ≥2,5 mm in V2-V3 and ≥1 mm in all other leads.• Women (any age): ≥1,5 mm in V2-V3 and ≥1 mm in all other leads.• Men & women V4R and V3R: ≥0,5 mm, except from men <30 years in whom the criteria is ≥1 mm.• Men & women V7-V9: ≥0,5 mm.

The ST segment elevations in ischemia are dynamic. A patient may initially present with ST segment elevations that do not fulfill the ECG criteria, only to develop magnificent ST segment elevations a few minutes later. Indeed, a dynamic (varying) ST segment is suggestive of myocardial ischemia. It is wise to connect the patient to continuous ECG (ST) monitoring in order to detect such dynamics.

ST segment elevations with concave ST segment

Concave ST segment elevations pose a diagnostic challenge (Figure 1 B). Such ST segment elevations are extremely common in all populations. They occur in young, old, healthy and diseased individuals. For example, roughly 90% of males aged <30 years display concave ST segment elevations in leads V2–V3. This explains why guidelines require higher ST segment elevations in these leads (see criteria above). However, one must be careful. There are plenty of cases of transmural ischemia presenting with concave ST elevations. Moreover, the ST segment may have a concave appearance if the T-wave is prominent (such as in hyperkalemia, early repolarization or even early phases of ischemia). To conclude, concave ST segment elevation is atypical of ischemia, but they do not rule out ischemia.

Other features of ischemic ST segment elevations

In STE-ACS (STEMI) the level of the J point is typically close to the level of the T-wave apex (i.e the height difference between the J point and the apex of the T-wave is typically small). Moreover, ischemic ST segment elevations are typically accompanied by reciprocal ST segment depressions. These ST segment depressions are mirror images of the ST segment elevations, and they are seen in leads with a roughly opposite angle to the leads with ST elevations. Importantly, reciprocal ST segment depressions strongly suggest transmural ischemia. This is also consistent with the vector theory; elevation in one lead should be recorded as depression in a lead with an opposite angle of observation. However, reciprocal ST segment depressions may be missing. There are three explanations as to why reciprocal ST segment depressions may be absent:

There is no ECG lead with the opposite angle of observation.

The injury currents are not strong enough to be detected on leads with opposite angle of observation.

Other vectors may interfere with the injury currents, and inhibit them from being detected by leads with opposite angles of observation.

The electrocardiographic natural course of STE-ACS (STEMI)

Figure 2 presents the entire electrocardiographic (ECG) development in STE-ACS/STEMI. Note that a patient with STEMI may present during any of the phases illustrated in this figure, which is why it should be studied in detail.

Figure 2. The electrocardiographic natural course in STEMI (ST elevation myocardial infarction).

Pitfalls

Acute transmural ischemia located in the basal portions of the lateral wall of the left ventricle (referred to as the posterolateral wall) does not result in ST segment elevations on the conventional 12-lead ECG, simply because none of the leads are able to detect these injury currents. Instead, reciprocal ST segment depressions appear in the anterior chest leads (V1–V3). Similarly, acute transmural ischemia located in the right ventricle is frequently missed when only using the standard leads. In order to correct this, one may connect right-sided chest leads V4R and V5R. For details, refer to STEMI (STE-ACS) Without ST Segment Elevations.

Figure 3. Examples of STE-ACS (STEMI). Note that these patients presented with pathological Q-waves, which means that these ECGs were recorded several hours after symptom onset or those are signs of old infarction.

Differential diagnoses to ST segment elevations

This section is of paramount importance to anyone seeing patients who may have heart disease. Every physician, nurse and paramedic should be able to confidently differentiate 15 different causes of ST segment elevations, which is why a detailed presentation follows. Each differential diagnosis is discussed separately, starting with the most common form of ST segment elevation, namely male/female pattern.

  1. Male/female pattern (“Normal ST segment elevation”).

Male/female pattern is by far the most common type of ST segment elevation. It is completely benign and no study to date has associated this pattern with any increased risk of cardiovascular or all-cause mortality. The prevalence has been examined thoroughly in males (particularly in the US arm), which is why it is usually referred to as male pattern, but it is also common in females. Nevertheless, studies show that among males aged 16 to 58 years, roughly 90% display  ≥1 mm ST segment elevation in ≥1 chest lead. The prevalence declines to 30% among males aged 70 years or above. In females, on the other hand, the prevalence is steady throughout the age span, being approximately 20%. It is a blatant, but a far too common mistake (even among cardiologists and electrophysiologists) to confuse male/female pattern with early repolarization.

ECG characteristics of male/female pattern

A representative ECG example is presented in Figure 4.

The ST segment elevations are most pronounced in leads V2–V4, where they might reach 3 mm, or even more. Women consistently display less ST segment elevation than men. The ST segment elevations are less pronounced in the lateral chest leads, and rarely exceed 1 mm in leads V5–V6.

The ST segment has a concave appearance.

The T-wave apex is substantially higher than the J point.

The greater the QRS amplitude, the greater the ST segment elevation.

Male/female pattern may also appear in the limb leads (particularly II, aVF and III). However, it is much less pronounced in the limb leads (typically <1 mm).

In some textbooks, male/female pattern is referred to as “normal ST segment elevation”.

Figure 4. Male/female pattern. Also called “normal ST segment elevation”.

  1. Early repolarization

Early repolarization is another frequently misunderstood condition. Early repolarization occurs in 5–10% of all males (US data). It is somewhat less common among women (prevalence 2–4%). The condition has been recognized for decades, and it has been regarded as a benign form of ST segment elevation. The term “early repolarization” was used to describe what appeared to be premature repolarization on the ECG. As seen in Figure 5, the ST segment elevations are indeed associated with what appears to be an interruption in the QRS complex and initiation of repolarization. However, no study to date has been able to demonstrate that the repolarization is actually early and, moreover, this condition is associated with 5 times as great a risk of sudden cardiac death. The prefix “benign” must therefore not be used. The risk of sudden cardiac death is greatest if the early repolarization pattern occurs in the inferior limb leads (II, aVF and III).

ECG characteristics of early repolarization

The ST segment elevations are concave and most pronounced in the chest leads. T-waves have high amplitude.

The hallmark of early repolarization is the end-QRS slurring or end-QRS notching (both may occur on the same ECG). The entire notch must be above the baseline. The slur must start before the baseline is reached. Refer to Figure 5, panel A.

The end-QRS slur and end-QRS notch are described with the terms Jonset, Jpeak, Jtermination (Figure 5, panel A). In case of chest pain, the level of ST segment elevation is measured in Jtermination.

A recent consensus report on early repolarization (MacFarlane et al, 2016, JACC) stated the following criteria for early repolarization:

Notch or slur in the transition between R-wave and ST segment. ST segment elevation is almost always present.

Jpeak is ≥1 mm in at least two anatomically contiguous leads (V1–V3 do not count).

QRS duration <120 ms.

Figure 5. Early repolarization (after MacFarlane et al, 2016, Eur Hear J).

  1. Left ventricular hypertrophy (LVH)

The hallmark of left ventricular hypertrophy (LVH) is the large QRS amplitudes; large R-waves are seen in V5–V6 and deep S-waves in V1–V2. Secondary ST-T changes are frequently seen in V1–V2 (ST segment elevations) and V5–V6 (ST segment depression). Refer to Figure 6 for ECG example.

The ECG in left ventricular hypertrophy

Large R-waves in V5–V6 and deep S-waves in V1–V2.

Concave ST segment elevations in V1–V3. The deeper the S-wave, the greater the ST segment elevation.

Secondary ST segment depressions are seen in V5–V6.

Figure 6. Left ventricular hypertrophy causes secondary ST-T- changes, including ST segment elevations.

  1. Left bundle branch block (LBBB)

Interpretation of ischemia is notoriously difficult in presence of left bundle branch block (LBBB). This is because the left bundle branch block causes marked alterations of left ventricular de- and repolarization. Left bundle branch block always causes prominent secondary ST-T changes which may both imitate and mask ischemia. Several studies have shown that the majority of patients inappropriately referred to the catheterization laboratory (for PCI) with suspicion of STE-ACS/STEMI have left bundle branch block. Hence, left bundle branch block poses a diagnostic challenge.

Early studies, dating back to the 1990s, demonstrated that patients with chest discomfort and new left bundle branch block who were referred immediately to PCI had better survival than comparable patients who were not immediately referred to PCI. A significant proportion of these patients had a total occlusion which could be treated with PCI. Ever since these studies, guidelines recommend that patients with chest discomfort and newly diagnosed left bundle branch block should be referred immediately to the catheterization laboratory with the purpose of performing PCI. However, this will result in referral of many patients without the need of PCI (absence of total occlusion in coronary artery), and the reasons are as follows:

A significant proportion of the left bundle branch blocks are not new, but simply new to the health care system (e.g lack of previous ECG recordings).

Even if the left bundle branch block is new, the occlusion may not be total, in which case PCI does not confer any survival benefit.

These topics will be discussed in detail in the chapter Left Bundle Branch Block (LBBB) in Acute Myocardial Infarction and Ischemia. For the purpose of this discussion, the focus will now be redirected to the secondary ST-T changes caused by left bundle branch block.

ECG in left bundle branch block

Left bundle branch block frequently causes ST segment elevations in leads V1–V2. The ST segment elevation typically has a concave ST segment.

ST segment depressions are seen in leads V5, V6, aVL and I.

The hallmark of left bundle branch block is the wide QRS complex (QRS duration ≥0.12 s), deep S-wave in V1–V2, large and clumsy R-wave in V5, V6, aVL and I.

These ECG changes are shown in Figure 7, which should be studied carefully.

Figure 7. Left bundle branch block (LBBB) also causes secondary ST-T changes, including ST segment elevation.

  1. Acute perimyocarditis (myocarditis)

Myocarditis and pericarditis tend to accompany each other, which is why the term perimyocarditis may be used. This condition may cause severe retrosternal chest pain, very similar to that observed in acute myocardial infarction. It also causes ST segment elevations, but these are typically easy to differentiate from ST segment elevation myocardial infarction (STEMI/STE-ACS). The ST segment elevations in perimyocarditis are generalized, which means that they occur in the majority of the ECG leads. This is highly unusual in STEMI/STE-ACS, in which the ST elevations are confined to the ischemic myocardial area (which in turn depends on the site of the artery occlusion). In the most classical case of perimyocarditits, there are ST segment elevations in all leads except lead V1. The morphology of the ST segment elevations reminds of early repolarization, and there may even be a notch in the J-point. However, the ST segment elevations in perimyocarditis rarely exceed 4 mm (which they certainly may exceed in STEMI/STE-ACS). Moreover, there are no reciprocal ST segment depressions in myocarditis and there are never concomitant T-wave inversions. In STEMI/STE-ACS, on the other hand, reciprocal ST segment depressions are typical and there may be T-wave inversions in the same leads showing ST segment elevation.

T-wave inversion may, however, occur in perimyocarditis, but only after normalization of the ST segment elevations (i.e these two ECG changes do not occur simultaneously).

Finally, the PR segment is frequently depressed in perimyocarditis. This may appear as a downsloping PR segment (in most leads). The only exception is lead V1, which tends to display a PR segment elevation.

An example of perimyocarditis is provided in Figure 8.

Figure 8. Perimyocarditis (myocarditis) causes generalized ST segment elevations.

  1. Hyperkalemia

Hyperkalemia may cause ST segment elevations in leads V1–V2. The ST segment is typically straight. Pronounced hyperkalemia may cause ST segment elevations similar to those seen in Brugada syndrome.

Other signs of hyperkalemia are also present (wide QRS complexes, high tented T-waves, diminished P-wave amplitude.

Correction of serum potassium levels will normalize the ECG changes.

Figure 9. ST-segment elevations due to hyperkalemia.

  1. Brugada syndrome

Brugada syndrome is a rare channelopathy (i.e. an electrical disorder caused by abnormal or absence of ion channel function) that predisposes the individual to syncope, malignant ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation) and sudden cardiac death. There are three types of ECG presentations, referred to as type 1, type 2 and type 3 Brugada syndrome. Refer to Figure 10 for ECG examples of type 1, 2 and 3 Brugada syndrome.

The most typical (and diagnostic) is type 1 Brugada syndrome. It reminds somewhat of right bundle branch block (RBBB) in leads V1–V3, but the QRS duration is not prolonged in leads V5–V6 (this is not consistent with right bundle branch block, in which there must be wide QRS complexes). The ST segment elevation has a coved shape (often described as “shark tail”) in V1, V2 or V3. The ST segment starts at the apex of the second R-wave and is downsloping (panel A, Figure 10). The T-wave is negative (inverted).

In type 2 and type 3 Brugada syndrome, the ST segment elevation is saddleback shaped (panels B and C, Figure 10). The difference between type 2 and type 3 is that the ST segment elevation in type 2 is elevated ≥2 millimeters (it is lower in type 3 Brugada syndrome).

For details, please refer to Brugada syndrome.

Figure 10. The three types of Brugada syndrome and the characteristic ST segment elevations.

  1. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D)

Arrhythmogenic right ventricular cardiomyopathy / dysplasia (ARVC / ARVD) may cause ST segment elevations in V1–V3 similar to those seen in Brugada syndrome.

  1. Pre-excitation & WPW (Wolff-Parkinson-White syndrome)

Pre-excitation (i.e premature activation) of ventricular myocardium due to an accessory pathway between atria and ventricle results in abnormal depolarization of the ventricles, which leads to abnormal repolarization. The secondary ST-T changes manifest as ST elevations and ST depressions. Pre-excitation may also cause abnormal Q-waves. Refer to Figure 11 for ECG example. Refer to Pre-excitation & WPW (Wolff-Parkinson-White syndrome) for details on pre-excitation syndromes.

Figure 11. Pre-excitation causes secondary ST-T changes, including ST segment elevations.

  1. Electrical cardioversion

Transient (usually minutes) ST segment elevations may follow electrical cardioversion. The ST segment elevations are similar to those seen in Brugada syndrome. Refer to Figure 12 for ECG example.

Figure 12. Electrical cardioversion resulting in ST-segment elevations.

  1. Takotsubo cardiomyopathy (broken-heart syndrome, apical ballooning syndrome, stress-induced cardiomyopathy)

Takotsubo cardiomyopathy is a rather peculiar and acute condition. Much research has been devoted to this condition in recent years. Virtually all cases of takotsubo cardiomyopathy occur in situations with extreme stress, such as car accidents, gun violence, other threats, or any other situation in which the individual’s life is (or perceived as it is) at danger. Takotsubo cardiomyopathy is much more common in women. The typical patient presents with severe chest pain, dyspnea and in some cases hemodynamic compromise. The ECG shows localized ST segment elevations, T-wave inversions and occasionally pathological Q-waves. Troponin levels are frequently elevated. Hence, takotsubo cardiomyopathy cannot be differentiated from ST segment elevation myocardial infarction (other than the anamnesis). These patients are referred to immediate catheterization, in which no coronary occlusions can be found, but injection of contrast media reveals that the apical portion of the left ventricle is dilated (hence the term apical ballooning syndrome). This syndrome was first described in 1991 in Japan, and the authors termed it takotsubo, which is the Japanese word for a kind of octopus trap (the left ventricle takes the shape of that octopus trap).

Studies from the US and Japan have estimated that up to 2% of patients referred to PCI with suspicion of STE-ACS/STEMI, actually have takotsubo. Previous studies reported that 98 out of 100 cases had a full recovery. More recent studies (Omerovic et al) have reported mortality rates reaching 4%.

80% of patients have localized ST segment elevations (mostly in the chest leads). The morphology of the ST segment elevations cannot be differentiated from those seen in STEMI/STE-ACS.

64 % have T-wave changes (mostly inversions) accompanying the ST segment elevations.

32% have pathological Q-waves.

Refer to Takotsubo cardiomyopathy (apical ballooning, stress-induced cardiomyopathy) for details.

  1. Prinzmetal’s angina (variant angina, coronary artery vasospasm)

Prinzmetal’s angina is caused by coronary artery vasospasm. The vasospasm causes total occlusion of the coronary artery, which results in ST segment elevations. However, the vasospasm and thus the ischemia is virtually always transient and resolves before the development of infarction. The ST segment elevations are followed by T-wave inversions which may persist for days or even weeks.

13. Pulmonary embolism

Pulmonary embolism may cause ST segment elevations in V1, V2, II, aVF and III. However, the most common ECG finding in pulmonary embolism is sinus tachycardia. Occasionally the S1Q3T3 pattern may be seen; this means that there is a prominent S-wave in lead I, large Q-wave in lead III and T-wave inversion in lead III. Moreover, T-wave inversions in lead V1–V3 are common in pulmonary embolism. Finally, a new right bundle branch block (RBBB) should always raise suspicion of pulmonary embolism in patients with dyspnea.

Figure 13. Pulmonary embolism with ST-segment elevations in right sided chest leads.

  1. Hypothermia & hypercalcemia

Both these conditions may engender J-waves (in any leads). J-waves are also called Osborn’s waves, particularly in the context of hypothermia and hypercalcemia. However, there are two other J-wave syndromes, namely Brugada syndrome and early repolarization.

Figure 14. Osborn’s wave (J-wave).

J-waves (Osborn’s waves) and J-wave syndromes are discussed separately.

  1. Proximal aortic dissection

Aortic dissection may engage the aortic bulb (bulbus aortae) and thus occlude the coronary artery ostia (most frequently the right coronary artery ostium). The ensuing occlusion causes ST segment elevations and transmural ischemia. The prognosis of this condition is extremely poor.

  1. Left ventricular aneurysm

Left ventricular aneurysm is a complication of transmural infarctions (STEMI) and may cause persistent ST-segment elevations. These may persist for months or even years. The ST segment elevations occur in the ECG leads reflecting the aneurysmatic area.

Chapter 13: ST elevation myocardial infarction (STEMI) without ST elevations on 12-lead ECG

This chapter covers situations in which the 12-lead ECG does not exhibit ST segment elevations, but the condition should be managed as STEMI (ST Elevation Myocardial Infarction) in terms of treatment and interventions. As discussed previously, STEMI is the result of a complete and proximal occlusion in a coronary artery, which results in transmural myocardial ischemia. The term transmural ischemia implies that the ischemia affects all wall layers – from endocardium to epicardium – in the myocardium affected by the occlusion. Transmural ischemia yields ST segment elevations on ECG. ST elevations are the hallmark of STEMI. However, there are situations with transmural ischemia that do not yield ST elevations. It is important to recognize these situations since they should be managed clinically as STEMI. The explanation for this is simple: transmural ischemia is due to a complete and proximal artery occlusion and such occlusions must be managed with immediate PCI (Percutaneous Coronary Angiography).

Transmural ischemia (infarction) without ST segment elevations on ECG

There are two situations in which transmural ischemia does not present with ST-segment elevations on the conventional 12-lead ECG. These situations are as follows:

Transmural ischemia located in the posterolateral portion of the left ventricle.

Transmural ischemia located in the right ventricle.

Both these situations do, however, yield ECG changes that indicate the underlying pathology. It is important to be aware of the characteristic ECG changes as they have implications for the management of these patients. Also, note that posterolateral and right ventricular infarction may occur simultaneously (if both territories are affected by the same artery occlusion). Approximately 30% of patients with posterolateral infarction will also have right ventricular infarction; among these patients, roughly 10% have hemodynamically significant right ventricular infarction. Hemodynamic effects of right ventricular infarction include low cardiac output, hypotension, sensitivity to drugs that reduce preload (nitrates, morphine, diuretics), high-degree AV block, tricuspid regurgitation, cardiogenic shock, right ventricular free wall rupture and cardiac tamponade. The most common of these are hypotension, low cardiac output and sensitivity to drugs that reduce preload.

Posterolateral (posterior, inferobasal) STEMI (STE-ACS)

The heart is rotated 30° to the left in the thorax. This positions the basal portion of the left lateral wall posteriorly in thorax (Figure 1). This area is most frequently designated as the posterolateral wall, but it may also be referred to as the posterior wall, or the inferobasal wall. Transmural ischemia located in this area yields an injury current (ST vector) directed towards the back, where there is no exploring electrode (in the 12-lead ECG) that can present the ST segment elevations (Figure 1). Thus, the 12-lead ECG does not display ST segment elevations during posterolateral transmural ischemia. On the other hand, leads V1–V3 (occasionally V4) may detect the injury currents and present them as ST segment depressions. These depressions are reciprocal ST segment depressions, meaning that they mirror the ST segment elevations. If the terminal portion of the T-wave in V1–V3 is positive, it increases the likelihood of posterolateral ischemia. Such positive T-waves are reciprocal (mirror images) to posterolateral T-wave inversions (negative T-waves). Moreover, V1–V3 may also show larger R-waves, which are reciprocal to posterolateral Q-waves.

As mentioned above, posterolateral infarction may be accompanied by inferior infarction if the occlusion affects both vascular territories. This will result in ST segment elevations in II, aVF and III.

Figure 1. Posterolateral (posterior, inferobasal) transmural ischemia causes reciprocal ST-segment depressions in V1–V3 (occasionally V4). Leads V7–V9 must be placed to reveal the ST-segment elevations.

North American (AHA, ACC) and European (ESC) guidelines recommend that patients presenting with ST segment depressions in V1–V3 should be managed as patients with STE-ACS (STEMI) if there are symptoms suggestive of myocardial ischemia. It is also recommended that leads V7, V8 and V9 be connected to the patient, as these leads may reveal the ST segment elevations on the back. In clinical practice, this is often performed by simply placing the electrodes to lead V4, V5 and V6 on the back.

One might wonder what the probability is that the patient actually has NSTE-ACS (NSTEMI) since they present with ST segment depressions on the 12-lead ECG (recall that ST segment depression is the hallmark of NSTE-ACS/NSTEMI). The answer is rather simple: the probability that the patient has NSTE-ACS/NSTEMI is small and the vast majority has STE-ACS/STEMI. This is explained by the fact that NSTE-ACS/NSTEMI rarely presents with ST-segment depressions exclusively in V1–V3. ST segment depressions in V1–V3 in patients with NSTE-ACS/NSTEMI are almost invariably accompanied by ST segment depressions in other leads (particularly V5) and that is not consistent with posterolateral transmural ischemia.

To conclude, patients with chest discomfort who display ST segment depressions in leads V1–V3 are likely have posterolateral transmural ischemia and should be managed as STE-ACS/STEMI (ST elevation myocardial infarction).

ECG criteria for posterolateral (posterior, inferobasal) ST segment elevation myocardial infarction (STE-ACS/STEMI):

ST-segment elevation in V7-V9: ≥0,5 mm in at least one lead (males and females).

Differentiating posterolateral ischemia from right ventricular hypertrophy (RVH)

It is occasionally difficult to differentiate right ventricular hypertrophy (RVH) from posterolateral ischemia. Both these conditions cause ST segment depressions in V1–V3 along with large R-waves (Figure 2 shows right ventricular hypertrophy). The following rules will distinguish the two conditions in the vast majority of cases:

Right ventricular hypertrophy shifts the electrical axis to the right.

The terminal portion of the T-wave is not positive in right ventricular hypertrophy.

The ST-segment depressions have an upwards bulging ST segment in right ventricular hypertrophy, whereas the ST segment is usually horizontal or downwards bulging in ischemia.

Figure 2. Right ventricular hypertrophy.

Right ventricular infarction

The artery supplying the right ventricle is branched proximally from the right coronary artery. It follows that a proximal occlusion in the right coronary artery may cause right ventricular infarction. This is, however, uncommon and even rarer is an occlusion in the artery supplying the right ventricle. No standard lead in the 12-lead ECG is adequate to detect right ventricular ischemia. Leads V1–V2 may appear to be able to do so but these leads primarily record the electrical activity of the interventricular septum. Nevertheless, right ventricular infarction does occasionally cause ST segment elevation in lead V1 and occasionally V2. If ST-segment elevation is present in both leads, it must be higher in lead V1 for it to be consistent with right ventricular infarction. In order to capture the ST segment elevations over the right ventricle, one must use two additional leads, namely V3R and V4R. Occasionally the ST segment elevations will also be present in V5R and V6R (but the elevation in these leads is not necessary for the diagnosis). Refer to Figure 3.

Figure 3. Right sided chest leads in right ventricular infarction.

Note that the ST segment elevations in right ventricular infarction have short duration and rarely persist after 6 hours. This is because the right ventricle is a thin-walled chamber, which is why the infarction process is completed much faster.

Suspicion of right ventricular infarction should always arise when ST segment elevations are seen in lead V1. In the vast majority of cases, there will also be ST segment elevations in leads II, III and aVF (i.e there is inferior infarction as well), because the right coronary artery supplies the inferior wall in 90% of all individuals.

Clinical characteristics of patients with right ventricular infarction have been discussed above.

ECG criteria for right ventricular infarction:

ST-segment elevation ≥0,5 mm in V3R and V4R (men and women).

ST-segment elevation ≥1 mm in V3R and V4R in men aged less than 30 years.

Left bundle branch block (LBBB) may mask or imitate transmural ischemia

Whereas transmural ischemia located in the right ventricle or posterolateral wall of the left ventricle may avoid ST elevations on 12-lead ECG, left bundle branch block (LBBB) may both imitate and/or mask acute transmural ischemia. Moreover, studies have demonstrated that patients presenting with chest pain and left bundle branch block may benefit from acute angiography (with the intent to perform PCI). North American and European guidelines, therefore, recommend (2017) that patients with left bundle branch block and suspicion of acute coronary syndrome should be managed as STEMI.

Assessment of ischemia is difficult in presence of left bundle branch block. This is because left bundle branch block causes marked alterations in left ventricular de- and repolarization. Left bundle branch block always causes secondary ST-T changes which may imitate and/or mask ischemia. Left bundle branch block typically manifests with ST segment elevations in leads V1–V3, whereas leads V5, V6, I and aVL show ST segment depressions (Figure 4 below). Clinicians frequently confuse these elevations and depressions with those caused by STEMI. Several studies have shown that the majority of patients inappropriately referred to the catheterization laboratory (for PCI) with a suspicion of STE-ACS/STEMI actually have left bundle branch block.

Nevertheless, patients with chest discomfort and new or presumably new left bundle branch block should be referred immediately to the catheterization laboratory for angiography. As mentioned above, studies dating back to the 1990s showed that patients with chest discomfort and a new (or presumably new) left bundle branch block who were referred immediately to PCI had better survival than comparable patients not referred to the catheterization laboratory. Angiography revealed that a significant proportion of these patients had a total occlusion that could be managed with PCI. It is likely that the acute myocardial infarction is the cause of the left bundle branch block in these cases (ischemia and infarction may cause bundle branch blocks). However, subsequent studies demonstrated that many (perhaps even the majority of) patients with chest pain and (presumed) new LBBB did not have an acute occlusion and therefore referral for PCI was unnecessary. There are several reasons as to why only a minority have an acute occlusion:

A significant proportion of the left bundle branch blocks are not new, but simply new to the health care system (e.g lack of previous ECG recordings).

Even if the left bundle branch block is new, the occlusion may not be total, in which case PCI does not confer any survival benefit.

Regardless, North American and European guidelines still (2017) advocate that patients with chest discomfort and new or presumed new left bundle branch block should be managed as STE-ACS/STEMI.

Separate chapters are devoted to ischemia interpretation in the setting of left bundle branch block (LBBB) and general aspects of left bundle branch block (LBBB).

Figure 4. Left bundle branch block (LBBB) with typical ST elevations (V1–V2) and ST depressions (V5-V6).

Chapter 14: T-waves in ischemia: hyperacute, inverted (negative), Wellen’s sign & de Winter’s sign

A thorough discussion regarding the physiology of the T-wave was previously provided. Only aspects relevant to ischemia will be discussed here. The T-wave is notoriously difficult to judge, which is why a rather comprehensive discussion is warranted. The normal T-wave will be described first. Then, ischemic T-wave changes – i.e hyperacute T-waves, inverted T-waves, flat T-waves, Wellen’s syndrome and de Winter’s syndrome – will be discussed in detail.

The normal T-wave

The normal T-wave is concordant with the QRS complex, meaning that it has the same direction as the net direction of the QRS complex. A net positive QRS complex should be followed by a net positive T-wave (refer to the previous discussion on concordance/discordance and Figure 1). If the T-wave and the QRS complex head in opposite directions, the T-wave is said to be discordant which is abnormal. Because most ECG leads have net positive QRS complexes (during normal circumstances) the T-wave is typically positive in all leads. It is, however, common to have a negative T-wave in lead V1, which also has a net negative QRS complex (i.e the negative T-wave is actually concordant with the QRS, which makes this a normal finding).

Figure 1. Discordance and concordance between QRS complex and ST-T segment.

The transition from ST segment to T-wave should be smooth. The amplitude of the T-wave is rarely >6 mm in the limb leads. In the chest leads the amplitude is highest in V2–V3; males may display up to 10 mm T-wave amplitude in these leads, although most have <6 mm in V2–V3. T-wave amplitude is on average 3 mm in V2–V3 in females and it rarely exceeds 8 mm. Note that the amplitude of the T-wave is related to the amplitude of the QRS complex (large QRS amplitudes yield large T-wave amplitudes, and vice versa). Last but not least, the normal T-wave is slightly asymmetric; the slope of the descending limb is slightly steeper than the ascending limb.

A rather detailed reference regarding the direction of T-waves follows:

I, II, -aVR, V5 and V6 should display positive T-waves in adults.

aVR displays a negative T-wave in adults.

III and aVL may occasionally display an isolated (single) T-wave inversion. The term isolated implies that none of the neighboring leads display T-wave inversions.

aVF generally shows a positive T-wave but it may occasionally be flat.

V1 may show an inverted or flat T-wave (particularly common in women). The inversion is concordant with the QRS complex, which is also negative in V1.

V7–V9 should display a positive T-wave.

T-wave abnormalities are common and occur in a wide range of conditions. Unfortunately, many clinicians tend to misinterpret the T-wave and some find it difficult to put T-wave changes into clinical context. Therefore, we will now discuss each T-wave abnormality and clarify common misunderstandings.

The inverted (negative) T-wave

T-wave inversion means that the T-wave is negative. By definition, the T-wave is negative if the terminal portion of the T-wave is below the baseline. T-wave inversions are actually graded according to the amplitude (depth). Strictly speaking the term T-wave inversion refers to T-waves that are 1 to 5 mm negative (deep). The term deep T-wave inversion is applied to T-waves 5 to 10 mm deep. The term gigantic T-wave inversion is used if the T-wave is deeper than 10 mm. Myocardial ischemia may present with any degree of T-wave inversion. Myocardial ischemia may also present with flat T-waves, which are defined as T-waves with an amplitude between +1 and -1 mm.

Ischemic T-wave inversions

It is a widespread misunderstanding that isolated T-wave inversions indicate acute (ongoing) ischemia. Isolated T-wave inversions  – i.e T-wave inversions without concomitant ST segment deviation (elevation or depressions) – is never a sign of acute ischemia. T-wave inversions with concomitant ST segment deviations are, however, typical of ischemia but in that scenario, it is actually the ST segment deviation that reflects the ischemia. The reason why guidelines include isolated T-wave inversions as valid criteria for myocardial infarction is simply that isolated T-wave inversions occur after the ischemia has resolved (i.e they confirm that ischemia has occurred, but it is not ongoing). Isolated T-wave inversions in persons presenting with symptoms of myocardial ischemia are referred to as post-ischemic T-wave inversions. To clarify, isolated T-wave inversions indicate that there has been ischemia.

Ischemic T-wave inversions are symmetric (the normal T-wave is asymmetric) and maybe, but rarely are, deeper than 10 mm. ECG leads with the opposite angles of observation (opposite to leads with T-wave inversions) usually display positive T-waves. Post-ischemic T-waves may be accompanied by negative U-waves, which further increases the likelihood of ischemia as the underlying cause.

The T-wave inversions following myocardial infarction usually resolve within days or weeks, but they may become chronic (defined as persisting >1 year). Normalization of T-wave inversion after infarction indicates some recovery in the infarct area.

Figure 2 must be studied carefully. It presents the characteristics and significance of all clinically relevant T-wave inversions.

Figure 2. Various T-wave abnormalities, including T-wave changes related to myocardial ischemia.

ECG criteria for acute myocardial infarction:

T wave inversion ≥1 mm in at least two anatomically contiguous leads. These leads must have evident R-waves, or R-waves larger than S-waves.

Evidence as to why isolated T-wave inversions do not indicate acute ischemia

The following observations indicate why isolated T-wave inversions cannot be a sign of acute (ongoing) ischemia.

Patients with stable coronary artery disease (angina pectoris) never display new isolated T-wave inversions during exercise stress testing.

When ECG is recorded during ongoing chest pain (angina pectoris), T-wave inversions never occur without concomitant ST-segment deviation (depression/elevation).

Patients with myocardial infarction and isolated T-wave inversions have a prognosis similar to patients with completely normal ECG.

Inverted T-waves develop between 12 and 24 hours after symptom onset in STEMI/STE-ACS. These T-waves succeed the ST-segment elevations and thus indicate that there is no longer any ongoing ischemia.

T-wave inversions with rapid normalization during PCI (percutaneous coronary intervention) indicate reperfusion of the artery.

Biphasic (diphasic) T-waves

A biphasic T-wave has a positive and a negative deflection. It should be noted that the term “biphasic” is unfortunate because (i) biphasic T-waves carry no particular significance and (ii) a T-wave is classified as positive or inverted based on its terminal portion; if the terminal portion is positive then the T-wave is positive and vice versa.

Wellen’s syndrome (Wellen’s sign, LAD-T-Wave Inversion Pattern)

As evident from the discussion above, isolated T-wave inversions are not acute and perhaps not even more alarming than a normal ECG (among patients with chest discomfort). There is one notable exception to this rule, namely Wellen’s syndrome. Patients with Wellen’s syndrome have recently (within 24–48 hours) had pronounced angina pectoris, but may experience no symptoms during the presentation. They display deep and symmetric T-wave inversions in leads V1–V6, aVL and I (at least in leads V2–V5). There is no significant ST segment deviation (elevation or depression) and troponins are usually below the upper reference limit (or just slightly elevated). This syndrome is caused by severe and proximal stenosis in LAD (left anterior descending coronary artery). These patients typically have rich collateral coronary circulation. A representative ECG is presented in Figure 3. Note that in some cases of Wellen’s syndrome the initial part of the ST segment may be slightly upsloping.

Figure 3. Characteristic T-wave inversions caused by Wellen’s syndrome. This ECG pattern is commonly referred to as Wellen’s sign.

Approximately 10% of patients with acute coronary syndromes have Wellen’s syndrome; 75% of these will develop massive anterior myocardial infarction with a high risk of developing heart failure unless revascularization is carried out expeditiously. Wellen’s syndrome is therefore a case of isolated T-wave inversion which is very acute. Angiography should be carried out immediately to minimize the risk of developing massive infarction. The risk is particularly high in patients presenting with T-wave inversions in leads I and aVL, since virtually all those patients have very severe and proximal LAD stenosis.

Non-ischemic T-wave inversion (negative T-waves due to other causes)

Secondary T-wave inversions may be caused by left bundle branch block, right bundle branch block, pre-excitation, left ventricular hypertrophy, right ventricular hypertrophy, and pacemaker rhythm (if the pacemaker stimulates in the ventricular myocardium). These are all common conditions in which the depolarization of the ventricles is abnormal, and this leads to abnormal repolarization (ST-T segment). ST-T changes seen in these conditions are referred to as secondary ST-T changes, and they include ST-segment deviation (elevation/depression) and T-wave inversion. Note that the T-wave inversion may persist for some time after normalization of the depolarization (if that occurs at all). This is a phenomenon called T-wave memory, and it is often seen among patients with pacemakers (T-waves continue to be inverted even when the beats are not paced. Figure 4 displays these secondary T-wave inversions.

Figure 4. Secondary ST-T changes due to LBBB (left bundle branch block), LVH (left ventricular hypertrophy), RBBB (right bundle branch block), pre-excitation (WPW syndrome) and RVH (right ventricular hypertrophy).

Cerebrovascular insult pattern implies the presence of deep or gigantic symmetric T-wave inversions in leads V1–V6, and occasionally the limb leads. This occurs in patients with stroke (in most cases intracerebral hemorrhage). Prolonged QT interval and evident T-waves may also occur. According to Surawicz and Schindler, up to 30% of patients with hemorrhage may display this ECG pattern, which is shown in Figure 2, panel D.

Hypertrophic cardiomyopathy may cause deep isolated T-wave inversions in leads V2–V5. These T-wave inversions are accompanied by increased R- and S-wave amplitudes. Refer to Figure 2, panel D.

Hyperacute T-waves

Large T-waves occur in several conditions such as hyperkalemia, early repolarization and male/female pattern. However, ischemia may cause very large symmetric T-waves with a broad base (contrary to hyperkalemia which causes large T-waves with a narrow base). Such hyperacute T-waves (Figure 2, panel B) occur within seconds after total occlusion of a coronary artery and usually resolve within minutes (they are succeeded by ST-segment elevations). Hence, hyperacute T-waves are the first ECG change in STE-ACS/STEMI. Since they are short-lived it is uncommon to encounter them in clinical practice. Recall that T-waves should not exceed 10 mm in chest leads and 5 mm in limb leads.

de Winter’s sign (persistent hyperacute T-wave syndrome)

As mentioned above hyperacute T-waves have a short duration. There is one alarming exception, namely de Winter’s sign, in which hyperacute T-waves persist for hours and are accompanied by ST-segment depressions with upsloping ST-segments. This syndrome, which is a sign of proximal LAD occlusion, was reported in 2008. The ST-segment depressions are 1–3 mm deep in V1–V6, with an upsloping ST-segment that continues in hyperacute T-waves. This pattern has been reported to occur in 2% of patients undergoing acute PCI towards LAD. Refer to Figure 5.

Figure 5. de Winter’s sign.

Pseudonormalized T-waves

If patients with previously known T-wave inversions (verified on previous ECG recordings) display normalization of these inversions during chest pain, one must suspect myocardial ischemia. This phenomenon, in which inverted T-waves become normalized, is referred to as pseudonormalization and it strongly suggests ischemia. Importantly, this rule applies regardless of the cause of the T-wave inversions (left bundle branch block, left ventricular hypertrophy, pre-excitation, right bundle branch block, right ventricular hypertrophy, pacemaker etc). In the case of left bundle branch block, pseudonormalization (occurs in V5, V6, aVL and I) is almost diagnostic for myocardial ischemia. Similarly, patients who have developed T-wave inversions after ischemia/infarction may actually develop pseudonormalization of these in case of re-ischemia/re-infarction.

Chapter 15: ECG manifestations of left main coronary artery (LMCA) occlusion and critical stenosis

Left main coronary artery (LMCA) occlusion is a rare but catastrophic manifestation of acute coronary syndromes. The LMCA supplies a large myocardial territory through the left anterior descending (LAD) and left circumflex (LCx) arteries (Figure 1). Acute obstruction can lead to rapid hemodynamic deterioration, cardiogenic shock, malignant ventricular arrhythmias, or sudden cardiac death. The resulting extensive ischemia causes immediate myocardial stunning (akinesia) and electrical instability.

Fewer than 1% of patients with ST-elevation myocardial infarction (STEMI) who reach the catheterization laboratory are found to have complete LMCA occlusion, likely because most such occlusions result in prehospital cardiac arrest and death. As in other acute coronary events, the thrombotic process is dynamic, with varying degrees of occlusion that may provide a window of opportunity for reperfusion. In addition, some patients present with severe LMCA stenosis exacerbated by other conditions, and these must also be recognized.

Prompt identification of LMCA involvement is therefore critical. The 12-lead electrocardiogram (ECG) is an immediately available diagnostic tool that can provide essential clues to LMCA occlusion or critical stenosis. This chapter reviews the ECG features suggestive of significant LMCA disease, including acute occlusions, subtotal stenoses, and discusses associated clinical presentations, prognostic implications, and management strategies.

In the GRACE ECG substudy of >5000 patients with non-ST elevation ACS (Yan et al), ST elevation in lead aVR was relatively uncommon (7%). Patients with greater ST elevation in aVR had higher crude in-hospital and 6-month mortality (up to 18% at 6 months for >1 mm elevation, vs 7.6% with no elevation).

Figure 1. Coronary artery anatomy in angiographic and computed tomography (CT) views. (A) Angiographic schematic showing the right coronary artery (RCA), left main coronary artery (LMCA), left anterior descending artery (LAD), and left circumflex artery (LCx) with major branches. The RCA gives rise to the sinoatrial nodal branch (SN, 1), conus branch (CB, 2), right ventricular branch (RV, 3), acute marginal branch (AM, 4), atrioventricular nodal branch (AV), right posterior descending artery (RPDA, 4), and right posterolateral branch (RPLB, 16). The LMCA (5) bifurcates into the proximal (6), mid (7), and distal (8) LAD, with diagonal branches (D1, 9; D2, 10) and septal branches (S). The LCx (11) gives rise to obtuse marginal branches (OM1, 12; OM2, 14), the left posterior descending artery (LPDA, 15), and the left posterolateral branch (LPLB, 18). (B) Corresponding CT schematic with coronary artery origins from the right coronary cusp (RCC), left coronary cusp (LCC), and noncoronary cusp (NCC), showing the same branches as in panel A for cross-modality comparison.

Clinical features

Occlusion of the left main coronary artery (LMCA) abruptly interrupts blood flow to both the left anterior descending (LAD) and left circumflex (LCx) coronary artery territories, resulting in extensive myocardial ischemia or infarction involving the anterior, septal, and lateral walls, and the posterior wall if the LCx supplies the posterior descending artery (PDA) in a left-dominant circulation (i.e. 10-15% of cases). Clinically, patients present with severe chest pain, diaphoresis, hypotension, pulmonary edema, malignant arrhythmias, and rapid progression to cardiogenic shock. Ventricular fibrillation or asystole may occur early due to the massive ischemia.

Complete LMCA occlusion is typically fatal within minutes, hence its designation as the “widow-maker.” Patients who survive long enough for clinical evaluation often have some residual antegrade flow, a dynamic thrombus, or collateral circulation that limits infarct size. In such cases, ECG patterns may provide critical clues to an LMCA culprit lesion. In contrast, a critical but subtotal LMCA stenosis may cause subendocardial ischemia during exertion or increased myocardial demand, serving as a warning sign of impending total occlusion. These patients may present with non-ST-elevation acute coronary syndrome (NSTE-ACS), refractory angina, or hemodynamic instability, and are at high risk for progression to complete occlusion. In both acute total occlusion and critical high-grade stenosis, the ECG may demonstrate characteristic changes that should alert clinicians to the presence of LMCA disease and the urgent need for revascularization.

Clinical features that should raise suspicion for LMCA occlusion include severe chest pain, hypotension or cardiogenic shock and extensive ischemic ECG changes, especially diffuse ST-segment depression with aVR elevation, in the setting of severe hemodynamic instability. Lead aVR displays ST-segment depression on machines using the Cabrera format.

Prognosis of LMCA occlusions

The prognosis of left main coronary artery (LMCA) occlusion is poor in the absence of rapid revascularization. Reported in-hospital mortality rates for acute LMCA STEMI vary widely, ranging from approximately 40% to as high as 70% in some series. Even in cases of critical LMCA non–ST-elevation acute coronary syndrome (NSTE-ACS) due to subtotal occlusion or severe stenosis, the risk of death remains substantial without prompt revascularization. The magnitude of ST-segment elevation in lead aVR has been correlated with adverse outcomes. For example, an aVR elevation of ≥0.5 mm has been associated with a fourfold increase in mortality in ACS, and an elevation of ≥1 mm with an approximately six- to sevenfold increase (Puricel et al, Lawton et al). Marked aVR elevation (≥1.5–2 mm) is often associated with particularly high mortality; one study reported mortality rates of 20–75% in such patients, depending on the clinical presentation (Wong et al).

Classic ECG Patterns Indicative of Left Main Coronary Artery Occlusion

Several characteristic electrocardiographic (ECG) patterns have been described in association with acute left main coronary artery (LMCA) occlusion or severe stenosis. These patterns typically reflect either diffuse subendocardial ischemia, as seen in incomplete occlusion or critical stenosis, or extensive transmural myocardial infarction, as occurs in complete occlusion. The principal ECG manifestations are ST-segment elevation in lead aVR, with widespread ST depression (Wong et al).

Figure 2. ECG examples of cases with LMCA occlusions.

Diffuse ST-Segment depression with ST elevation in aVR

The most widely recognized ECG manifestation of left main coronary artery (LMCA) ischemia is widespread horizontal ST-segment depression in multiple leads, typically six or more, often including leads I, II, aVL, aVF, and V4–V6, accompanied by ST-segment elevation in lead aVR (Figure 2A-2B). This pattern reflects global subendocardial ischemia. Because lead aVR is electrically opposite to the left-sided leads (I, II, aVL, V5–V6), diffuse ST-segment depression, particularly in the lateral leads, produces reciprocal ST-segment elevation in aVR (Wong et al).

On ECG machines that display the inverted aVR lead (–aVR), ST-segment elevation in aVR will appear as ST-segment depression.

In the setting of critical LMCA stenosis (subtotal occlusion), inadequate coronary flow to meet myocardial oxygen demand results in pronounced, diffuse ST-segment depression (most prominent in the lateral leads) with reciprocal ST-segment elevation in aVR, and often in V1. Clinically, this diffuse ischemia pattern is observed in high-risk non–ST-elevation myocardial infarction (NSTEMI) or unstable angina (UA) and indicates a large myocardial territory at risk.

Classic diagnostic criteria include ST-segment elevation in aVR ≥1 mm and ST-segment elevation in aVR greater than or equal to that in V1. When these criteria are met in the context of ongoing ischemic symptoms, they are highly predictive of LMCA disease or severe multivessel coronary artery disease (CAD). In a landmark study, ST-segment elevation in aVR ≥1 mm was the strongest independent ECG predictor of severe LMCA or triple-vessel disease requiring coronary artery bypass grafting (CABG) in NSTEMI patients. Similarly, aVR elevation ≥1 mm in conjunction with multilead ST-segment depression demonstrates approximately 75–93% specificity for LMCA or triple-vessel disease in non–ST-elevation acute coronary syndromes (NSTE-ACS). Importantly, the absence of ST-segment elevation in aVR essentially excludes significant LMCA stenosis; if aVR is isoelectric or shows depression during an acute coronary syndrome, critical LMCA disease is unlikely. Therefore, lead aVR should always be carefully evaluated in ACS patients.

According to the European Society for Cardiology, ST depression ≥1 mm in ≥6 ECG leads (inferolateral ST depression), coupled with ST-segment elevation in aVR and/or V1, suggests multivessel ischaemia or left main coronary artery obstruction, particularly if the patient presents with haemodynamic compromise. According to the American College of Cardiology, in patients with ischemic symptoms, ST-segment elevation in lead aVR (with or without elevation in V1) combined with multilead ST-segment depression often represents diffuse ischemia due to significant stenosis involving the left main and/or 3-vessel disease (Harhash et al, Gibbs et al), although it can be seen in other non-ACS conditions causing a demand/supply mismatch (Knotts et al).

Extensive Anterior–Lateral ST Elevation (“Spatially Extensive STEMI”)

Figure 3. Dynamic ECG changes in occlusion of LMCA. Adapted from Zhan et al.

While many left main coronary artery (LMCA) lesions present with the subendocardial ischemia pattern described above, a subset, particularly complete occlusions without collateral circulation, produce a STEMI pattern involving multiple myocardial territories (Figure 3). In such cases, the ECG demonstrates ST-segment elevation in the anterior precordial leads and high lateral leads (aVL, I), constituting an anterolateral STEMI. Typically, ST elevation is observed in leads V2–V6, I, and aVL, often with concomitant elevation in V1 and aVR. A large study identified this as a distinct STEMI pattern of LMCA occlusion: approximately one-third of LMCA occlusions exhibited ST elevation from V1 (or V2) through V6 and in leads I and aVL. This pattern reflects transmural injury across the extensive territory supplied by the left main artery. The ECG appearance is essentially that of a combined extensive anterior wall myocardial infarction (MI) and lateral wall infarction. For example, ST elevation may be present in V3–V4 (anterior) and in leads I and aVL (lateral), sometimes accompanied by ST depression in the inferior leads due to reciprocal changes from lateral STEMI; a combination suggesting a very proximal occlusion (LMCA or proximal left anterior descending [LAD] artery with left circumflex [LCx] involvement).

Thus, widespread ST elevation (anterior and lateral) in a patient with hemodynamic instability should prompt strong consideration of LMCA occlusion, particularly if there is no ST elevation in the inferior leads. These extensive STEMI cases frequently demonstrate intraventricular conduction disturbances—such as new right bundle branch block (RBBB) with left anterior fascicular block (LAFB), secondary to septal infarction. Up to approximately 37% of acute LMCA occlusions are associated with LAFB, and about 17% present with combined RBBB and LAFB (bifascicular block), reflecting injury to the left bundle branch system from septal involvement. A prolonged QRS duration or new bundle branch block in the setting of anterolateral MI should heighten suspicion for a very proximal lesion (LMCA or proximal LAD).

In the setting of a subtotal occlusion of the LMCA, ischemia is typically subendocardial and involves much of the left ventricular myocardium. This produces a consistent pattern of widespread ST-segment depression, most prominent in the lateral and inferior leads, accompanied by reciprocal ST-segment elevation in lead aVR (and occasionally in V1). In contrast, complete LMCA occlusion results in transmural infarction involving both the left anterior descending (LAD) and left circumflex (LCx) territories, manifesting as ST-segment elevation in leads reflecting the anteroseptal wall (V1–V4) and the lateral wall (I, aVL, V5–V6) simultaneously. In such cases, lead aVR may also demonstrate ST-segment elevation.

The basal septum is typically supplied by the first septal perforator branch of the LAD. Infarction in this region generates a primary injury current directed toward aVR. Thus, ST-segment elevation in aVR can arise from two distinct mechanisms: (1) reciprocal changes secondary to diffuse subendocardial ischemia (the most common mechanism), and (2) direct transmural infarction of the basal septum in the context of a proximal LAD or LMCA occlusion. Clinically, if ST elevation in aVR is accompanied by concurrent ST elevation in V1–V3 (anteroseptal leads), this suggests a proximal LAD occlusion involving the septum, which may result from either LMCA occlusion or a very proximal LAD thrombus. Conversely, if aVR shows ST elevation while the precordial leads predominantly exhibit ST depression, the mechanism is more likely purely reciprocal, reflecting diffuse subendocardial ischemia, more typical of critical LMCA stenosis, subtotal occlusion or severe triple-vessel coronary artery disease rather than complete occlusion.

Differentiating left main coronary artery occlusion from other ECG patterns

The ECG patterns described above, particularly the aVR sign, characterized by ST-segment elevation in lead aVR accompanied by diffuse ST-segment depression, are not entirely specific for left main coronary artery disease, as they indicate severe myocardial ischemia that may arise from other etiologies. Clinicians should carefully consider and differentiate the following scenarios.

Proximal LAD occlusion

Proximal LAD occlusion, particularly before the first septal branch (S1), can produce ST elevation in aVR due to basal septal infarction. Unlike LMCA subocclusion, which usually shows ST elevation in aVR with ST depression in V2–V4, proximal LAD occlusion typically causes ST elevation in both aVR and V1–V4 (anteroseptal STEMI pattern). A key distinguishing clue is the relative height of ST elevation: aVR > V1 suggests LMCA disease, while V1 ≥ aVR favors isolated LAD occlusion (as described by Yamaji et al.). Despite these patterns, overlap exists, and clinical context with urgent angiography is critical for diagnosis.

Severe triple-vessel disease

Severe triple-vessel CAD (critical stenoses in LAD, LCx, and RCA) can mimic LMCA subocclusion on ECG, producing diffuse ST depression with ST elevation in aVR due to global subendocardial ischemia. The ECG patterns of both conditions are often indistinguishable, and both signify a large ischemic burden requiring urgent angiography and usually CABG. Ancillary clues (echocardiography, serial troponins, or subtle differences such as ST elevation in aVL favoring LMCA/proximal LAD vs. ST depression in aVL favoring multivessel disease) may help, but only angiography provides definitive differentiation. Clinically, ST elevation in aVR with widespread ST depression should always be treated as high-risk ischemia due to LMCA or severe multivessel disease.

Diffuse demand ischemia (non-cardiac or secondary causes)

Diffuse ST depression with ST elevation in aVR may also result from severe oxygen supply–demand mismatch, such as anemia, tachyarrhythmias, hypotension, hypoxemia, or post–cardiac arrest states. In these scenarios, ischemic changes are often transient and resolve with correction of the underlying condition (e.g., rate control in supraventricular tachycardia). Persistence of the pattern after stabilization, however, strongly suggests underlying coronary artery disease, including possible LMCA involvement. Clinical context is crucial: features such as severe chest pain, cardiovascular risk factors, elevated troponins, or disproportionate ST changes favor true LMCA ACS. When uncertainty exists, urgent cardiology assessment is essential, as missing a critical left main lesion can be fatal.

Management considerations and clinical algorithms

Conventional STEMI criteria (i.e. ≥1 mm ST‐segment elevation in two anatomically contiguous leads) typically mandate immediate catheterization laboratory activation. Yet left main coronary artery (LMCA) occlusion may present without these classic ST elevations. Typically, it manifests as diffuse ST‐segment depression together with ST‐elevation in lead aVR, which is formally classified as NSTE‐ACS, even though it represents one of the most life‐threatening presentations among acute coronary syndromes.

According to the 2022 ACC Expert Consensus Decision Pathway (Kontos et al) for acute chest pain, diffuse ST depressions with ST elevation in aVR should be managed as a high‐risk NSTEMI (NSTE‐ACS), unless there is clinical instability like hypotension or ventricular arrhythmias, in which case immediate angiography is indicated. 

The 2023 ESC ACS Guidelines similarly recognize that widespread ST depression plus ST elevation in aVR and/or V1 is suggestive of left main obstruction or severe multivessel ischemia, particularly in unstable patients, and recommend expedited invasive management in such settings.

In practice, when a patient with ongoing chest pain exhibits the ECG pattern of diffuse ST depression with aVR elevation, angiography should ideally be performed within two hours, analogous to the treatment time‐frames for NSTEMI with refractory ischemia. In cases of hemodynamic compromise (hypotension, acute heart failure, malignant arrhythmias), the patient should be managed emergently, activation of the cath lab without delay.

For stable patients who are pain‐free but demonstrate the high‐risk ECG pattern, prompt (“urgent”) angiography within the same clinical encounter (hours) is recommended rather than delayed evaluation over days.

Hemodynamic support

Given the rapid clinical deterioration often observed in these patients, clinicians should maintain a low threshold for initiating hemodynamic support. Historically, intra-aortic balloon pump (IABP) therapy has been employed in cases of cardiogenic shock due to left main coronary artery (LMCA) occlusion to augment coronary perfusion pending revascularization. More recently, percutaneous left ventricular assist devices (e.g., Impella) and,veno-arterial extracorporeal membrane oxygenation (VA-ECMO) have been utilized in LMCA myocardial infarction complicated by cardiogenic shock. In patients with borderline blood pressure or clinical evidence of impaired end-organ perfusion, early involvement of a dedicated shock team and initiation of mechanical circulatory support prior to or during percutaneous coronary intervention (PCI) can be life-saving.

Revascularization strategy

Once a left main coronary artery (LMCA) culprit lesion is identified, the optimal revascularization approach depends on the clinical scenario. In the setting of acute myocardial infarction with hemodynamic collapse, primary percutaneous coronary intervention (PCI) to the left main, often as an emergency or ‘bail-out’ stenting procedure, is frequently performed as a life-saving measure. However, PCI in an unprotected LMCA carries substantial risk and is often a temporizing measure. If the patient stabilizes, CABG is generally recommended for long-term management of LMCA disease, particularly in the presence of multivessel coronary artery disease, owing to its demonstrated survival benefit.

In stable patients with significant LMCA stenosis, surgical revascularization remains the treatment of choice to improve survival compared with medical therapy alone. Consequently, many patients undergo PCI as a bridge (‘salvage’ stenting) followed by CABG in the ensuing days or weeks, unless PCI is deemed definitive.

In certain cases, such as subtotal LMCA stenosis detected prior to infarction, urgent CABG can be performed before myocardial damage occurs. A critical point for cardiologists is to involve the cardiothoracic surgery team early when an ECG pattern suggestive of LMCA involvement is recognized. Even prior to coronary angiography, alerting the surgical team to a suspected LMCA lesion can expedite definitive management. In selected situations where surgery is contraindicated or PCI is preferred, a percutaneous approach with appropriate hemodynamic support may serve as definitive therapy.

Conclusion

In summary, the electrocardiographic manifestations of left main coronary artery (LMCA) occlusion or critical stenosis typically reflect global myocardial ischemia. The most characteristic pattern consists of diffuse ST-segment depression with reciprocal ST-segment elevation in lead aVR (and frequently in V1), or an anterolateral STEMI pattern involving multiple leads (I, aVL, V2–V6). Additional supportive findings include ST-segment elevation in lead aVR ≥1 mm (particularly when exceeding that in V1), new conduction disturbances such as left anterior fascicular block (LAFB) or right bundle branch block (RBBB), and severe, widespread ischemic changes. Patients with LMCA occlusion usually present in extremis, often with cardiogenic shock or cardiac arrest, and prognosis is highly dependent on prompt recognition and intervention. Although the aVR sign is not entirely specific—since proximal left anterior descending (LAD) artery occlusion or severe triple-vessel disease may produce similar ECG changes—its presence invariably indicates a high-risk acute coronary syndrome (ACS) requiring urgent, aggressive management. Current guidelines recommend expedited invasive evaluation in such scenarios. Vigilance for both subtle and overt ECG indicators of LMCA ischemia enables clinicians to activate appropriate diagnostic and therapeutic pathways, avoid potentially harmful pharmacologic interventions, mobilize interventional and surgical teams without delay, and provide timely hemodynamic support, thereby improving survival prospects. The ECG, obtainable within minutes of patient contact, remains an indispensable tool in the otherwise dire context of LMCA occlusion.

References

Yan AT, Yan RT, Kennelly BM, Anderson FA, Budaj A, López-Sendón J, et al. Relationship of ST elevation in lead aVR with angiographic findings and outcome in non-ST elevation acute coronary syndromes. Am Heart J 2007;154:71–78. https://doi.org/10.1016/j.ahj.2007.03.037

Hirano T, Tsuchiya K, Nishigaki K, Sou K, Kubota T, Ojio S, et al. Clinical features of emergency electrocardiography in patients with acute myocardial infarction caused by left main trunk obstruction. Circ J 2006;70:525–529. https://doi.org/10.1253/circj.70.525

Yamaji H, Iwasaki K, Kusachi S, Murakami T, Hirami R, Hamamoto H, et al. Prediction of acute left main coronary artery obstruction by 12-lead electrocardiography. ST segment elevation in lead aVR with less ST segment elevation in lead V(1). J Am Coll Cardiol 2001;38:1348–1354. doi: doi:10.1016/S0735-1097(01)01563-7

Figures

Chapter 16: ECG signs of myocardial infarction: pathological Q-waves & pathological R-waves

Pathological Q-waves are evidence of myocardial infarctionContents<span style="color: #000000;"><strong>ECG criteria for pathological Q-waves (Q-wave infarction)</strong></span>Pathological R-waves also indicate previous myocardial infarction

Myocardial infarction – particularly if extensive in size – typically manifests with pathological Q-waves. These Q-waves are wider and deeper than normally occurring Q-waves, and they are referred to as pathological Q-waves. They typically emerge between 6 and 16 hours after symptom onset, but may occasionally develop earlier. Standard textbooks have traditionally taught that the pathological Q-wave is a permanent ECG manifestation and that it represents transmural infarction (STEMI). However, recent studies challenge these notions. Pathological Q-waves may resolve in up to 30% of patients with inferior infarction. The amplitude of Q-waves may also diminish over time. Moreover, magnetic resonance imaging has suggested that pathological Q-waves may also arise due to extensive subendocardial infarction (NSTEMI).

If pathological Q-waves occur as a result of myocardial infarction, the infarction may be classified as Q-wave infarction (this has negligible clinical implication). Hence, Q-wave infarctions are mostly the result of transmural infarction (STEMI) but may be caused by extensive subendocardial ischemia (NSTEMI).

Establishing a diagnosis of Q-wave infarction requires that pathological Q-waves be present in at least two anatomically contiguous leads. In patients with STEMI, ST-segment elevations and pathological Q-waves occur in the same leads, which is why pathological Q-waves can be used to localize the infarct area.

Figure 1. Definition of pathological Q-waves.

ECG criteria for pathological Q-waves (Q-wave infarction)

LeadDefinition of pathological Q-waveNormal variants
V2–V3≥0,02 s or QS complex*None
All other leads≥0,03 s and ≥1 mm deep (or QS complex)Individuals with electrical axis 60–90° often display a small q-wave in aVL. Leads V5–V6 often display a small q-wave (called septal q-wave, explained in this article). An isolated QS complex is allowed in lead V1 (due to missing r-wave or misplaced electrode). Lead III occasionally displays a large isolated Q-wave; this is called a respiratory Q-wave, because its amplitude varies with respiration. Lead III may also display small Q-waves (not related to respiration) in individuals with electrical axis -30° to 0°.

The following figure shows pathological Q-waves in two patients with acute STEMI.

Figure 2. Examples of STE-ACS (STEMI). Note that these patients presented with pathological Q-waves, which means that these ECGs were recorded several hours after symptom onset or those are signs of old infarction.

Pathological R-waves also indicate previous myocardial infarction

Current European (ESC) guidelines suggest that R-waves may also be used to diagnose previous myocardial infarction.

Criteria for pathological R-waves:

R-wave ≥0,04 s in V1-V2 and R/S ratio ≥1 with concordant positive T-wave in absence of conduction defect.

R/S ratio > 1 implies that the R-wave is larger than the S-wave.

Chapter 17: Other ECG changes in ischemia and infarction

Pathological R-wave progression

Normal R-wave progression implies that the R-wave amplitude increases gradually from V1 to V5 and then diminishes again in V6. Refer to Figure 1. Abnormal R-wave progression implies that the gradual increase from V1 to V5 is absent. It may be broken, as in Figure 1. Any type of infarction may cause pathological R-wave progression. However, the specificity for pathological R-wave progression is considerably lower than pathological Q-waves and guidelines do not state any ECG criteria specific to R-wave progression.

Figure 1. Pathological R-wave progression is indicative of previous myocardial infarction.

U-wave changes

New U-waves (in absence of bradycardia) may indicate ischemia. If U-waves were present on previous recording, the amplitude must be increased in order to suggest ischemia. Inverted U-waves are even more typical of ischemia (but the sensitivity is low). U-wave changes always accompany other ischemic ST-T changes. They may occur in both NSTEMI and STEMI.

QTc prolongation

The QT (QTc) interval may be prolonged, shortened or unchanged in ischemia.

R-wave amplitude

Acute transmural ischemia may transiently increase the amplitude of the R-waves. This is believed to be due to delayed (and thus electrically unopposed) depolarization in the ischemic area.

Fragmented QRS complex

The definition of fragmented QRS complexes (Figure 2) are as follows:

QRS complex with more than 1 R wave and/or

notch in the descending limb of the R-wave and/or

notch in the descending limb of the S-wave

In case of complete/incomplete bundle branch block or pacemaker rhythm, >2 notches are required in the S-wave or R-wave.

Fragmented QRS complexes are indications of previous myocardial infarction. There are imaging studies demonstrating that QRS fragmentation is more common than the development of pathological Q-waves after infarction. The sensitivity of fragmented QRS for myocardial infarction was 86%, as compared with 36% for pathological Q-waves. However, the specificity was lower for fragmented QRS (89% vs 99%). The absence of fragmented QRS has a high negative predictive value (93%) for myocardial infarction. Moreover, fragmented QRS is associated with an increased risk of sudden cardiac death and ventricular arrhythmias.

Figure 2. Fragmented QRS complex. These QRS configurations are also indicate of previous myocardial infarction.

New conduction defect

Myocardial infarction/ischemia may be complicated with conduction defects (discussed in separate article).

Chapter 18: Supraventricular and intraventricular conduction defects in myocardial ischemia and infarction

Bradycardia and conduction defects, such as bundle branch block, fascicular block and AV block, are common in myocardial ischemia and infarction. These conditions may be seen as signs of ischemia, which is why one must be familiar with them. In order to completely understand the different complications related to ischemia/infarction in the conduction system, one must be familiar with the vascular supply to these components. Figure 1 presents all relevant parts of the conduction system and their source of blood supply.

Figure 1. The component of the cardiac conduction system and the vascular supply. RCA = right coronary artery. LAD = Left anterior descending coronary artery. LCX = left circumflex coronary artery.

Arterial blood supply of the conduction system

Figure 1 presents the components of the conduction system and the arterial blood supply. The first third of the right bundle branch run in the endocardium, near the ventricular cavity, and it may to some extent receive oxygen from the blood in the ventricular cavity. The right bundle branch then runs deeper into the myocardium, where roughly one third of its length is located. It then runs closer to the endocardium, again, in its final third. The right bundle branch does not give off any Purkinje fibers during its course through the interventricular septum. It starts to branch off at the anterior papillary muscle’s origin. The interventricular septum obtains Purkinje fibers from the left bundle branch.

Coronary artery dominance

The coronary artery that supplies the PDA (posterior descending coronary artery), which supplies the inferior wall of the left ventricle, determines the coronary artery dominance. A right-dominant system implies that the PDA is supplied by the right coronary artery (RCA). A left-dominant system implies that the PDA is supplied by the left circumflex coronary artery (LCX). Right-dominant system is by far the most common anatomy, occurring in 90% of all individuals.

Figure 2. Coronary arteries in a right-dominant system.

Bundle branch blocks

Bundle branch blocks may be caused by ischemia/infarction. A new bundle branch block in a patient presenting with chest discomfort is strongly suggestive of ongoing ischemia/infarction. Among all patients with acute myocardial infarction the prevalence of right and left bundle branch block on arrival ECG is 6% and 7%, respectively. A proportion of these patients have a new bundle branch block, which in the case of left bundle branch block should lead the clinician to activate the catheterization laboratory (discussed in Left bundle branch block and ischemia/infarction). Studies demonstrate that individuals with acute myocardial infarction who do not display bundle branch block on the arrival ECG, will in most cases not develop bundle branch block during the hospital stay.

As discussed previously, the presence of bundle branch blocks renders ischemia interpretation more difficult, which explains why individuals with bundle branch blocks are treated sub-optimally (in terms of evidence based medications and use of PCI), as compared with individuals without bundle branch blocks. Moreover, individuals with bundle branch block have poorer survival than their counterparts with intact bundle branches.

Individuals with ischemic heart disease (or myocardial infarction) who present with right bundle branch block typically also have a fascicular block. This condition is referred to as bifascicular block. The anterior fascicle is most likely to be defect because it is most sensitive to myocardial ischemia. Note that isolated fascicular blocks are uncommon in acute myocardial infarction.

Left bundle branch block (LBBB)

Left bundle branch block and ischemia/infarction has been discussed previously.

Right bundle branch block (RBBB)

The right bundle branch block mainly affects the terminal portion of the QRS complex, resulting in a second R-wave (referred to as R’) in V1–V3 and a broad and deep S-wave in V5–V6.  However, right bundle branch block only affects the depolarization of the right ventricle; the left ventricle will be depolarized, which is why infarct criteria for the QRS complex (pathological Q-waves) may be applied in the presence of right bundle branch block.

The right bundle branch block will also cause secondary ST-T changes in lead V1–V3 but these forces are not strong enough to mask ischemic ST-T changes arising from the left ventricle (because it has stronger electrical potentials). The classical ECG changes (and ECG criteria) seen in STE-ACS/STEMI and NSTE-ACS/NSTEMI do apply in the presence of right bundle branch block. Thus, ECG interpretation of ischemia may proceed as usual in the presence of right bundle branch block.

One should also be observant regarding pseudonormalization of T-wave inversions (i.e. finding that known T-wave inversions have become “normal”). This is a sign of ischemia if it occurs in V1–V3.

As mentioned above, right bundle branch block is often accompanied by a fascicular block. In the vast majority of cases, it is the anterior fascicle that is defective in ischemia/infarction. This yields Q-waves in V2–V3, but these Q-waves are usually small and do not reach the criteria for pathological Q-waves.

Interestingly, Widimsky et al (European Heart Journal, 2014) reported that new right bundle branch block (with or without fascicular block) may be as strong a predictor of acute occlusion as is left bundle branch block. They also demonstrated that in-hospital mortality for patients with new right bundle branch block was at least on a par with patients with new left bundle branch block. The authors suggested that new right bundle branch block should be given the same significance as new left bundle branch block.

Atrioventricular (AV) blocks and bradycardia (bradyarrhythmia)

These conduction defects arise in ischemia/infarction due to an imbalance in the autonomic nervous system (temporary autonomic dysfunction is common in myocardial infarction) or as a direct consequence of ischemia/infarction. Importantly, conduction defects caused by inferior wall ischemia/infarction are transient in the vast majority of cases, whereas conduction defects due to anterior wall infarction tend to be permanent. There are no data on differences in the incidence of these conduction defects in NSTE-ACS/NSTEMI and STE-ACS/STEMI. However, approximately 7% of patients with NSTE-ACS/NSTEMI develop high-degree AV-block (second-degree AV-block or higher).

Conduction defects caused by inferior wall ischemia/infarction

Conduction defects may arise anywhere between the onset of ischemia and a few days after completion of the infarction. Sinus bradycardia occurs in up to 40% of patients with inferior wall myocardial ischemia/infarction. AV blocks are also common. Both sinus bradycardia and AV-blocks are usually caused by autonomic imbalance, more precisely increased vagal tone. This phenomenon only occurs in inferior wall ischemia/infarction. Importantly, sinus bradycardia and AV-block due to increased vagal tone is reversible and usually resolve within a week. Administration of atropine will increase the heart rate (i.e inferior wall ischemia/infarction is sensitive to atropine).

AV blocks may also be caused by edema or accumulation of adenosine in the AV system. This type of AV block usually occurs sub-acutely (after 24 hours) and also resolves spontaneously. It is typical that this type of AV block displays a gradual normalization from third-degree AV block to second-degree to first-degree and finally to normal AV conduction. This type of AV block, however, is not sensitive to atropine.

High-degree AV block (second-degree AV-block type 2 or third-degree AV-block) occurs in 10% of patients with inferior ischemia/infarction. The conduction defect is usually located in the AV node, which means that an escape rhythm usually arises distal to the defect. Escape rhythms generated proximal to the bifurcation of the His bundle will have normal QRS complex (QRS duration <0.12 s), whereas those arising distal to the bifurcation will have wide QRS complexes.

AV blocks in inferior wall ischemia/infarction rarely cause circulatory compromise (unless the ejection fraction is not markedly reduced). Moreover, the vast majority of AV blocks due to inferior wall ischemia/infarction resolve spontaneously within a week.

Tabell 1. Conduction defects in inferior wall ischemia/infarction

DefectCommentPrognosis
Sinus bradycardiaThe most common complications. Affects up to 40% of cases.Caused by increased vagal tone and is therefore transient.
Sinus node dysfunctionLess common. May be seen in the sub-acute phase (>24 hours)Mostly permanent.
First-degree AV-blockCommonMajority resolves within 1 week.
Second-degree AV-block, Mobitz type 1 (Wenckebach block)Relatively common.Majority resolves within 1 week.
Second-degree AV-block, Mobitz type 2Uncommon. Mobitz type II is more common in anterior wall ischemia/infarction.Majority resolves within 1 week.
Third-degree AV-blockCommon (10% of inferior wall ischemia/infarctions). Usually caused by intranodal defect. Evolves gradually from 1st, to 2nd to 3rd degree block, which culminates with asymptomatic bradycardia. Much less common in anterior wall ischemia/infarction (prevalence 3%).Majority resolves within 1 week.

Conduction defects caused by anterior wall ischemia/infarction

Conduction defects caused by anterior wall infarction are caused by necrosis and thus not reversible. The cause is almost invariably occlusion in the LAD (left anterior descending coronary artery) resulting in necrosis of the interventricular septum. AV blocks in anterior infarction are due to necrosis in the bundle of His, which is why any escape rhythm usually has wide QRS complexes (most often with right bundle branch pattern). Prolonged PR interval is very common.

Second-degree AV-blocks in anterior infarction are usually Mobitz type II. Extensive septal necrosis may result in third-degree AV block. Development of third-degree AV block is typically preceded by a new right bundle branch block with left or right axis deviation. This should alert the clinician to the risk of third-degree AV block. The right bundle branch block caused by septal infarction is usually associated with Q-wave in V1 (QR complex). Because the right bundle branch and the anterior fascicle both obtain blood supply from the proximal septal branches of LAD, it is common with the combination of right bundle branch block and anterior fascicular block (i.e bifascicular block) in anterior wall infarction. The combination of right bundle branch block and posterior fascicular block is much less common. Notably, bifascicular block markedly increases the risk of third-degree AV-block. The risk is especially high if there is simultaneous first-degree AV block (this is often referred to as trifascicular block); a permanent pacemaker will mostly be needed in that scenario.

Anterior wall infarctions with third-degree AV-block are associated with very high mortality. Some studies have reported up to 80% mortality rate.

Chapter 19: ECG localization of myocardial infarction / ischemia and coronary artery occlusion (culprit)

Determining the localization of myocardial infarction and ischemia, as well as identifying the occluded coronary artery and the location of the occlusion, is clinically important. As discussed below, this information can aid in diagnosing ischemia and infarction and guide appropriate management strategies. For instance, administering nitroglycerin to alleviate ischemic chest pain may lead to hemodynamic collapse in patients with right ventricular ischemia or infarction. Recognizing ECG signs of right ventricular involvement is, therefore, important. Such knowledge is valuable for most clinicians. For cardiologists – particularly interventional cardiologists – this knowledge is of critical importance as they must be able to directly pinpoint where the coronary artery occlusion is located. The term culprit – which means “the guilty one” – is used to denote the occluded coronary artery. In the majority of cases, it is only possible to determine the ischemic/infarct area (and thus the culprit) if the ECG displays ST segment elevations. However, there are a few characteristic ECG syndromes (e.g. Wellen’s syndrome, de Winter’s sign, widespread ST segment depressions) that point to the left anterior descending artery (LAD) as the culprit.

The coronary arteries: a brief overview

The two primary coronary arteries originate from the aortic bulb (Figure 1):

The right coronary artery (RCA) originates on the right aspect of the aortic bulb.

The left main coronary artery (LMCA) originates from the left anterior aspect of the aortic bulb. The LMCA is short and branches into the two arteries supplying the anterior and left side of the heart, as follows:

The left anterior descending coronary artery (LAD).

The left circumflex coronary artery (LCX).

Figure 1 is important, as it shows the coronary arteries and their relation to the ECG leads. Note that Figure 1 is a right-dominant system (i.e PDA is supplied from RCA).

Figure 1A. The coronary arteries and their relation to the ECG leads. Localization of myocardial infarction / ischemia is done by using ECG changes to determine the affected area and subsequently the occluded coronary artery (culprit).

Figure 1B. Detailed diagram of coronary artery segments. CT = computerized tomography.

LMCA = Left main coronary artery (5)

LAD = left anterior descending artery:

proximal segment (6)

medial segment (7)

apical segment (8)

first diagonal branch (D1) (9)

second diagonal branch (D2) (10)

LCX = Left circumflex artery

proximal segment (11)

obtuse marginal branch (OM) (12)

distal segment (13)

left posterolateral branch (PL) (14)

posterior descending artery (PDA) (15)

Right coronary artery (RCA)

proximal segment (1)

medial segment (2)

distal segment (3)

posterior descending artery (PDA) (4)

Additional coronary artery segments:

RPLB: Posterolateral branch of the right coronary artery (16)

Intermediary artery (17)

LPLB: Posterolateral branch of the left circumflex artery (18)

Coronary artery dominance: left dominance vs. right dominance

The coronary artery that supplies the PDA (posterior descending coronary artery), which supplies the inferior wall of the left ventricle, determines the coronary artery dominance (Figure 1). A right-dominant system implies that the PDA is supplied by the right coronary artery (RCA). A left-dominant system implies that the PDA is supplied by the left circumflex coronary artery (LCX). Right-dominant system is by far the most common anatomy, occurring in 90% of all individuals.

Figure 2 is also important to study, as it shows the arterial supply of the conduction system.

Figure 2. The arterial supply of the conduction system. As seen, the sinoatrial node is supplied by the right coronary artery in 60% of individuals, and by the left circumflex artery in the remainder. The atrioventricular node is supplied by the right coronary artery in 90% (right dominant system) of individuals, whereas in the remaining 10% the supply comes from the left circumflex artery (left dominant system).

Localization of myocardial infarction or ischemia using the ECG: the implications of ST segment elevation

It is possible to localize the ischemic area by using the ECG if there are ST-segment elevations. The reason why ST segments are indicative of the ischemic area has been discussed (read ST-T changes in ischemia). Briefly, the ECG leads that display ST-segment elevations do reflect the ischemic area. Hence, ST-segment elevations in leads V3–V4 are caused by transmural ischemia located in the anterior wall of the left ventricle. ST-segment elevations in leads II, aVF and III are due to transmural ischemia located in the inferior wall of the left ventricles. Table 1 shows an overview of the relation between leads with ST-segment elevations and ischemic area. An exhaustive discussion follows below.

Table 1: Localization of ischemic area in ST Elevation Myocardial Infarction (STEMI/STE-ACS)

Leads with ST segment elevationsAffected myocardial areaOccluded coronary artery (cuprit)
V1–V2SeptalProximal LAD.
V3–V4AnteriorLAD.
V5–V6ApicalDistal LAD, LCx or RCA.
I, aVLLateralLCx.
II, aVF, IIIInferior90% RCA. 10% LCx.
V7, V8, V9 (reciprocal ST depressions are frequently evident in V1–V3)Posterolateral (also referred to as inferobasal or posterior)RCA or LCx.

Localizing the ischemic area in NSTE-ACS/NSTEMI is much more difficult because leads with ST-segment depressions do not reflect the ischemic area. The electrophysiological explanation to this has been discussed previously (read ST-T changes in ischemia). Thus, ST-segment depressions in leads V3–V4 do not necessarily imply that the ischemia is located to the anterior wall. Therefore it is commonly stated that ST-segment depressions (as well as T-wave inversions) cannot be used to localize the ischemic area. There are two notable exceptions to this rule, namely Wellen’s syndrome and de Winter’s sign, both of which are caused by proximal occlusions in the LAD and thus cause anterior wall ischemia/infarction.

Note that the discussion so far only concerns the left ventricle. Specification of the ischemic/infarct area refers to the walls of the left ventricle. For example, the expression anterior infarction implies infarction of the anterior wall of the left ventricle. Similarly, inferior infarction implies infarction of the inferior wall of the left ventricle. Right ventricular infarction is uncommon (it occurs if an occlusion is located in the proximal RCA). Figure 3 shows the walls of the left ventricle, and the ECG leads reflecting these walls.

Occlusion in the right coronary artery (RCA)

Areas supplied by the right coronary artery

The right coronary artery supplies the entire right ventricle via the right marginal artery (r. marginalis dx).

In 90% of individuals, the right coronary artery gives off the posterior descending artery (PDA) which supplies the inferior wall of the left ventricle. When the RCA gives off PDA, the anatomy is referred to as right-dominant system (if the Lcx gives off PDA, it is referred to as left-dominant system).

In patients with right-dominance, the RCA supplies the atrioventricular (AV) node.

In 60% of individuals, the right coronary artery gives off branches to the sinoatrial (SA) node.

The posterior third of the interventricular septum is supplied by the right coronary artery.

Arteries to the posterior wall (these arteries branch off after the right marginal artery) may be given off by the RCA (and otherwise the LCx).

Occlusion in the right coronary artery

Occlusion in the RCA causes inferior wall infarction in individuals with right-dominance (i.e if the RCA gives off the PDA, which is the case in 90% of all individuals). If the occlusion occurs proximally, it may affect the blood supply to the right ventricle and thus cause right ventricular infarction (this is uncommon). Occlusion in the RCA may also cause posterior wall infarction. Details follow.

Inferior wall infarction causes ST-segment elevations in leads II, III and aVF. The ST-segment elevation is highest in lead III and the majority of cases display reciprocal ST-segment depressions in lead aVL and I.

Inferior and posterior (inferobasal) infarction – Posterior wall infarction occurs if the arteries supplying the posterior wall are affected. This causes ST-segment elevations in lead II, III, aVF, V7, V8 and V9. Reciprocal ST-segment depressions are seen in V1–V3, aVL and I. It is common that V1–V3 displays unusually high R-waves and positive T-waves during posterior wall infarction (these are reciprocal changes to posterior Q-waves and T-wave inversions, respectively).

Inferior infarction and right ventricular infarction – None of the standard leads in the 12-lead ECG is adequate to capture the injury currents arising in the right ventricle. It is a common misunderstanding that V1 and V2 record right ventricular activity (V1 and V2 primarily observe the electrical activity of the interventricular septum). However, V1 and V2 may occasionally display ST-segment elevations during right ventricular infarction (the elevations should be higher in V1). To verify right ventricular infarction one must connect the right-sided chest leads (V3R, V4R, V5R and V6R, which show ST-segment elevations). Since infarction of the right ventricle affects treatment alternatives, it is recommended that these right-sided chest leads be used if there is suspicion of right ventricular infarction. Note that the ST-segment elevations in right ventricular infarction have a much shorter duration than infarction of the left ventricle (because the right ventricular wall is much thinner than the left, and therefore the infarction is completed faster).

Occlusion in the left anterior descending coronary artery (LAD)

Areas supplied by the left anterior descending coronary artery

The LAD supplies the anterior two-thirds of the interventricular septum (this area is referred to as anteroseptal area).

The LAD supplies the large anterosuperior wall (often referred to as the anterior wall) and the apical part of the lateral wall.

The LAD may stretch to the inferior wall and supply its most apical area (this area is referred to as the inferoapical area). Occasionally the LAD is very long and supplies a significant portion of the inferior wall; this type of LAD is called wrap-around LAD (because it wraps around the apex).

Occlusion in the left anterior descending artery

Occlusion in the LAD causes anterior infarction. ECG changes and extension of the infarction depend heavily on the site of the occlusion. The more proximal the occlusion the greater the infarction and the more pronounced ECG changes. ST-segment elevations may be present in leads V1–V6, and frequently aVL, I (the latter two may be affected because the diagonals given off by the LAD supply the apical part of the lateral wall). There are virtually always reciprocal ST-segment depressions in III and aVF.

Proximal occlusion in LAD – Proximal occlusion in LAD causes massive infarction involving the basal parts, anterosuperior wall, lateral wall and the interventricular septum. The more proximal the occlusion, the more leads display ST-segment elevation. Occlusion proximal to the first septal and diagonal branch causes ST-segment elevations in V1–V4, aVL and I, as well as reciprocal ST-segment depressions in II, III, aVF, -aVR and, frequently, V5 (occasionally V6). A new right bundle branch block is common. Occlusion between the first septal and first diagonal usually spares the interventricular septum (absence of ST-segment elevation in V1).

Distal occlusion in LAD – Occlusion distal to the first diagonal and first septal will spare the basal parts of the anterior wall. The ST-vector will be pointed more downward. ST-segment elevations are seen in V2–V6. There are no ST-segment elevations in V1, I or aVL, and no reciprocal ST-segment depressions in II, III, aVF and -aVR.

Occlusion in a long LAD (“wrap around LAD”) – If the LAD is very long and supplies a significant portion of the inferior wall, occlusion may cause inferior ST-segment elevations. Thus, a very distal occlusion in the LAD may be somewhat deceptive.

Noteworthy – Occlusion in the first diagonal may cause ST-segment elevations in aVL and I, without any other noteworthy ST-segment elevations. Occlusion in the main septal branch may cause ST-segment elevations in V1–V2, and reciprocal ST-segment depressions in V5, V6, II, III and aVF. It should also be noted that recent studies with magnetic resonance imaging have revealed that what was once firmly believed to be a septal infarction (i.e ST-segment elevation in V1–V2) appears to be more of an apical infarction.

Occlusion in the left circumflex coronary artery (LCx)

Areas supplied by the left circumflex coronary artery

In 90% of individuals, the coronary circulation is right-dominant, meaning that the PDA is given off by the RCA. In these individuals, the LCx only supplies the basal and mid parts of the posterolateral wall. As discussed previously, this part of the left ventricle is difficult to capture with the conventional leads in the 12-lead ECG.

In 10% of individuals, the coronary circulation is left-dominant, meaning that the PDA is given off by the LCx. Thus the LCx supplies the inferior wall in 10% of all individuals.

The LCx supplies the AV node in 10% of all individuals.

Occlusion in the left circumflex artery

Posterior (posterolateral, inferobasal) infarction – If the LCX only supplies the posterolateral wall, occlusion will lead to posterolateral infarction (also referred to as posterior or inferobasal infarction). ECG changes resemble those seen in posterior infarction due to occlusion in the RCA, namely ST-segment elevations in V7–V9 and reciprocal ST-segment depressions in V1–V3, along with high R-waves and positive T-waves in the same leads (V1–V3).

Inferoposterior infarction – If LCx gives off PDA, occlusion will cause inferior infarction as well, and thus ST-segment elevations in II, III and aVF (occasionally also in aVL, I, but rarely V5–V6).

Occlusion in the left main coronary artery (LMCA)

Because LMCA is the origin to LAD and LCX, occlusion will cause a massive infarction, with a very poor prognosis. One should suspect occlusion in the LMCA if there are ST-segment elevations in most ECG leads (in persons with left-dominance, it will include the inferior wall).

Chapter 20: The ECG in assessment of myocardial reperfusion

The ECG is an invaluable tool to assess whether an occlusion has been resolved and blood flow has been restored. This assessment is performed daily in the catheterization laboratory in patients undergoing acute PCI. The PCI operator may use the ECG to obtain immediate confirmation on whether the intervention was successful. This is particularly important in STE-ACS (STEMI) and the following parameters on the ECG are assessed:

Normalization (return) of ST-segment elevations

Rapid T-wave inversion

Normalization (return) of ST-segment elevations

Successful reperfusion results in rapid and marked normalization (return) of ST-segment elevations. If the reperfusion is complete (after a total occlusion) the ST-segment is normalized within one hour, and this confirms that the coronary artery flow is patent. The rapid ST-segment return is explained by rapid normalization of myocardial cell membrane potentials in the ischemic area. Myocardial cells are capable of normalizing their membrane potentials immediately as oxygen becomes available. Recall that ST-segment elevations also become normalized as a part of the natural course of myocardial infarction (refer to Figure 2 below). However, that type of normalization is much slower and it is explained by the gradual death (and thus the disappearance of membrane potential) in the ischemic area.

ECG is a better marker of reperfusion than angiography itself. Studies have shown that angiographic blood flow does not always correlate with myocardial perfusion on the microvascular level. This is presumably explained by distal microembolization and dysfunctional microcirculation. Indeed, studies show that 15–35% of patients with STE-ACS/STEMI have inadequate microvascular flow despite patent epicardial blood flow. In such cases, the ECG will be more sensitive (and show a lesser amount of normalization) than evident from angiography. Thus, the ECG is the preferred method of quantifying microvascular blood flow in the myocardium, simply because ST-T changes directly reflect myocardial perfusion.

ST-segment return is particularly important to assess in patients treated with thrombolysis, because reperfusion may be inadequate and/or transient with thrombolysis therapy (PCI is superior to thrombolysis also in this aspect). Guidelines recommend that thrombolysis should result in 50% ST-segment return (i.e reduction of the ST-segment elevation by 50%) within 60 minutes after administration of thrombolysis. Otherwise, one must consider rescue-PCI.

For the purpose of assessing ST-segment return, one should preferably use continuous ST-segment monitoring. If monitoring equipment is not available, 12-lead ECGs should be repeated every 5–10 minutes, while observing the patient’s symptoms. ST-segment return is quantified in the leads with the highest ST-segment elevation.

Figure 2. The electrocardiographic natural course in STEMI (ST elevation myocardial infarction).

Inversion of T-waves indicates reperfusion

The slow natural normalization of ST-segment elevation (in untreated patients) is depicted in Figure 2. As evident, such ST-segment elevations are succeeded by gradual inversion of the T-waves. These T-waves are called post-ischemic T-waves and they indicate that the infarction process is more or less completed. Post-ischemic T-wave inversions emerge at the earliest 4–6 hours after an episode of ischemia/infarction, but no later than 24 hours. However, T-wave inversions following reperfusion develop within 4 hours and such T-waves are robust indicators of successful reperfusion (patent artery). This is also associated with better prognosis, return of R-wave amplitudes, and improved left ventricular function.

Accelerated ventricular rhythm (idioventricular rhythm)

This rhythm has been discussed previously in this article. Briefly, accelerated ventricular rhythm (also called idioventricular rhythm) is a benign ventricular rhythm with a heart rate of 60–100 beats per minute (faster than ventricular rhythm, but slower than ventricular tachycardia). Idioventricular rhythm is seen in 15–50% of patients undergoing reperfusion and it indicates that reperfusion has been successful and the artery is patent. This arrhythmia rarely causes hemodynamic effects and terminates spontaneously after a few minutes. No studies have found an association between this rhythm and survival.

Chapter 21: Approach to patients with chest pain: differential diagnoses, management & ECG

Chest pain is one of the most common symptoms in the emergency department, as well as in primary health care. The cause (etiology) of chest pain varies according to age, sex, risk factors, type of symptoms etc. Chest pain is one of the most nuanced symptoms in clinical practice and it is fundamental to be able to differentiate benign from serious etiologies. Therefore, when encountering a patient with chest pain the primary task is to exclude or verify the following potentially life-threatening causes of chest pain:

Ischemic heart disease: stable angina pectoris, unstable angina pectoris, acute myocardial infarction (AMI). Note that unstable angina pectoris and acute myocardial infarction are categorized under acute coronary syndromes (ACS).

Aortic dissection

Pneumothorax

Pulmonary embolism

Mediastinitis (rare condition)

In addition to these five conditions, there are numerous other causes of chest pain, but the other causes are either subacute or non-acute. The history-taking must be systematic and accurate because the history itself is often sufficient to make a diagnosis or identify a few likely diagnoses. The table below shows a systematic history taking in patients presenting with chest pain (chest discomfort) or other symptoms suggestive of the five conditions listed above. It is important that history taking and physical examination is carried out systematically and carefully without delaying time to treatment.

History taking, physical examination, ECG and laboratory tests are the cornerstones of management of patients with chest pain. A 12-lead ECG recording must be registered and interpreted within 10 minutes of arrival at the hospital. The ECG differentiates between ST elevation acute coronary syndromes (STE-ACS) and non-ST elevation acute coronary syndromes (NSTE-ACS). The division into STE-ACS and NSTE-ACS has profound implications for management and treatment of patients with acute coronary syndromes. Moreover, clinicians must clarify whether the ECG was recorded during chest pain, since an ECG without signs of ischemia during chest pain in principle excludes myocardial ischemia as the cause of the pain. Refer to The ischemic cascade for details.

History taking in patients with chest pain (chest discomfort)

HISTORY PARAMETERQUESTIONSCOMMENTS
Risk factors for the 5 serious etiologiesFamily history (focus on ischemic heart disease, aortic dissection, pulmonary embolism, pneumothorax). Hypertension.Smoking.Dyslipidemia (hyperlipidemia).Obesity and/or diabetes.Psychosocial stress.Alcohol abuse.Physical inactivity.Unhealthy diet.Cerebral / peripheral vascular disease.Cancer.Acute coronary syndromes cause symptoms already at rest.Stable ischemic heart disease does not cause symptoms at rest unless the stenosis is so grave that myocardial oxygen demands cannot be satisfied even at rest.Ischemic chest pain is more easily provoked after a meal because food intake redistributes blood to the gastrointestinal tract which reduces blood availability in the heart.Symptoms of ischemic heart disease are generally not related to body position or respiration.
Triggering factorsSymptoms triggered by exercise/effort (what level of exercise)?Symptoms at rest?Symptoms more easily provoked after a meal?Symptoms provoked by (or after a period of) stress?Symptoms related to body position or respiration?Ischemic chest pain is usually described as pressure, squeezing, or a crushing sensation across the precordium and may radiate to the neck, shoulder, jaw, back, upper abdomen, and left or right arm.
Onset and evolutionHow do symptoms start (suddenly or gradually)?When did the patient first note the symptoms and how have the symptoms developed over time?In stable ischemic heart disease, symptoms are typically not present at rest but they occur during exercise when the oxygen demand in the myocardium is increased. Ischemic chest pain typically has a gradual onset, reaching a maximum within a few minutes and if the pain subsides, it does so gradually.Some patients with acute coronary syndromes have an established diagnosis of ischemic heart disease, while others have never had any symptoms prior to developing the acute coronary syndrome.In stable ischemic heart disease, the symptoms tend to worsen over time, meaning that they arise at lower levels of exercise and are more severe. This usually takes months or years to develop.
Localization of painWhere is the pain located?Diffuse or distinct location?Pain radiating to the left?More severe on the left side?Ischemic heart disease typically causes diffuse pain over a wide area of the anterior chest wall (the pain is not localized). Ischemic heart disease also tends to cause pain radiating to the left arm, neck, shoulder or jaw. Patients typically report that the pain is more severe on the left side of the chest.
Pain qualityDescribe the type of pain (pressure/cramp/crushing, cutting, burning etc).Ischemic chest pain is usually described as pressure, squeezing, or a crushing sensation across the precordium and may radiate to the neck, shoulder, jaw, back, upper abdomen, left or right arm.
Associated symptomsPain radiation to arm, neck, jaw or back?Cold sweats?Anxiety?Nausea or vomiting?Presyncope / syncope?Palpitations?Dyspnea?Reflux?Fever?Ischemic chest pain causes symptoms from the autonomic nervous system, most notably diaphoresis (sweating), nausea, and vomiting.Dyspnea suggests either a cardiac or pulmonary etiology.Presyncope/syncope suggests either a cardiac or pulmonary etiology.Palpitations suggest either a cardiac or pulmonary etiology.
Alleviating factorsPain alleviated by rest?Pain alleviated by nitroglycerin?Ischemic chest pain is typically alleviated by rest and by administration of nitroglycerin. However, these characteristics are not specific to ischemic chest pain.
Frequency of symptomsHow many episodes of chest pain?When was the worst / longest episode and its duration?Increased frequency and/or intensity last month?Time of the latest episode?Myocardial infarction occurs after 20 minutes of severe ischemia. It may take up to 6 hours for troponin levels to increase significantly after myocardial infarction, which is why troponin results are not conclusive before 6 hours after the last episode of pain. Thus, if 6 hours have passed since the last episode of pain, the troponin tests will be able to determine whether the patient developed myocardial infarction.In patients with stable ischemic heart disease, increased frequency and/or intensity of the symptoms the last month suggests that they have developed unstable angina pectoris (which is an acute coronary syndrome).
OtherRecent infections (particularly airway infection)?Chest trauma?Heavy physical exertion?All these suggest non-ischemic causes.
Alarming signsSevere pain.Affected general appearance.Cutting pain and/or back pain.Morphine-resistant pain.Diabetics, elderly and women.Epigastralgia.Pulmonary edema.Severe pain increases the likelihood of serious etiologies.If the patient’s general appearance is affected, it increases the likelihood of serious etiologies.Cutting pain and/or back pain (particularly if it has migrated down along thorax) suggests aortic dissection.Morphine-resistant pain suggests serious etiologies.Diabetics, elderly and women may have atypical symptoms, which is why angina equivalents (dyspnoea, sweating, extreme fatigue, atypical pain) must be assessed. In elderly dyspnoea is as common as angina in acute myocardial infarction. Note that epigastralgia may be caused by inferior myocardial infarction.Pulmonary edema.

The severity of symptoms in patients with angina pectoris should be graded according to the Canadian Cardiovascular Society (CCS):

Grade IOrdinary physical activity does not cause angina, such as walking and climbing stairs. Angina with strenuous or rapid or prolonged exertion at work or recreation.
Grade IISlight limitation of ordinary activity. Walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, or in cold, or in wind, or under emotional stress, or only during the few hours after awakening. Walking more than two blocks on the level and climbing more than one flight of ordinary stairs at a normal pace and in normal conditions.
Grade IIIMarked limitation of ordinary physical activity. Walking one or two blocks on the level and climbing one flight of stairs in normal conditions and at normal pace.
Grade IVInability to carry on any physical activity without discomfort, anginal syndrome may be present at rest.

Characteristics of various causes of chest pain

Ischemic chest pain: angina pectoris and acute coronary syndromes

Ischemic chest pain causes diffuse discomfort over a wide area of the anterior chest wall. The pain is typically not localized and is described as a pressure, cramp or crushing sensation. The pain may radiate to either arm, neck, back or shoulder. Radiation to the arms rarely reaches the fingertips. These symptoms are more severe when the ischemia causes myocardial infarction. Shortness of breath (dyspnea) frequently accompanies chest discomfort and some patients may have difficulties discerning these symptoms.

Several factors influence the symptoms presented. Women, elderly and persons with diabetes frequently present with atypical symptoms; notably, these three groups may present with only dyspnea. In fact, in the elderly with acute myocardial infarction, dyspnea is as common as chest discomfort. Moreover, women with acute myocardial infarction report back pain, neck pain and jaw pain more often than males.

Stable angina pectoris and acute coronary syndromes differ in several aspects, which are now clarified.

Angina pectoris: Angina pectoris is a diffuse pain over the anterior chest wall. It is described as a pressure, cramp or crushing sensation. Angina pectoris is diagnosed when the ischemic heart disease is stable, which implies that symptoms only appear in situations with increased myocardial workload, and symptoms subside when the workload returns to normal. The most typical scenario is angina pectoris provoked by exercise and mental stress. Both these scenarios increase heart rate and workload which subsequently causes ischemia. However, in stable angina pectoris, the symptoms must subside within minutes after resting or after administration of nitroglycerin. Otherwise, the condition is not stable. Angina pectoris is more easily provoked by cold. Some patients have angina pectoris due to coronary artery vasospasm, but this is considerably less common than atherosclerosis.

Unstable angina pectoris: Unstable angina pectoris is defined as angina pectoris that has changed and become aggravated recently (up to 30 days). Three scenarios are typically defined as unstable angina pectoris: (1) angina pectoris at rest, or with minimal exertion, lasting 10 minutes or longer; (2) new-onset angina with severe pain; (3) angina pectoris which has worsened by becoming more frequent, more severe and with longer duration. Nitroglycering has insufficient effect. Patients with unstable angina pectoris are at considerable risk of developing acute myocardial infarction. Unstable angina pectoris and all types of acute myocardial infarction are categorized as acute coronary syndromes (ACS); their underlying etiology is the same, namely a ruptured atherosclerotic plaque.

Acute myocardial infarction (AMI): The pain is similar to unstable angina pectoris but more severe. Duration is virtually always longer than 15 minutes but shorter than 12 hours. Autonomic symptoms such as nausea, diaphoresis etc are very common.

Classification of acute coronary syndromes (acute myocardial infarction) is presented in the following figure.

Figure 1. Chest pain is the hallmark of myocardial ischemia. It signals that there is ongoing (acute) myocardial ischemia. Careful assessment of the symptoms is crucial to promptly establish a working diagnosis. Chest pain due to myocardial ischemia is rather characteristic, which means that the vast majority of patients with acute coronary syndromes can be treated before troponin test results have arrived. Hence, assessment of symptoms and ECG is sufficient to manage patients with chest pain.

Pericarditis and perimyocarditis

Pericarditis may also cause chest pain on the anterior chest wall; the pain area varies from the size of a coin to a hand.

The pain is often correlated with respiration. Deep breaths typically aggravate the pain.

The pain is often alleviated by leaning forward or to the left side.

The intensity of the pain may very well be equal to the pain in ACS.

Gastrointestinal chest pain

May also be located on the anterior chest wall.

Described as a pressure or burning sensation.

Can be aggravated by physical exertion and alleviated by food intake.

Nitroglycerin may relieve the pain caused by esophageal spasms.

Gastric ulcers are relieved by acid inhibitors.

Reflux esophagitis is relieved by standing up or drinking milk.

Esophagitis and esophageal spasm may mimic the pain in myocardial ischemia.

Pulmonary chest pain

Severe pneumonia can cause chest pain correlated with respiration.

Musculoskeletal chest pain

Musculoskeletal chest pain may be located anywhere on the chest wall and back.

The pain is usually sharp, typically related to body position and intermittent.

Tietze’s syndrome should be considered. It is a benign inflammation of one or more of the costal cartilages. The chest pain is accompanied by tenderness and swelling of the affected cartilage. The cartilages are usually tender upon palpation and the pain is aggravated with respiration. Although it may be very painful, Tietze’s Syndrome is considered to be a benign syndrome that generally resolves in 3 months.

Spondylitis may cause back pain if located in the thoracic vertebrae.

Rib fractures cause located chest pain which correlates with respiration. Palpation provokes severe pain. The pain subsides gradually within 3 weeks.

Vascular chest pain (aortic dissection)

Aortic dissection may sometimes present with symptoms that are indistinguishable from acute myocardial infarction. Symptom presentation also depends on where the dissection originates and whether it continues to dissect. The pain is, as compared with acute myocardial infarction, more often described as a tearing, ripping or shearing pain that radiates to the neck or down the back. The pain is very severe and resistant to morphine unless high doses are administered. Shortness of breath is very common as are autonomic symptoms such as paleness, diaphoresis and nausea. Notably, neurological symptoms are rather specific to aortic dissection; the dissection may cause occlusion of large arteries supplying both the cerebral, abdominal and extremities circulation. Thus, neurological, abdominal and peripheral pain may be seen during aortic dissection.

Cardiac neurosis

Anxiety and stress may cause chest pain. Many individuals with chest are worried their symptoms may be caused by myocardial infarction, which further exacerbates their symptoms. The pain is usually located to the left and it is aggravated during periods of stress or anxiety. Frequently the pain has a fairly precise location to the left; patients tend to point with a finger towards the location of the pain. The symptoms are not related to exercise. Some patients also experience palpitations, hyperventilation, dyspnea and irregular heartbeats.

Physical examination

A complete physical examination is always warranted. Emphasis should, however, be put on the following parameters:

General appearance – Any sign of affected general appearance may indicate that the underlying cause is serious.

Heart rate – The heart rate does not distinguish between the differential diagnoses, but it must be assessed to evaluate circulatory status.

Blood pressure – The blood pressure should be measured in both arms if there is suspicion of aortic dissection. A difference in pressure (between the left and right arm) greater than 15 mmHg increases the suspicion of aortic dissection.

Oxygen saturation

Respiratory rate

Body temperature

Signs of heart failure

Inspect and palpate the thoracic wall. Clarify whether the pain is related to palpation, rotation of the torso or any other body position, arm movements etc.

ECG changes in ischemia/infarction

ECG changes in myocardial ischemia and infarction have already been discussed. Briefly, the following ECG changes suggest myocardial ischemia or infarction.

ST segment elevation (STEMI)

ST segment depression (NSTEMI)

T-wave changes: flat T-waves, inverted T-waves, hyperacute T-waves

Pathological Q-waves, QS complex, Pathological R-wave progression, Fragmented QRS segment

New left bundle branch block (LBBB)

New arrhythmias (both bradycardia and tachycardia)

New conduction defects

If possible, the ECG should be recorded during ongoing chest pain. The reason for this is that chest pain that does not provoke ischemic ECG changes is not caused by myocardial ischemia/infarction (please refer to The ischemic cascade). Thus, an ECG with no signs of ischemia, recorded during chest pain, excludes myocardial ischemia as the underlying cause of the symptoms. Moreover, it is important to compare the current ECG with a previous recording, if such is available.

It is recommended that the ECG be repeated at 5–15 minutes intervals (even in the emergency room). Myocardial ischemia is a dynamic process and 60% of the ischemic episodes that are detected with ECG are asymptomatic.

Consider additional ECG leads if there is suspicion of posterior (posterolateral) myocardial infarction or right ventricular infarction.

Laboratory tests

Troponin T or troponin I is used to detect myocardial necrosis (refer to Diagnostic criteria for acute myocardial infarction). It may take up to 6 hours for troponin levels to increase significantly after acute myocardial infarction. Thus, troponin samples are not conclusive until 6 hours after the last episode with chest pain. In clinical practice, troponin samples are taken on arrival and 6 hours later. A third sample may be taken 24 hours after survival. Blood lipids and glucose must always be analyzed. D dimer is only analyzed if there is suspicion of pulmonary embolism.

Radiological examinations

Chest X-ray is generally not indicated. However, it may be considered if there is suspicion of pneumothorax, pleuritis, pneumonia or heart failure.

Computerized tomography (CT) is indicated if there is suspicion of aortic dissection or pulmonary embolism. Modern CT protocols are capable of elucidating both these differential diagnoses.

Echocardiogram, including an assessment of the aorta, is recommended and may guide both diagnostics and therapy.

Risk stratification of patients with acute coronary syndromes (ACS)

Use evidence-based risk models to estimate the risk of infarction and death.

GRACE: www.outcomes-umassmed.org/grace

TIMI: www.timi.org

Chapter 22: Stable Coronary Artery Disease (Angina Pectoris): Diagnosis, Evaluation, Management

Evaluation and management of stable coronary artery disease

Chronic coronary syndrome (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.

ClassificationDefinition
Typical angina pectorisTypical 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 pectorisAtypical angina meets two of three above criteria.
Non-anginal chest pain or discomfortNon-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

ClassSeverity
Class IAngina only during strenuous or prolonged physical activity.
Class IISlight limitation, with angina only during vigorous physical activity.
Class IIISymptoms with everyday living activities, ie, moderate limitation.
Class IVInability 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

ModalitySensitivity (%)Specificity (%)
Exercise stress testing (exercise ECG)40-50%85 -90%
Stress echocardiography80-85%80-88%
Stress SPECT73-92%63-87%
Stress echocardiography with dobutamine79-83%82-86%
Stress MRI with dobutamine72-79%81-91%
Stress echocardiography with vasodilator90-91%75-84%
Stress SPECT with vasodilator67-94%61-85%
CTA coronary artery95-99%64-83%
Stress PET with vasodilator91-97%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.

Myocardial perfusion imaging (SPECT, PET)

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 healthcare 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.

CategoryAgents
Non-selective beta-blockersPropranololBucindolol (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-blockersAcebutolol (has sympathomimetic activity)AtenololBetaxololBisoprololCeliprolol (has sympathomimetic activity)MetoprololNebivololEsmololNebivolol (also β1 agonist)
β2 selective beta-blockersButaxamine

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.

VerapamilDiltiazemAmlodipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine, Nitrendipine
CLASSNon-dihydropyridinesNon-dihydropyridinesDihydropyridines
SELECTIVITYCardiac calcium channelsCardiac calcium channels and vascular L-type calcium channels.Vascular L-type calcium channels
NEGATIVE INOTROPIC EFFECTYes. Should be avoided in heart failure.Yes. Should be avoided in heart failure.No. Can be used in heart failure.
REDUCTION OF HEART RATEYesYesNo
ANTI-ANGINAL EFFECTYes, pronounced.Yes, pronounced.Yes, less than verapamil and diltiazem.
BLOOD PRESSURE LOWERING EFFECTSmallSmallPronounced
VASOSPASTIC EFFECTReduces vasospasm.Reduces vasospasm.Reduces vasospasm.
SIDE EFFECTSBradycardia, 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

ClassAgentBrand namesIndication in CCS
NSAIDAcetylsalicylic acidAspirinAll patients with CCS should receive aspirin.
P2Y12 InhibitorsTicagrelorBrilinta, BriliqueYes
CangrelorKengrealDuring PCI
PrasugrelEffientYes
ClopidogrelPlavixYes
GP IIb/IIIA inhibitorsTirofibanAggrastatDuring PCI
AbciximabReoProDuring PCI
EptifibatideIntegrilinDuring PCI
PAR-1 antagonistsVorapaxarZontivityNo

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

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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.

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Chapter 23: NSTEMI (Non-ST Elevation Myocardial Infarction) & Unstable Angina: Diagnosis, Criteria, ECG, Management

The focus of this chapter is the diagnosis and management of patients with Non-ST Elevation Myocardial Infarction (NSTEMI) and unstable angina (UA), which are collectively referred to as NSTE-ACS (Non-ST Elevation Acute Coronary Syndromes). This chapter deals with the pathophysiology, definition, criteria and management of patients with NSTEMI and unstable angina. Although ECG changes in NSTEMI and unstable angina have been discussed previously (refer to Classification of Acute Coronary Syndromes, and Ischemia and the ST Segment and ST segment depressions), a rehearsal of ECG characteristics and criteria is provided here. Management (treatment) of NSTEMI and unstable angina will be discussed in detail. The clinical definitions and recommendations presented in this chapter are in line with recent guidelines (2020) issued by the American Heart Association (AHA), American College of Cardiology (ACC) and the European Society for Cardiology (ESC). The chapter will start with basic concepts of NSTEMI and unstable angina and then elaborate the discussion gradually.

As in STEMI, the hallmark of NSTEMI and unstable angina is chest pain (chest discomfort). However, the chest pain caused by NSTEMI and unstable angina is less severe than the pain in acute STEMI. This is explained by the fact that NSTEMI and unstable angina are caused by partial (incomplete) coronary artery occlusions; a partial occlusion results in a reduction of coronary blood flow and this causes subendocardial ischemia (i.e ischemia that only affects the subendocardium). STEMI, on the other hand, is caused by a complete coronary artery occlusion, which results in the complete stop of blood flow and thus more extensive myocardial ischemia (referred to as transmural ischemia). Yet, the pain caused by NSTEMI and unstable angina is considerable and most patients are therefore markedly affected. Other symptoms – such as dyspnea, cold sweat, nausea, etc – are also common in NSTEMI and unstable angina (please refer to Approach to Patients with Chest Pain).

As in patients with STEMI, those with NSTEMI and unstable angina are at considerable risk of developing life-threatening ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation) and subsequently cardiac arrest. Although ventricular arrhythmias may occur any time after coronary artery occlusion, the vast majority occur within the first hour(s). Hence, the majority of all fatal cases of NSTEMI and unstable angina occur during the first hour(s). This underlines the importance of prompt diagnosis and intervention.

NSTEMI & unstable angina: different but similar

NSTEMI and unstable angina are different in one fundamental aspect: NSTEMI is by definition an acute myocardial infarction, whereas unstable angina is not an infarction. Unstable angina is only diagnosed if there is no evidence of myocardial infarction (necrosis). However, unstable angina is considered an acute coronary syndrome because it is an imminent precursor to myocardial infarction. Approximately 50% of patients with unstable angina progress to myocardial infarction within 30 days if left untreated. Moreover, the pathophysiology of NSTEMI and unstable angina is very similar: both are due to partial (incomplete) coronary artery occlusions, which implies that there remains residual blood flow in the artery. Moreover, management of NSTEMI and unstable angina is virtually equal and this explains why NSTEMI and unstable angina have traditionally been grouped.

The chain of care in NSTEMI and unstable angina

Management of patients with acute coronary syndromes is permeated by the mantra time is myocardium, which refers to the progressive loss of myocytes following the occlusion of a coronary artery. The size, location, and duration of the occlusion are of prime importance but additional factors may also influence the infarction process, which is normally completed between 2 and 12 hours after symptom onset. The continuous loss of myocardium and the electrical instability call for prompt diagnosis and treatment. Therefore, most communities have developed a regional system of care which includes the dispatch center, ambulance, emergency department, catheterization laboratory, and cardiology ward. These units must act in concert to reduce the delay from symptom onset to treatment.

General principles of management of NSTEMI and unstable angina

Management of NSTEMI and unstable angina has improved dramatically over the past three decades and continues to evolve. NSTEMI and unstable angina are treated with anti-ischemic (to alleviate ischemia) and anti-thrombotic (to counteract the thrombus) agents. Most patients undergo coronary angiography within 48 hours or earlier if the patient is at high risk of death or other complications. Symptoms, hemodynamic status, ECG changes, troponin levels and comorbidities dictate whether angiography should be performed promptly. Interestingly, acute angiography (which is routine in STEMI) has never been proven to reduce mortality or morbidity in NSTEMI or unstable angina. Guidelines do not recommend acute angiography in patients with NSTEMI or unstable angina. Guidelines recommend that PCI should be done within 24 hours of NSTEMI/unstable angina, if possible. Low-risk patients may be evaluated after 48–72 hours. Management is discussed in detail below.

Note that STEMI (ST Elevation Myocardial Infarction) is discussed in a separate chapter.

Definitions and classification of acute coronary syndromes (acute myocardial infarction)

The term acute coronary syndrome (ACS) has been discussed previously (refer to Introduction to Ischemic Heart Disease and Classification of Acute Coronary Syndromes). An acute coronary syndrome is caused by an abrupt reduction in coronary blood flow. The reduction in coronary blood flow is due to atherothrombosis, which occurs when an atherosclerotic lesion disrupts. Atherotrombosis obstructs coronary blood flow and causes ischemia in the myocardium supplied by the artery. Figure 1 shows the process from atherothrombosis to the classification of acute coronary syndromes.

Figure 1. Disruption of atherosclerotic lesions results in atherothrombosis which causes an abrupt reduction in coronary blood flow. STE-ACS (STEMI) occurs if the occlusion is complete (total), whereas NSTE-ACS (NSTEMI and unstable angina) occurs if the occlusion is partial.

As discussed previously, ischemia results in ECG changes. The type of ischemia will determine which type of ECG changes occur.  Hence, acute coronary syndromes can be classified according to the ECG. The classification is based solely on the presence of ST segment elevations. This simple classification separates two rather different syndromes, namely STE-ACS (which includes STEMI) and NSTE-ACS (which includes NSTEMI and unstable angina). Details follow:

STE-ACS (ST Elevation Acute Coronary Syndrome) is defined as an acute coronary syndrome with ST elevations on ECG. STE-ACS has been discussed previously (refer to STEMI – ST Elevation Myocardial Infarction and ST Elevations in Ischemia and Infarction). Virtually all patients with STE-ACS develop myocardial infarction, which is then classified as STEMI (ST Elevation Myocardial Infarction).

NSTE-ACS (Non-ST Elevation Acute Coronary Syndrome): All acute coronary syndromes that do not meet criteria for STE-ACS are automatically classified as NSTE-ACS. For the sake of clarity: NSTE-ACS is defined as an acute coronary syndrome without ST elevations on ECG. The majority of patients with NSTE-ACS will exhibit elevated troponins, which is evidence for myocardial infarction and therefore defines the condition as NSTEMI (Non-ST Elevation Myocardial Infarction). Cases that do not display elevated troponins are classified as unstable angina (UA). The vast majority of patients with NSTEMI or unstable angina present with ST segment depressions and/or T-wave inversions on ECG.

NSTE-ACS is accordingly subdivided into NSTEMI and unstable angina, depending on whether troponin levels are increased. Elevated troponins (with a pattern consistent with myocardial necrosis; refer to Diagnosis of Acute Myocardial Infarction) are evidence for myocardial infarction (i.e NSTEMI), whereas normal troponins rule out myocardial infarction (i.e unstable angina). Figure 2 presents the natural history and classification of acute coronary syndromes.

Figure 2. Classification of acute coronary syndromes into STE-ACS (STEMI, ST elevation myocardial infarction) and NSTE-ACS (Non STEMI and unstable angina [UA]).

Epidemiology of NSTEMI and unstable angina

Mortality in acute myocardial infarction has declined by 50% during the last three decades. This is explained by increased use of revascularization (percutaneous coronary intervention or fibrinolysis), advances in anticoagulants and antiplatelet agents, as well as aggressive primary preventive strategies using statins, blood pressure-lowering drugs and antidiabetic drugs. Reduced smoking rates have certainly also contributed to the observed trends.

In 1990, STEMI accounted for roughly 50% of all acute myocardial infarctions. The incidence of STEMI has declined gradually since then. Currently, STEMI represents 25–40% of all cases of acute myocardial infarction. During the same period, NSTEMI increased from 50% to 60–75% of all infarctions. This is explained by the implementation of increasingly sensitive biomarker (troponin) assays for the detection of myocardial necrosis (i.e infarction). In 2017 it was possible to detect myocardial infarctions 100 times smaller than what was possible in 2001. Hence, many patients who would have previously been diagnosed as unstable angina are nowadays classified as NSTEMI. It is expected that the proportion classified as unstable angina will continue to decline as troponin assays become more sensitive.

Despite the advances in the management and detection of NSTEMI and unstable angina, these conditions cause considerable mortality and morbidity worldwide.

NSTEMI and unstable angina are caused by partial (incomplete) occlusions

The severity of acute coronary syndromes depends mainly on the location, size and duration of the occlusion. Considering the location, proximal occlusions are more severe than distal occlusions, simply because a proximal occlusion will affect more artery branches and therefore more myocardium. Concerning the size of the occlusion, it is obvious that a total (complete) occlusion will be more devastating than a partial (incomplete) occlusion. STEMI is caused by total occlusions (located proximally); such occlusions result in transmural ischemia/infarction, which implies that the ischemia/infarction stretches from the endocardium to the epicardium in the affected region. NSTEMI and unstable angina, on the other hand, are due to partial (incomplete) occlusions, which means that some blood flow remains in the artery; such occlusions result in subendocardial ischemia/infarction, which implies that only the subendocardial layer is affected. The reason why the subendocardium is affected by partial occlusions has been discussed previously (refer to Classification of Acute Coronary Syndromes and Myocardial Infarction). Refer to Figures 1, 2 and 3.

Figure 3. NSTE-ACS (Non-STEMI) is caused by a partial occlusion, which means that there is some residual flow in the artery. The ischemia will affect the subendocardium which has the poorest prerequisites in the case of ischemia. The subendocardium is too far away from the blood in the ventricular cavity and the oxygen level in the coronary artery is reduced because oxygen has been extracted during the passage through the myocardium. In the case of STE-ACS, the entire cross-section becomes ischemic/infarcted.

Acute and long-term complications of NSTEMI and unstable angina

The acute complications of NSTEMI and unstable angina are similar to those seen in STEMI, but occur at lower rates. Please refer to Acute and Long-Term Complications of STEMI for details. Figure 4 summarizes the complications.

Figure 4. Acute, sub-acute and long-term complications of acute (STEMI) and myocardial infarction in general. RCA = Right Coronary Artery. Adapted from GW Reed et al, The Lancet (2017).

ECG in NSTEMI & unstable angina

NSTEMI and unstable angina typically cause ST segment depressions, which are frequently accompanied by negative (inverted) T-waves or flat T-waves. Importantly, leads that display ST depressions do not necessarily reflect the ischemic area. This implies that ST depressions in leads V3–V4 are not necessarily due to anterior wall ischemia. Similarly, ST depressions in leads II, aVF and III do not imply that the ischemia is located on the inferior wall. In other words, ST depressions do not localize the ischemic area and therefore the ECG cannot be used to determine the location of ischemia in patients with NSTEMI or unstable angina. This contrasts against ST elevations, which are indicative of the ischemia area (refer to Localization of Acute Myocardial Ischemia and Infarction for details).

Ischemic ST depressions are characterized by a horizontal or downsloping ST segment. North American and European guidelines assert that the ST segment must be either downsloping or horizontal, otherwise ischemia is unlikely to be the cause (Figure 5). An in-depth discussion on ST depressions is provided in the chapter ST Segment Depressions in Ischemia and Infarction.

Figure 5. Characteristics of ischemic ST segment depressions.

ECG criteria for the diagnosis of NSTEMI and unstable angina

Criteria for ischemic ST segment depression

New horizontal or downsloping ST segment depressions ≥0,5 mm in at least two anatomically contiguous leads.

Criteria for ischemic T-wave inversions

T wave inversion ≥1 mm in at least two anatomically contiguous leads. These leads must have evident R-waves or R-waves larger than S-waves.

Pathological (infarction) Q-waves

Pathological Q-waves arise if the infarction is extensive, which is usually not the case in patients with NSTEMI. Hence, patients with NSTEMI typically do not develop pathological Q-waves. However, in some instances, the subendocardial injury may be extensive in patients with NSTEMI, which may result in pathological Q-waves. Note that unstable angina does not result in any QRS changes because the condition does not lead to myocardial necrosis (infarction).

Normal ECG in patients with NSTEMI or unstable angina

A minority of patients with NSTE-ACS display normal ECG on arrival. It is unusual, however, to display a normal ECG throughout the course. Most patients with normal ECG on arrival will develop some ECG changes during the process. Moreover, a normal ECG on arrival does not rule out myocardial ischemia/infarction; some infarctions are too small to engender ECG changes and others may be dynamic over time and initially present without ECG changes.

Clinical assessment and initial evaluation of patients with NSTEMI and unstable angina

Early management in NSTEMI and unstable angina

Patients with NSTEMI or unstable angina must be referred immediately to the emergency department (ED). The patient should preferably be transported by the emergency medical services (EMS). Studies have demonstrated several benefits of utilizing the EMS, such as reduced delay to evidence-based therapies and reduced delay to be seen by ED physician. Yet, the EMS is heavily underutilized in patients with acute myocardial infarction (AMI); according to the NRMI registry, approximately half of patients with AMI use the EMS. Moreover, studies also demonstrate that patients who use the EMS have higher mortality and morbidity, as compared with the overall population with acute coronary syndromes. This is explained by the fact that patients who use the EMS have more comorbidities, higher prevalence of cardiovascular disease and are generally older.

The EMS should immediately assess vital functions and address hemodynamic, electrical and respiratory instability. If the patient is hemodynamically stable, a brief history (focus on coronary risk factors and current symptoms) and risk stratification should be performed. Evidence-based therapies can be started already in the ambulance. Oxygen, morphine, nitrates and aspirin are safe and effective to administer en route to hospital. A defibrillator must always be ready and venous access should be established. Vital parameters include heart rate, heart rhythm, blood pressure, respiratory rate, oxygen saturation and consciousness. ECG and chest pain (or other symptoms suggestive of ACS) must also be evaluated.

Prehospital 12-lead ECG

A 12-lead ECG should be performed at earliest opportunity and evaluated immediately. Prehospital personnel have proven to be highly capable of recognizing ischemic ECG changes and they may transmit ECGs electronically to the hospital for further evaluation. If the initial ECG is not diagnostic, additional ECGs can be performed if time and other circumstances allow. Although prehospital troponin analysis is available, it is generally discouraged since it does not improve survival.

Emergency department (ED)

The same clinical parameters must be assessed in the emergency department (ED). Assessment of complications (e.g heart failure) is important as such may require additional interventions. New 12-lead ECGs are performed and serial recordings are acquired if appropriate. Guidelines state that a 12-lead ECG should be evaluated within 10 minutes after patient arrival in the ED. Supplementary leads (V3R, V4R, V7, V8 and V9) may be necessary. Continuous monitoring with 12-lead ECG (ST segment monitoring) increases the detection of ischemia, but such equipment is frequently unavailable.

Cardiac troponin I or T levels are obtained at presentation and 3 to 6 hours after symptom onset. Rising or falling values, with at least one value above the upper normal limit is evidence for acute myocardial infarction. Note that normal troponins do not rule out myocardial infarction until 6 hours after the latest episode of symptoms (it may require 6 hours for troponins to increase following myocardial necrosis).

Objective evidence of myocardial ischemia/infarction: ECG & cardiac troponins

Patients with objective evidence of myocardial ischemia – i.e ischemic ECG changes or elevated troponins – should receive anti-ischemic and anti-thrombotic agents immediately (provided that there are no contraindications). Patients without objective evidence of myocardial ischemia (i.e those who only present with symptoms, such as chest pain) should be observed in a chest pain unit so that serial ECGs and troponins can be evaluated. Guidelines recommend that patients without objective evidence of ischemia should undergo exercise stress testing once their condition has stabilized. Stress myocardial perfusion imaging, stress echocardiography or CTCA (computerized tomography of coronary arteries) are more expensive alternatives but offer greater sensitivity and specificity.

Management in the emergency department (ED)

Anti-ischemic and anti-thrombotic agents should be given without delay if the suspicion of NSTEMI or unstable angina is strong, provided that there are no contraindications. Among the potentially life-threatening differential diagnoses, aortic dissection is the most important one since it is a contraindication to several agents used in acute coronary syndromes.

All patients with NSTE-ACS (NSTEMI or unstable angina) are treated similarly with respect to anti-ischemic and anti-thrombotic drugs. Management must, however, be individualized with respect to coronary angiography (PCI). The majority of patients should undergo angiography within 24 hours, but high risk patients should be evaluated with angiography earlier. Guidelines recommend the use of validated risk models to estimate the risk of acute myocardial infarction, 30-days and 1-year mortality. TIMI, GRACE and PURSUIT are such risk models and they are all easy to use. The higher the estimated risk, the earlier should angiography be performed.

Calculate TIMI Risk Score for NSTEMI / Unstable Angina

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TIMI SCORE30-days mortality30-days acute MIProbability of revascularization
0-11,2%2,3%1,2%
21,0%2,1%6,0%
31,7%3,7%9,5%
42,5%5,0%12,2%
55,6%8,5%14,3%
6-76,5%15,8%20,9%

As always in patients with acute coronary syndromes, non-steroidal anti-inflammatory drugs (NSAID) should be withheld during the acute phase. NSAIDs (except from aspirin) increase mortality in patients with acute coronary syndromes.

Evidence-based therapies for NSTEMI

Oxygen in acute NSTEMI or unstable angina

Oxygen is given if oxygen saturation is <90%. There is no evidence that oxygen confers any benefit.

There is no data to support or refute any benefit of oxygen in patients with NSTEMI or unstable angina. Guidelines recommend oxygen if oxygen saturation is <90%. Oxygen is also appropriate in patients with pulmonary edema, heart failure and mechanical complications (free wall rupture, ventricular septum defect, mitral prolapse) of NSTEMI or unstable angina.

Analgesics in acute NSTEMI & unstable angina

Morphine sulfate is administered to all patients with acute NSTEMI or unstable angina. Caution is required in patients with hypotension.

Pain activates the sympathetic nervous system which leads to (1) peripheral vasoconstriction, (2) positive inotropic effect and (3) positive chronotropic effect. This increases the workload on the heart and therefore aggravates the ischemia. Adequate doses of analgesics are necessary to prevent the potentially harmful effects of the sympathetic nervous system. Analgesics also alleviate pain and relieves anxiety.

Morphine is the drug of choice. Morphine also causes dilatation of the veins, which reduces cardiac preload. Reduction in preload results in reduced workload on the left ventricle and this may alleviate both ischemia and severity of pulmonary edema.

The required dose of morphine depends on age, body mass index (BMI) and hemodynamic status. Reduced doses are warranted in patients with hypotension because morphine may cause additional vasodilatation. An initial dose of 2 to 5 mg IV is recommended. Injections may be repeated every 5 minutes until 30 mg have been administered. Naloxone (0.1 mg IV, and repeated every 10 minutes if necessary) may be administered if there are signs of morphine overdose. Morphine may cause bradycardia which can be managed with atropine 0.5 mg IV (repeated as necessary). If a total of 30 mg morphine is insufficient to relieve the pain, one should suspect aortic dissection.

NSAID (nonsteroidal anti-inflammatory drugs) and selective cyclooxygenase II (COX-2) inhibitors are contraindicated (these drugs increase mortality in acute coronary syndromes).

Note that nitrates and beta blockers also exert analgesic effects (explained below). It is crucial that the use of morphine does not limit the use of beta blockers, since they potentiate each others negative hemodynamic effect and only beta blockers reduce mortality.

Nitrates (nitroglycerin)

Nitrates are administered to the vast majority of patients with STEMI. Nitrates do not affect the prognosis but relieves symptoms.

Nitrates cause vasodilatation by relaxing smooth muscle in arteries and veins. The ensuing vasodilatation reduces venous return to the heart which decreases cardiac preload. This reduces the workload on the myocardium and thus the oxygen demand. Nitrates therefore relieves ischemic symptoms (chest pain) and pulmonary edema.

A dose of 0.4 mg (sublingual or tablet) is given and may be repeated 3 times with 5 minute intervals. Nitroglycerin infusion should be considered if the effect is inadequate (severe angina) or if there are signs of heart failure. Infusion may be initiated with 5 μg/min and titrated up every 5 minutes to 10–20 μg/min. The dose is titrated until symptoms are relieved or a maximal dose of 200–300 μg/min is reached.

Nitrates should not be administered in (1) patients with hypotension, (2) suspicion of right ventricular infarction, (3) sever aortic stenosis, (4) hypertrophic obstructive cardiomyopathy or (5) pulmonary embolism. Administration should proceed with caution if blood pressure drops >30 mmHg from baseline. As with morphine, use of nitrates must not limit the use of beta blockers and ACE inhibitors (these drugs affect blood pressure and heart rate).

Beta blockers in NSTEMI and unstable angina

Oral beta blockers should be given to all patients in maximal tolerated dose and continued indefinitely. Therapy should be initiated within 24 hours. Intravenous beta blockers is potentially harmful in patients with NSTEMI or unstable angina.

Beta blockers are likely to reduce morbidity and mortality. However, the evidence for beta blockers in NSTEMI or unstable angina is less robust than for STEMI. Beneficial effects of beta blockers have been demonstrated in the acute and long-term setting. Early studies demonstrated that beta blockers may reduce the risk of progression from unstable angina to NSTEMI.

Beta blockers have a negative inotropic and negative chronotropic effect, which reduces heart rate (duration of diastole becomes prolonged), cardiac output and blood pressure. The workload on the myocardium is reduced and oxygen demand is subsequently reduced. Prolongation of diastole will give extra time for the myocardium to be perfused (the myocardium is perfused only during diastole). A large body of evidence – particularly in patients with STEMI but also in NSTEMI and unstable angina – demonstrates that beta blockers increase survival, reduce morbidity and improve left ventricular function. Beta blockers presumably also protect against ventricular tachyarrhythmias (ventricular tachycardia).

Treatment with beta blockers should start early within 24 hours, provided that the patient is hemodynamically stable. Starting with oral metoprolol 25 mg four times daily is recommended. The dose is titrated up until maximal tolerated dose or 200 mg is reached. Sustained-release preparations are preferred once the maximal dose is reached. Metoprolol, carvedilol and bisoprolol are all evidence-based beta blockers.

Contraindications and caution

Beta blockers should be avoided or postponed in the following scenarios:

Patients with acute heart failure should not be given beta blockers during the acute phase of NSTEMI or unstable angina. Once the heart failure is stabilized, beta blockers are extremely beneficial in heart failure and should therefore be initiated.

Patients at risk of cardiogenic shock should not be given beta blockers due to the negative inotropic and chronotropic effects.

Patients with first-degree AV block should perform a second ECG after initiation of beta blockers, since the first-degree AV block may progress to higher degrees of AV block. Second-degree and third-degree AV block (without pacemaker) are contraindications.

Patients with obstructive pulmonary disease should be given beta-1 selective agents (e.g bisoprolol).

Nondihydropyridine calcium channel blockers (CCB)

Patients with continuing or recurring ischemia and contraindication to beta blockers may benefit from oral CCBs (e.g verapamil, diltiazem).

Calcium channel blockers are considered if the patient is intolerant to beta blockers. Verapamil and diltiazem reduce angina symptoms and may (evidence is vague) be beneficial in patients with NSTEMI or unstable angina. CCBs may occasionally be considered in patients with continuing or recurring ischemia despite the appropriate use of beta blockers, nitrates and morphine.

Calcium channel blockers should be avoided as initial therapy in patients with significant left ventricular dysfunction, increased risk of cardiogenic shock, first-degree AV block, second-degree AV block or third-degree AV block (without a cardiac pacemaker).

Antithrombotic therapy

Antiplatelet agents

A loading dose of aspirin (160 mg to 320 mg) should be given immediately to all patients. Aspirin is then continued indefinitely (maintenance dose 80 mg daily).

A loading dose of a P2Y12-receptor inhibitor should also be given immediately and then continued for 12 months. There are three alternatives:

Clopidogrel, 600 mg loading dose – The least effective of the P2Y12-receptor inhibitors.

Prasugrel, 60 mg loading dose.

Ticagrelol 180 mg loading dose – The preferred agent to be combined with aspirin.

Aspirin

Aspirin has an astonishing effect in NSTEMI and unstable angina: it reduces 30-days mortality by 50%. Aspirin is also effective in preventing re-infarction beyond 30-days and must never be discontinued without careful consideration. The optimal dose of aspirin is unknown but studies show that maintenance doses between 80 mg and 1500 mg are equally effective; hence, 80 mg is preferred as it minimizes the risk of gastrointestinal bleeding. Similarly, loading doses greater than 320 mg do not confer any additional benefit, which is why a loading dose of 320 mg is recommended.

Dual antiplatelet therapy (DAPT)

Optimal antiplatelet effect requires addition of either ticagrelol, prasugrel or clopidogrel. Combining aspirin with any of these is referred to as DAPT (dual antiplatelet therapy). An individual assessment of bleeding risk is warranted and DAPT should be avoided if the risk is high. DAPT is continued for 12 months in all patients. The indication is stronger in patients who undergo PCI with the placement of stent.

Clopidogrel

The addition of clopidogrel to aspirin will additionally reduce the risk of death, stroke and acute myocardial infarction by 20%, at the expense of 28% increased risk of bleeding. A loading dose of 600 mg followed by a maintenance dose of 80 mg daily is recommended. Clopidogrel is withheld 5 days before planned CABG (coronary artery bypass grafting). Although clopidogrel causes fewer bleedings than prasugrel and ticagrelol, it is less effective and therefore a secondary choice.

Prasugrel

As compared with clopidogrel, prasugrel offers a greater reduction in the risk of cardiovascular death, acute myocardial infarction, stroke and stent restenosis. Prasugrel is indicated (loading dose 60 mg, maintenance dose 10 mg) if PCI is planned and the patient is not already on clopidogrel. Prasugrel should be avoided if the risk of bleeding is high, as well as in patients with previous TIA (transient ischemic attack) or stroke. The maintenance dose is reduced to 5 mg daily in patients older than 75 years as well as in patients weighing less than 60 kg. Prasugrel is withheld 7 days before the planned CABG.

Ticagrelol

As compared with clopidogrel, ticagrelol is more potent and has a more rapid onset of effect. A loading dose of 180 mg is followed by a maintenance dose of 90 mg twice daily. As compared with clopidogrel, ticagrelol reduces the risk of cardiovascular mortality by 21% and acute myocardial infarction by 16%. Ticagrelol causes 19% more bleeding. The reduction in mortality and myocardial infarction outweighs the risk of bleeding, which is why ticagrelol is now recommended to all patients with NSTEMI or unstable angina (combined with aspirin).

Intravenous antiplatelet agents: Glycoprotein (GP) IIb/IIa receptor antagonists

GP IIb/IIIa inhibitors are administered in the catheterization laboratory. These drugs are highly potent platelet inhibitors which should be considered in high risk patients.

These agents (abciximab, tirofiban, eptifibatid, elinogrel) block the GP IIb/IIIa receptor which is located on the membrane of platelets and binds platelets to fibrinogen and von Willebrand factor. This class of drugs is the most potent platelet inhibition available. Randomized controlled clinical trials demonstrated that GP IIb/IIIa inhibitors reduce the risk of death and acute myocardial infarction among patients undergoing PCI (patients received aspirin and clopidogrel before GP IIb/IIIa inhibitors were administered during PCI). It is, however, unknown how to optimally administer GP IIb/IIIa inhibitors when administering DAPT.

Anticoagulants in NSTEMI and unstable angina

Fondaparinux is the drug of choice and should be given to all patients in the acute setting. Enoxaparin, heparin or thrombin inhibitors are secondary alternatives.

Fondaparinux

Fondaparinux (2,5 mg daily, treatment duration 4 to 5 days) is the first choice among the anticoagulants. Fondaparinux is as effective as enoxaparin in terms of reducing acute myocardial infarction, death and re-ischemia, but only causes half as many bleedings. Fondaparinux is therefore preferred over enoxaparin. Fondaparinux should be combined with unfractionated heparin (50 E/kg) in patients undergoing PCI to reduce the risk of catheter-associated thrombosis during PCI.

Heparin

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH; dalteparin, enoxaparin) have been studied extensively in patients with NSTEMI and unstable angina. Enoxaparin (1 mg/kg subcutaneously every 12 hours) and dalteparin appear superior to UFH. Treatment is continued until a clinically stable condition is reached, which usually implies 2 to 8 days of treatment.

Direct thrombin inhibitors

These drugs (hirudin, bivalirudin, argotroban) confer 20% reduced risk of death and acute MI as compared with UFH, at the expense of twice as many bleedings. Due to the high risk of bleeding, these drugs are only recommended in patients intolerant to heparin (heparin-induced thrombocytopenia). Bivalirudin has been studied extensively and may be considered in patients undergoing PCI.

Angiography and revascularization (PCI, CABG)

Because the coronary occlusion in NSTEMI and unstable angina is partial, there is some residual perfusion (blood flow) in the ischemic zone. Therefore, revascularization (PCI) is less urgent and can generally be delayed without worsening the prognosis. Indeed, no study to date has proven any beneficial effect of immediate PCI in patients without ST elevations. Nevertheless, virtually all patients should undergo angiography to evaluate the coronary arteries. The purpose of coronary angiography is to determine whether there are any acute occlusions that can be treated with either PCI or CABG.

Features guiding the timing of revascularization for unstable angina or NSTEMI

As a general rule, virtually all patients should undergo angiography within 72 hours.

Immediate angiography (angiography within 2 hours) is recommended in patients with the following presentation:

Malignant ventricular arrhythmias (sustained ventricular tachycardia, ventricular fibrillation, cardiac arrest).

Hemodynamic instability

Heart failure – Killip III–IV)

Severe chest pain (refractory angina) despite adequate use of anti-ischemic and analgesic agents.

Early angiography (angiography within 24 hours) is recommended in patients with the following presentation:

High-risk score (TIMI ≥4, GRACE >140)

High troponins.

Persistent high-risk or dynamic electrocardiographic changes.

ST elevation not meeting STEMI criteria.

Angiography after 25–72 hours is recommended in the following situations:

No features requiring an immediate or early invasive strategy.

Intermediate-risk score (TIMI 2−3, GRACE 109−140).

Recurrent angina or signs of ischaemia despite therapies.

Ejection fraction <40%, diabetes, renal insufficiency  (estimated glomerular filtration rate <60 mL/min/1.73 m.), prior coronary artery bypass grafting, or percutaneous coronary intervention within 6 months.

If PCI is performed, the patient should receive a stent.

Patients who are not candidates for angiography are managed with an ischemia-guided strategy. This is reasonable in low-risk patients (TIMI ≤1, GRACE <109), patients at hospitals without PCI facilities, and on the basis of the patient’s preferences. An ischemia-guided strategy may be converted to an invasive strategy if the patient’s condition deteriorates.

References

2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes

Acute coronary syndromes (acs) in patients presenting without persistent st-segment elevation (management of)

2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction

Third Universal Definition of Myocardial Infarction (ACC, AHA, ESC joint statement)

ACUTE MYOCARDIAL INFARCTION IN PATIENTS PRESENTING WITH ST-SEGMENT ELEVATION (MANAGEMENT OF)  – European Society for Cardiology

GW Reed et al, The Lancet (2017): Acute Myocardial Infarction

JL Anderson et al, The NEw England Journal of Medicine (2017): Acute Myocardial Infarction

Figures

Chapter 24: STEMI (ST Elevation Myocardial Infarction): Diagnosis, ECG, Criteria, and Management

Acute ST Elevation Myocardial Infarction (STEMI) is the most severe manifestation of coronary artery disease. This chapter deals with the pathophysiology, definitions, criteria and management of patients with acute STEMI. Although ECG changes in acute STEMI have been discussed previously (refer to ECG Changes in Acute Myocardial Infarction), a rehearsal is provided below. Management of acute STEMI is discussed in detail below. The clinical definitions and recommendations presented in this chapter are in line with guidelines issued by the American Heart Association (AHA), American College of Cardiology (ACC) and the European Society for Cardiology (ESC). A large body of evidence, based on randomized controlled clinical trials, supports the concepts and recommendations presented in this chapter.

ECG examples of ST Elevation Myocardial Infarction (STEMI)

STEMI Example 1

STEMI Example 2

STEMI Example 3

STEMI Example 4

STEMI Example 5

STEMI Example 6

STEMI Example 7

STEMI Example 8

STEMI Example 9

STEMI Example 10

STEMI Example 11

STEMI Example 12 ECG examples of acute STEMI (ST-elevation myocardial infarction).

Overview of management

Click the diagram to enlarge.

Chest pain (discomfort) is the hallmark symptom of myocardial ischemia and is particularly pronounced in patients experiencing acute STEMI. The severity of symptoms in STEMI patients, compared to those with Non-ST-Elevation Myocardial Infarction (NSTEMI) or unstable angina (UA), is attributed to the greater extent of ischemia present in STEMI. In STEMI, a complete coronary artery occlusion leads to transmural ischemia, affecting a larger portion of the myocardium, thereby intensifying chest pain. In contrast, NSTEMI and UA typically involve partial occlusions, resulting in subendocardial ischemia and comparatively milder symptoms. For the same reason, patients with STEMI are at higher risk of life-threatening ventricular arrhythmias in the acute phase. Ventricular tachycardia (VT) and ventricular fibrillation (VF) may occur at any time after occlusion of the coronary artery. Indeed, ventricular tachycardia and ventricular fibrillation cause the vast majority of all deaths in the acute phase of STEMI. Death due to ventricular dysfunction, or mechanical complications, is much less common in the acute phase.

The chain of care in acute STEMI

Optimal care for patients with STEMI requires a well-coordinated system involving both prehospital and hospital-based services. In larger communities, regional STEMI care systems have been established to quickly identify and manage these patients. This integrated approach relies on seamless collaboration between the dispatch center, ambulance services, emergency department (ED), catheterization laboratory, and cardiology ward. Each component must function cohesively to ensure timely and effective treatment. This chapter provides an overview of the entire care continuum, from prehospital assessment to hospital discharge.

Diagnosing acute STEMI

The diagnosis is straightforward using the electrocardiogram (ECG). Prehospital personnel have proven to be capable of recognizing STEMI using 12-lead ECG. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of EMS personnel in detecting STEMI are as follows (Ducas et al, Mencl et al.):

Sensitivity: EMS personnel demonstrate high sensitivity in detecting STEMI, with one study reporting a sensitivity of 75%. Thus, 25% of STEMI cases are missed by the EMS.

Specificity: The specificity is relatively lower at 53%, highlighting challenges in distinguishing STEMI from conditions that mimic its presentation.

Positive Predictive Value (PPV): The PPV is 59.5%, indicating that slightly over half of the cases identified as STEMI by EMS are true positives.

Negative Predictive Value (NPV): The NPV is exceptionally high at 99.7%, suggesting that EMS personnel are highly reliable in ruling out STEMI when it is not present.

This underscores the strengths and limitations of EMS personnel in prehospital STEMI identification, emphasizing their ability to rule out STEMI effectively while facing challenges in confirming the diagnosis. Importantly, patients who utilize the EMS may have better outcomes, since several evidence-based therapies (including reperfusion) can be started in the prehospital setting.

The measurement of cardiac troponins is not required to diagnose acute STEMI, as the diagnosis is based on the clinical presentation (most notably chest pain) and ST-segment elevations on the ECG. However, cardiac troponins are routinely analyzed as soon as the clinical situation permits.

General principles of treatment

STEMI management involves a combination of anti-ischemic agents, antiplatelet therapies, anticoagulants, and reperfusion strategies, such as percutaneous coronary intervention (PCI) or fibrinolysis. Reperfusion therapy is critical and must be initiated promptly, as acute STEMI results from complete arterial occlusion requiring immediate restoration of blood flow. Nearly all patients with acute STEMI should be referred to the catheterization laboratory for coronary angiography, with the goal of performing PCI. Anti-thrombotic therapies, including antiplatelet agents, anticoagulants, and reperfusion interventions, significantly reduce mortality by preventing thrombus progression and restoring coronary artery patency, ultimately improving myocardial perfusion and patient outcomes. An overview of reperfusion strategies is presented in Figure 1.

Figure 1. Reperfusion strategies in acute STEMI, NSTEMI and UA (NSTE-ACS).

Diagnosis and definition of acute STEMI (ST Elevation Myocardial Infarction)

ST Elevation Myocardial Infarction (STEMI) is an acute coronary syndrome (ACS). There are two types of acute coronary syndromes:

STE-ACS (ST Elevation Acute Coronary Syndrome) is defined by the presence of significant ST segment elevations on ECG. If a patient with such ECG changes develops myocardial infarction (defined by elevated troponin levels in the blood), the condition is classified as STEMI (ST Elevation Myocardial Infarction). STEMI is only diagnosed when elevated troponin levels have been confirmed; until then, the condition is classified as STE-ACS. However, in clinical practice, STE-ACS and STEMI are equivalent because virtually all patients with chest pain and ST elevations on ECG will have elevated troponin levels.

NSTE-ACS (Non ST Elevation Acute Coronary Syndrome) is defined by the absence of ST segment elevations on ECG. All patients who do not meet the criteria for STEMI will automatically be classified as NSTE-ACS. The majority of these patients will exhibit elevated troponin levels, which classifies the condition as NSTEMI (Non ST Elevation Myocardial Infarction). Those who do not display elevated troponin levels are classified as unstable angina pectoris (UA). Patients with NSTE-ACS typically present with ST segment depressions and/or T-wave inversions.

This classification of acute coronary syndromes is illustrated in Figure 2.

Figure 2. Classification of acute coronary syndromes into STE-ACS (STEMI, ST Elevation Myocardial Infarction) and NSTE-ACS. The latter includes NSTEMI (Non-ST Elevation Myocardial Infarction) and unstable angina.

In summary, the diagnosis of acute myocardial infarction (AMI) requires evidence of myocardial necrosis, indicated by elevated troponin levels. The distinction between ST-elevation acute coronary syndrome (STE-ACS, or STEMI) and non-ST-elevation acute coronary syndrome (NSTE-ACS, encompassing NSTEMI and unstable angina) lies in the presence of ST-segment elevations on the ECG. While this classification may appear somewhat arbitrary, it effectively differentiates two distinct conditions in terms of coronary artery thrombosis. These conditions require tailored management approaches to optimize patient survival and outcomes.

Pathophysiology of STE-ACS (ST Elevation Acute Coronary Syndrome) and STEMI (ST Elevation Myocardial Infarction)

STEMI is a clinical syndrome characterized by symptoms of myocardial ischemia—most notably chest pain or discomfort—accompanied by ST-segment elevations on the ECG and elevated troponin levels. As mentioned, nearly all patients presenting with clinical signs of myocardial ischemia (e.g., chest pain) and ST-segment elevations will also have elevated troponin levels, making ST-elevation acute coronary syndrome (STE-ACS) clinically synonymous with STEMI. As illustrated in Figure 1, STEMI results from a thrombosis located proximally in a coronary artery. The thrombus is typically large enough to cause a complete occlusion, obstructing blood flow through the artery. This leads to severe ischemia in the myocardium supplied by the affected artery and its branches. The ischemia is transmural, meaning it involves the entire thickness of the myocardial wall, from the endocardium to the epicardium (Figure 3).

Figure 3. STEMI is caused by a complete proximal occlusion in the epicardial segment of the coronary artery. The resulting ischemia affects all myocardial layers within the region supplied by the artery and its branches. Consequently, the ischemia (and eventual infarction) extends through the entire thickness of the myocardial wall, from the endocardial layer to the epicardial layer.

Video 1 and Video 2 show the obstruction of blood flow in a patient with STEMI (Video 1) and the result of PCI (Video 2).

Video 1 (above): This angiogram shows a catheter placed in the left circumflex coronary artery. The artery is occluded and therefore not filled with contrast.

Video 2 (above): The same patient after balloon inflation and placement of a stent. Flow can now be visualized in the artery (Todt et al).

Epidemiology of ST Elevation Myocardial Infarction

Incidence of STEMI

In 1990, STEMI constituted nearly 50% of all acute coronary syndrome (ACS) cases. Since then, the incidence of STEMI has steadily declined, and in recent years, it accounts for approximately 25% to 40% of all acute myocardial infarction (AMI) cases. Conversely, the incidence of NSTEMI has risen, likely attributable to the increased sensitivity of modern troponin assays, enabling the detection of smaller myocardial injuries (Martin et al.).

Mortality in STEMI

Mortality in STEMI has also declined dramatically in the past decades. In-hospital mortality is currently 5% and 1-year mortality is 7–18%. Roughly 70% of patients with STEMI are men. Women, on the other hand, have a longer delay from symptom onset to first medical contact, and women are also less likely to receive evidence-based interventions, such as PCI and fibrinolysis. To some extent, this may be explained by the fact that women tend to present with atypical symptoms more frequently than men (Smilowitz et al.). Almost one in four patients with STEMI have diabetes, which also confers an increased risk of complications (e.g. heart failure) and death (both in the acute setting and the long term). Elderly and patients with renal disease are also less likely to receive recommended interventions, despite evidence of benefit from such measures.

Acute and long-term complications of acute STEMI

Acute myocardial infarction, STEMI in particular, can lead to multiple acute and long-term complications, each with potentially serious consequences. Life-threatening arrhythmias such as ventricular tachycardia and ventricular fibrillation may occur at any time following the coronary artery occlusion, with the highest risk during the first few hours. These ischemia-induced arrhythmias are responsible for the majority of deaths in the acute phase, but their likelihood decreases significantly after about 6 hours. The risk of hazardous arrhythmias persists in cases with extensive myocardial infarction, particularly when accompanied by heart failure, which can trigger chronic myocardial remodeling. This remodeling process may subsequently lead to ventricular arrhythmias in the long term. Mechanical complications also pose significant risks following AMI. The most frequent is papillary muscle rupture, which can cause cardiogenic shock. Although less common, rupture of the interventricular septum or left ventricular free wall can occur and are often fatal. Additionally, ischemic bradyarrhythmias are frequently observed, especially in cases of inferior infarctions.

Papillary muscle rupture (PMR) in acute myocardial infarction

Papillary muscle rupture (PMR) occurs in approximately 1% of patients following acute myocardial infarction (AMI). It typically develops within 2 to 7 days post-infarction. The posteromedial papillary muscle is most commonly affected, being 10 times more likely to rupture than the anterolateral papillary muscle. This vulnerability is attributed to its single blood supply, usually derived from the right coronary artery or left circumflex artery. Patients with PMR usually present with the sudden onset of severe mitral regurgitation, which leads to flash pulmonary edema, hypotension, and cardiogenic shock. A new systolic murmur may be detected, though it may be absent in cases of complete rupture or significant left ventricular dysfunction. Early surgical intervention, most commonly mitral valve replacement, is essential for survival, although outcomes remain poor.

Figure 4. Acute, sub-acute and long-term complications of acute (STEMI) and myocardial infarction in general. RCA = Right Coronary Artery. Adapted from GW Reed et al, The Lancet (2017).

ECG in acute STEMI (ST Elevation Myocardial Infarction)

The ECG is the key to diagnosing STEMI. ECG criteria for STEMI are not used in the presence of left bundle branch block (LBBB) or left ventricular hypertrophy (LVH) because these conditions cause secondary ST-T changes which may mask or simulate ischemic ST-T changes. ST segment elevation is measured in the J-point and the elevation must be significant in at least 2 contiguous ECG leads. Contiguous leads refer to leads that direct neighbors and reflect the same anatomical area; such as anterior leads (V1–V6), inferior leads (II, aVF, III) and lateral leads (I, aVL). For example, leads V3 and V4 are contiguous; V1 and V2 are also contiguous; aVL and I are also contiguous; V3 and V5 are not contiguous, because lead V4 is placed between these leads.

J point elevation of ≥1 mm is considered significant in all leads except leads V2 and V3. This is explained by the fact that most women and men display a slight ST elevation (J point elevation) in V2 and V3, which is why a higher J point elevation is required in these leads. Refer to Panel 1 for all ECG criteria for STEMI.

Panel 1: ECG criteria for the diagnosis of acute STEMI

New ST segment elevations in at least two anatomically contiguous leads:

Men age ≥40 years: ≥2 mm in V2-V3 and ≥1 mm in all other leads.

Men age <40 years: ≥2,5 mm in V2-V3 and ≥1 mm in all other leads.

Women (any age): ≥1,5 mm in V2-V3 and ≥1 mm in all other leads.

Men & women V4R and V3R: ≥0,5 mm, except from men <30 years in whom the criteria is ≥1 mm.

Men & women V7-V9: ≥0,5 mm.

In patients with STEMI, the ECG leads showing ST-segment elevations correspond to the ischemic region of the myocardium. For example, ST elevations in leads V3 and V4 (anterior chest leads) indicate anterior ischemia, while ST elevations in leads aVF and II suggest inferior ischemia. Figure 5 provides a visual representation of the four walls of the left ventricle and the specific ECG leads that reflect these myocardial regions, aiding in the localization of the ischemic area.

Figure 5. The four walls of the left ventricle and the ECG leads reflect these walls. The term “contiguous leads” refers to any two leads that are anatomical neighbors. Hence, ST elevation in leads V1 and V2 would fulfill the criteria for STEMI. ST elevation in V2 and V3 would also fulfill criteria for STEMI because these two leads are also anatomical neighbors, even if this illustration shows that V2 reflects the septal wall and V3 the anterior wall.

Characteristics of ischemic ST elevations

ST segment elevations with straight (horizontal, upsloping or downsloping) or convex ST segments strongly suggest acute STEMI (Figure 6A). Concave ST segment elevations, on the other hand, are less likely to be caused by ischemia (Figure 6B). This is noted in both North American and European guidelines. However, a concave ST segment does not rule out STEMI, it only reduces the probability of STEMI.

Figure 6. Differential diagnosis of ST elevations.

Other causes of ST segment elevations

Concerning differential diagnostics, at least 16 other conditions may also cause ST elevations. These conditions have been discussed in detail in the article ST elevations in ischemia, infarction and differential diagnoses. Some of these conditions are benign whereas others are potentially life-threatening.

Panel 2. Differential Diagnoses of ST-Segment Elevations

Male/female pattern (“Normal ST segment elevation”)

Early repolarization syndrome

Left ventricular hypertrophy (LVH)

Left bundle branch block (LBBB)

Acute pericarditis (myocarditis, perimyocarditis)

Hyperkalemia

Brugada syndrome

Pulmonary embolism

Aortic dissection

Arrhythmogenic right ventricular cardiomyopathy (dysplasia) – ARVD/ARVC

Pre-excitation (Wolff-Parkinson-White syndrome)

Electrical cardioversion

Takotsubo cardiomyopathy (broken heart syndrome, apical ballooning syndrome)

Prinzmetal’s angina (variant angina, coronary artery vasospasm)

Hypothermia & hypercalcemia

Left ventricular aneurysm

Reciprocal ST depressions, T-wave inversions (negative T-waves) and pathological Q-waves in STEMI

In most cases, the ST elevations are accompanied by reciprocal ST segment depressions. Such ST depressions are mirror images of the ST elevations and therefore occur in leads that are in the opposite angle, compared with the leads displaying ST elevations. Figure 7 presents two patients with acute STEMI and there are evident reciprocal ST depressions in both cases.

Figure 7. Two examples of STEMI with ST elevations, reciprocal ST depressions and pathological Q-waves.

In patients with STEMI, the ST segment elevations are gradually normalized (within 15 hours) and followed by T-wave inversions, which may persist for a month or longer. Pathological Q-waves may appear if the infarct area is large (the majority of STEMI patients develop such Q-waves). These Q-waves are abnormally wide and deep (Figure 7). They testify that the infarction was extensive. Infarctions that result in pathological Q-waves are referred to as Q-wave infarctions.

Aborted myocardial infarction (MI)

On rare occasions, the thrombus may resolve (either spontaneously or by means of reperfusion therapy) before the infarction process begins. In such cases, troponin levels are not elevated and the condition is classified as unstable angina pectoris or aborted myocardial infarction. This is, however, rare and virtually all cases of STE-ACS progress to STEMI.

Special considerations

The ECG may be deceptive in some patients with acute transmural ischemia. For example, some patients have underlying ECG abnormalities (e.g. LBBB) that make it very difficult to detect ischemic ECG changes. Other patients may have acute transmural ischemia located in areas not detected by any of the 12 standard leads. These circumstances are discussed below.

Left bundle branch block (LBBB) in patients with acute STEMI

Left bundle branch block (LBBB) occurs if the left bundle branch is dysfunctional and thus incapable of conducting the electrical impulse to the left ventricle. The activation of the left ventricle will depend on the impulses that spread from the right ventricle. This results in abnormal activation (depolarization) and recovery (repolarization) of the left ventricle. Abnormal repolarization results in pronounced ST-T changes, including ST elevations (leads V1–V3), ST depressions (leads V4, V5, V6, aVL, I) and inverted T-waves (leads with ST depressions). These ST-T changes are illustrated in Figure 6. Note that these ST-T changes are always normal, and expected, in patients with LBBB.

Figure 6. Left bundle branch block (LBBB) at two different paper speeds. Note the ST elevations and ST depressions.

There are three reasons why LBBB complicates the assessment of patients with suspected acute myocardial infarction:

Left bundle branch block (LBBB) can mimic acute STEMI, as it often presents with similar ECG changes, including ST-segment elevations, ST-segment depressions, and T-wave inversions. These overlapping features frequently lead to confusion between LBBB and acute STEMI. In fact, studies have shown that LBBB is the most common cause of false activations of the catheterization laboratory.

LBBB may mask (conceal) ongoing ischemia: LBBB causes severe disturbance of ventricular repolarization, which usually prevents other ST-T changes (such as those arising from ischemia) to come to expression on ECG. Therefore, ischemic ST-T changes (ST elevations, ST depressions, T-wave changes) are typically concealed in the setting of LBBB. A patient with acute STEMI may therefore display a normal LBBB pattern.

LBBB may be caused by ischemia/infarction: There are numerous causes of LBBB, such as heart failure, structural heart disease, fibrosis of the conduction system and acute myocardial infarction (particularly anterior STEMI). Hence, an acute myocardial infarction may actually result in LBBB which then masks the ischemic ST-T changes on ECG.

In summary, left bundle branch block (LBBB) can result from, mimic, or obscure acute myocardial ischemia and infarction, creating significant diagnostic challenges. These complexities led researchers to study patients presenting with LBBB and suspected acute myocardial infarction (AMI) by referring them for urgent reperfusion therapy, which at the time was primarily fibrinolysis (Wilner et al.). Their findings revealed that a substantial number of these patients had complete coronary artery occlusions, and outcomes improved when they were treated as acute STEMI cases.

For many years, European and North American guidelines recommended managing patients with symptoms of myocardial ischemia and new (or presumed new) LBBB as acute STEMI. However, subsequent studies found that this approach led to an unacceptably high rate of unnecessary catheterization laboratory activations. In response, the most recent North American guidelines (O’Gara et al.) advise that new (or presumed new) LBBB should not be considered diagnostic of AMI in isolation. Instead, patients with a high clinical suspicion of ongoing myocardial ischemia, regardless of ECG or biomarker findings, should be treated similarly to those with clear STEMI. Particularly, patients who remain symptomatic despite initial medical therapy, are hemodynamically unstable, or develop sustained ventricular arrhythmias. Similarly, the 2023 European Society of Cardiology (ESC) guidelines were updated to recommend that patients presenting with LBBB or RBBB and signs or symptoms strongly indicative of ongoing myocardial ischemia should be treated as having definitive STEMI, irrespective of whether the bundle branch block is previously documented (Byrne et al.).

Sgarbossa criteria for diagnosis of acute STEMI in the setting of LBBB

It is evident why researchers have faced challenges establishing ECG criteria for diagnosing acute STEMI in the presence of left bundle branch block (LBBB). Among the most useful and well-validated criteria are those developed by Sgarbossa and colleagues (Neeland et al.). These criteria, known as the Sgarbossa criteria, are summarized in Figure 7. For a comprehensive discussion, refer to the section LBBB and Acute Myocardial Infarction, which provides detailed insights into these criteria and their clinical application.

Figure 7. ECG criteria (Sgarbossa criteria) for acute STEMI in the setting of LBBB. Each criterion gives 2 to 5 points. Studies show that a cut-off of ≥3 points yields a sensitivity of 20–36% and specificity of 90–98% for acute STEMI in the setting of LBBB.

STEMI without ST elevations on ECG

There are situations in which acute transmural ischemia does not cause ST elevations on the 12-lead ECG and these situations are as follows:

Transmural ischemia located in the posterolateral region of the left ventricle. This is referred to as posterior, or posterolateral, or inferobasal STEMI. It causes ST depressions in leads V1–V3 (occasionally V4); these depressions are reciprocal ST segment depressions, mirroring the posterior ST segment elevations. The supplementary ECG leads V7, V8 and V9 must be connected to reveal the ST elevations.

Right ventricular infarction (STEMI): No lead in the standard 12-lead ECG is sufficient to reliably detect right ventricular infarction. Occasionally, ST-segment elevations may be observed in leads V1 and, less commonly, V2. However, to accurately identify ST-segment elevations in patients with right ventricular STEMI, the use of right-sided ECG leads, specifically V3R and V4R, is essential.

Note that posterolateral (posterior, inferobasal) infarction and right ventricular infarction have also been discussed previously.

Non-significant ST elevations

Transmural myocardial ischemia may occasionally produce sufficient ST elevation to meet the criteria in one lead but fail to reach the required threshold in the adjacent contiguous lead. In such cases, the formal criteria for STEMI may not be fulfilled, yet the patient could still be developing a STEMI. It is crucial to maintain a high suspicion for STEMI in patients presenting with chest pain, even if the ST elevations are below the diagnostic threshold. Indeed, the atherothrombotic process during STEMI is dynamic, meaning the size of the thrombus—and consequently the degree of coronary obstruction—can fluctuate minute by minute. It is recommended to perform serial ECG recordings at regular intervals (e.g., every 5 minutes) if the initial ST elevations do not meet the diagnostic criteria. This approach increases the likelihood of capturing dynamic changes indicative of STEMI.

Hyperacute T-waves

Large T-waves can occur in various conditions, including hyperkalemia and early repolarization. However, transmural ischemia may produce hyperacute T-waves, which are distinctly large, broad-based, and symmetric. These hyperacute T-waves appear within seconds of coronary artery occlusion and represent the earliest ECG manifestation of STEMI. They typically resolve within minutes, transitioning to ST elevations as the ischemia progresses. Although hyperacute T-waves are transient, they are not rare and are often seen in STEMI patients presenting with dynamic ECG changes (STEMI Example 9).

STEMI Example 9. Marked J-point (ST-segment) elevations and hyperacute T-waves.

Normalization of ECG changes in STEMI

In patients with STEMI the ST-T changes are normalized within days or weeks. QRS changes are mostly permanent, particularly Q-waves. Treatment and reperfusion therapy may modify the speed by which the ECG normalizes in patients with STEMI.

Risk stratification in the acute setting

Early risk assessment can improve outcomes in patients with acute STEMI. Several validated risk models have been developed to simplify risk stratification. These models typically include information regarding medical history, ECG findings, presenting features (notably hemodynamic status) and cardiac troponins. The most validated risk models are TIMI Score (Morrow et al.) and GRACE Score (Keith et al.). These vary concerning the type of risk estimated (short-term, long-term, myocardial infarction, death). The TIMI Score is the simplest to use, while the GRACE Score has demonstrated the highest accuracy.

TIMI Risk Score calculator for STEMI

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Interpretation of TIMI Score

Points30-days mortality
00,8%
11,6%
22,2%
34,4%
47,3%
512,4%
616,1%
723,4%
826,8%
9-1435,9%

Management of patients with STEMI

Occlusion of a coronary artery immediately causes ischemia in the myocardium supplied by the affected artery and its branches. The myocardium can endure ischemia for approximately 30 minutes before irreversible cell death occurs, resulting in myocardial infarction. As previously discussed (Classification of Acute Myocardial Infarction), STEMI is caused by a complete coronary occlusion, leading to extensive transmural ischemia and a significantly elevated risk of life-threatening ventricular arrhythmias. Ventricular tachycardia (VT) in acute ischemia is typically polymorphic and the risk of progression to ventricular fibrillation (VF) and death is high. The risk is highest within the first hour after symptom onset. The vast majority of all fatalities in the acute phase are attributed to ventricular arrhythmias, which can progress to asystole and ultimately cardiac arrest (Figure 8). Death from left ventricular dysfunction, resulting in cardiogenic shock, is much less common in the acute phase.

Figure 8. The progression from STEMI to VT, VF, asystole and death.

The prehospital phase

Due to the risk of ventricular arrhythmias and the progressive loss of myocardium, rapid assessment and initiation of treatments are crucial in patients with acute STEMI. A plethora of studies indicate that the vast majority of fatal myocardial infarctions occur outside the hospital, most often within the first hour. Hence, American and European guidelines recommend that patients with chest pain should use the EMS (Emergency Medical Service) for transportation to the hospital. EMS personnel should be trained in advanced cardiac life support and the early management of acute STEMI.

The prehospital chain of care is initiated at the emergency dispatch center. The dispatcher typically uses standardized protocols to assess the risk of acute STEMI, triage the patient (set a dispatch priority), give pre-arrival instructions and coordinate EMS to the scene. EMS can then immediately start a diagnostic workup, establish intravenous lines, assess vital functions, and address hemodynamic and electrical instability. Administration of aspirin, nitroglycerin, morphine and oxygen is generally safe in the prehospital setting. Importantly, the EMS can obtain a 12-lead ECG, which can be transmitted electronically to the hospital for further evaluation. In some instances, the EMS may even administer reperfusion therapy (fibrinolysis) en route to the hospital.

Studies have demonstrated the importance of prehospital delay in patients with acute STEMI. Each hour of prehospital delay increases mortality by 10%. Similarly, the risk of developing heart failure (due to acute STEMI) also increases by 10% per hour of treatment delay (Terkelsen et al.). Recognizing the prehospital potential can therefore reduce delay to interventions and subsequently reduce morbidity and mortality in patients with acute STEMI.

As mentioned above, the EMS can establish a diagnosis of STEMI using a 12-lead ECG. Although studies show that EMS personnel are highly capable of diagnosing STEMI, ECG tracings should be transmitted to the hospital for further evaluation. Without unnecessary delay, the patient should then be transported to a hospital with the facilities and expertise to perform percutaneous coronary intervention (PCI).

The emergency department

The first step in the management of patients with STEMI is rapid recognition since the effects of interventions (antithrombotic therapy, anti-ischemic therapy and reperfusion) are greatest when performed early. The diagnosis is confirmed with ECG (supplementary leads may be necessary, as discussed above). The presence of significant ST elevations in patients with chest pain (or other symptoms suggestive of myocardial ischemia) is sufficient to diagnose STEMI. All interventions (including reperfusion) may be performed before biomarkers (troponins) are available. Once the diagnosis is confirmed the patient must be continuously monitored (heart rate and rhythm, blood pressure, respiration, consciousness, symptoms, general appearance). A defibrillator must be ready and venous access should be secured. It is always wise to make a rapid assessment of the probability of aortic dissection before administering drugs that increase bleeding risk.

For clarity, STEMI is a clinical syndrome (defined by symptoms and ECG) and biomarkers are not required to initiate interventions. Therefore, anti-ischemic and antithrombotic medications should be administered immediately, provided that there are no contraindications. In some instances (discussed below) reperfusion may also be administered without delay.

The clinical examination must include vital parameters (consciousness, heart rate and rhythm, oxygen saturation, blood pressure, respiratory rate), signs of heart failure and pulmonary edema, and murmurs (mitral regurgitation, ventricle septum defect). Rapid assessment of bleeding risk should also be performed (discussed below).

Patients with clear symptoms of myocardial ischemia preceding sudden cardiac arrest should be transported to the catheterization laboratory immediately if circulation returns.

Any NSAID (Non-Steroidal Anti-Inflammatory Drug) should be withheld during the acute phase of STEMI, since these drugs increase morbidity and mortality, with aspirin being the only exception.

Evidence-based treatments for STEMI

Oxygen therapy in acute STEMI

Oxygen should be administered if oxygen saturation is <90%. There is no evidence that oxygen affects survival.

There is no data to support any beneficial effect of oxygen therapy in patients with normal oxygen levels, as measured by pulse oximetry. Randomized controlled trials (comparing oxygen with room air) did not show any benefit of administering oxygen to patients with normal oxygen levels (oxygen saturation >90% on pulse oximetry). Therefore, current guidelines recommend supplemental oxygen for patients with oxygen saturation <90%. Oxygen is also appropriate for patients with pulmonary edema, heart failure and mechanical complications (free wall rupture, ventricular septum defect, mitral prolapse) of acute STEMI (Hofmann et al.).

Analgesics in acute STEMI

Morphine

Morphine sulfate is administered to all patients with acute STEMI (2 to 5 mg, may be repeated every 5 to 30 minutes, as necessary). Caution is required in patients with hypotension.

Pain activates the sympathetic nervous system, resulting in peripheral vasoconstriction, increased myocardial contractility (positive inotropic effect), and an elevated heart rate (positive chronotropic effect). As a result, heightened sympathetic activity can increase myocardial workload, potentially exacerbating ischemia. This can be harmful in patients with STEMI, making adequate pain management a critical component of care. Morphine sulfate is the analgesic of choice. Morphine relieves pain and anxiety, and promotes venous dilation, which decreases cardiac preload. The latter alleviates the workload on the left ventricle.

The appropriate dose of morphine is determined by the intensity of pain, age, body mass index (BMI), and circulatory status. Reduced doses are necessary for patients with hypotension, as morphine may cause additional vasodilation. An initial intravenous dose of 2 to 5 mg is recommended, which can be repeated every 5 minutes as needed, up to a total of 30 mg. In cases of morphine overdose, naloxone (0.1 mg IV) can be administered and repeated every 10 minutes as necessary. Morphine-induced bradycardia may occur and can be managed with atropine, starting with 0.5 mg IV, which can be repeated as necessary. If pain persists despite the administration of large amounts of morphine, alternative diagnoses, such as aortic dissection, should be considered.

NSAID (Nonsteroidal anti-inflammatory drugs) and selective cyclooxygenase II (COX-2) inhibitors are contraindicated in acute STEMI.

Note that nitrates and beta-blockers also have analgesic effects. However, it is important that the administration of morphine does not restrict the use of beta-blockers. While morphine and beta-blockers can potentiate each other’s negative hemodynamic effects, beta-blockers provide antiarrhythmic benefits in the event of ventricular arrhythmias.

Nitrates (nitroglycerin) in acute STEMI

Nitrates

Nitrates are administered to the vast majority of patients with STEMI. It does not affect the prognosis but relieves symptoms. Sublingual nitroglycerin (0.4 mg; can repeat two times with 5-minute intervals) may therefore be given for relief of ischemic discomfort. Intravenous nitroglycerin is considered if ischemic discomfort is not relieved. Nitroglycerin is also considered in patients with congestive heart failure as well as patients with uncontrolled hypertension.

Nitrates (nitroglycerin) produce vasodilatation by relaxing the smooth muscle in arteries and veins. The vasodilatation reduces the venous return to the heart which decreases cardiac preload. This reduces the workload on the myocardium and thus myocardial oxygen demand. Nitrates relieve both ischemic symptoms (chest pain) and pulmonary edema. The vast majority of patients should be offered nitrates.

A dose of 0.4 mg (sublingual or tablet) is given and may be repeated 3 times at 5-minute intervals. Nitroglycerin infusion should be considered if the effect is inadequate (severe angina) or if there are signs of heart failure. An infusion may be initiated with 5 μg/min and titrated up every 5 minutes to 10–20 μg/min. The dose is titrated until symptoms are relieved or a maximal dose of 200–300 μg/min is reached.

Nitrates should not be administered in patients with hypotension, if there is suspicion of right ventricular infarction, severe aortic stenosis, hypertrophic obstructive cardiomyopathy or pulmonary embolism. Administration should proceed with caution if blood pressure drops >30 mmHg from baseline.

Beta-blockers in acute STEMI

Beta-blockers

• There is no evidence demonstrating that the routine use of beta-blockers after STEMI reduces morbidity or mortality.• It is evident that beta-blockers reduce morbidity and mortality in patients with acute MI who develop heart failure with reduced ejection fraction (HFrEF).• The AHA/ACC guidelines, last updated in 2013, broadly recommended beta-blockers after acute STEMI, despite the absence of evidence.• The 2023 ESC guidelines state that intravenous beta-blockers, preferably metoprolol, should be considered at the time of presentation for patients undergoing primary PCI, provided they show no signs of acute heart failure, have a systolic blood pressure (SBP) >120 mmHg, and have no other contraindications (Class IIa, Level of Evidence A).

Evidence for beta-blockers

Historically, beta-blockers were universally used during the pre-reperfusion era, prior to the widespread adoption of fibrinolysis and primary PCI, and demonstrated benefits in reducing infarct size and improving survival (Hoedmaker et al.). However, these early studies were conducted in an era where most patients experienced extensive myocardial infarctions with severe left ventricular dysfunction (Braunwald et al.). It is well established that beta-blockers reduce morbidity and mortality in patients with heart failure and reduced ejection fraction, regardless of the underlying etiology. More recently, the effectiveness of beta-blockers in patients with acute MI without left ventricular dysfunction has been questioned. A meta-analysis (Bangalore et al.) found no benefit of beta-blockers in this population. Despite this, guidelines have broadly recommended beta-blocker use, even in patients without left ventricular dysfunction (O’Gara et al.; Byrne et al.). The largest study to directly address this issue, REDUCE-AMI, examined whether long-term oral beta-blocker therapy in patients with acute MI and preserved left ventricular ejection fraction (≥50%) reduced the risk of death or recurrent MI compared to no beta-blocker therapy. REDUCE-AMI showed that long-term beta-blocker treatment did not lower the risk of the composite primary endpoint compared to no beta-blocker use (Yndigegn et al.).

Physiological effects of beta-blockers

Beta blockers exert negative inotropic and chronotropic effects, leading to a reduced heart rate (prolonging diastole), decreased cardiac output, and lower blood pressure. These effects collectively reduce myocardial workload, oxygen consumption, and oxygen demand. The prolongation of diastole also enhances myocardial perfusion, as coronary blood flow occurs primarily during diastole. The ability of beta-blockers to suppress ventricular arrhythmias is believed to stem from their anti-sympathetic effects.

If required, intravenous metoprolol can be administered in doses of 5 mg, repeated up to three times at intervals of 5–10 minutes, with continuous monitoring of heart rate and blood pressure during administration. For oral administration, metoprolol 25 mg can be given every six hours and titrated to the maximum tolerated dose, up to 200 mg daily. It is important to note that the evidence supporting the long-term use of beta blockers is limited to patients with heart failure and reduced ejection fraction.

Contraindications to beta-blockers

Patients with acute heart failure should not be given beta blockers during the acute phase. However, beta-blockers should be started early when heart failure has stabilized. Patients with first-degree AV block should perform a second ECG after administration of beta blockers, since the AV block may progress to higher degrees of AV block. Second-degree and third-degree AV block (without pacemaker) are contraindications. Patients with COPD (chronic obstructive pulmonary disease) should be given beta-1 selective agents (e.g. bisoprolol).

Antithrombotic therapy

Antiplatelet agents

Figure 9. Overview of antithrombotic therapy in patients with STEMI and NSTE-ACS (NSTEMI, unstable angina).

Aspirin (ASA)

An oral loading dose of aspirin (160 mg to 320 mg) should be given immediately to all patients. Aspirin is given in the prehospital setting and before primary PCI. Aspirin is continued indefinitely (maintenance dose 75–80 mg daily).

All patients should immediately receive aspirin (oral loading dose 160 to 320 mg) and then continue indefinitely at a maintenance dose 80 mg daily.

Early studies showed that aspirin has a remarkable effect, reducing 30-day mortality by 23% (ISIS-1, ISIS-2). A loading dose of 160 to 320 mg is indicated in all patients with acute STEMI. Patients who are unable to swallow may be given 300 mg as a suppository or 80 to 150 mg IV. All patients should receive a maintenance dose of 80 mg daily which is continued indefinitely. Hypersensitivity to aspirin is rare; in such cases, clopidogrel can be used as an alternative.

Dose adjustments

Aspirin does not require dose adjustment in patients with chronic kidney disease (CKD).

Dual antiplatelet therapy (DAPT)

DAPT with P2Y12-receptor inhibitors

• Dual antiplatelet therapy (DAPT) is recommended for all patients undergoing PCI. However, the optimal timing for initiating DAPT—specifically, the administration of P2Y12-receptor inhibitors in addition to aspirin—remains uncertain.• In patients with a working diagnosis of STEMI undergoing primary PCI, pre-treatment with a P2Y12-receptor inhibitor (administered before angiography) can be considered. Alternatively, the P2Y12-receptor inhibitor may be given at the time of PCI, once the coronary anatomy is known.• Clopidogrel is the least effective P2Y12-receptor inhibitor and should only be used when prasugrel or ticagrelor are contraindicated, unavailable, or if there is a high bleeding risk. Clopidogrel may also be appropriate in elderly patients.• Prasugrel should be preferred over ticagrelor in patients undergoing PCI. The ISAR-REACT 5 trial demonstrated the superiority of prasugrel compared to ticagrelor (Schupke et al.).

The optimal antiplatelet regime requires the combined use of aspirin with a P2Y12-receptor inhibitor (ticagrelor, prasugrel or clopidogrel), referred to as dual antiplatelet therapy (DAPT). An individual assessment of bleeding risk is warranted and DAPT should be avoided if the risk is high. DAPT is continued for 12 months in all patients, and the indication is stronger in patients undergoing PCI with placement of a stent (bare metal stent, or drug-eluting stent).

Pre-treatment with a P2Y12-receptor inhibitor

Pretreatment with a P2Y12 inhibitor refers to administering a loading dose of the P2Y12 inhibitor before evaluating coronary anatomy, typically in the ambulance, emergency department, or coronary care unit (Niezgoda et al.). The purpose of this approach is to achieve rapid platelet inhibition. However, evidence suggests that pretreatment does not provide significant cardiovascular benefits and may increase the risk of major bleeding events. Additionally, it can complicate urgent surgical procedures due to an elevated bleeding risk (Dawson et al.). Current guidelines do not provide clear recommendations on the optimal use of pretreatment. In current practice (2025), the administration of a P2Y12 inhibitor is often deferred until coronary anatomy has been assessed and a decision is made to proceed with PCI (requiring P2Y12 inhibitor administration) or surgery (P2Y12 inhibitors withheld). However, pretreatment is recommended when an early invasive approach is not planned, provided the patient has a low risk of bleeding.

Clopidogrel

The addition of clopidogrel to aspirin will additionally reduce mortality by 13%. A loading dose of 600 mg followed by a maintenance dose of 75 mg daily is recommended. The additional increase in bleeding risk is smaller with clopidogrel, as compared with prasugrel and ticagrelor.

Clopidogrel does not require dose adjustment in patients with chronic kidney disease (CKD).

Prasugrel

Prasugrel is a more potent antiplatelet agent compared to clopidogrel. Additionally, it has been shown to provide greater reductions in cardiovascular mortality, non-fatal acute myocardial infarction, and stroke (Wiviott et al.). Randomized clinical trials indicate that prasugrel is particularly effective in patients presenting with anterior STEMI. The recommended dosing regimen is a loading dose of 60 mg, followed by a maintenance dose of 10 mg daily. Prasugrel is contraindicated in patients with a history of stroke, transient ischemic attack (TIA), or liver failure. Furthermore, it should be used with caution in patients over 75 years of age or those weighing less than 60 kg, due to an increased risk of bleeding in these populations.

Dose adjustments and contraindications

In patients with body weight <60 kg, a maintenance dose of 5 mg once daily is recommended.

In patients aged ≥75 years, a maintenance dose of 5 mg once daily should be used.

No specific dose adjustment in CKD patients.

Prior stroke, TIA, liver failure, are contraindications for prasugrel.

Ticagrelor

Ticagrelor (loading dose 180 mg, maintenance dose 90 mg twice daily) is more effective than clopidogrel and reduces cardiovascular mortality, non-fatal acute myocardial infarction and stroke. Although the PLATO study showed that ticagrelor caused more serious bleedings, as compared with clopidogrel, the overall effect was beneficial and it was concluded that the benefits outweighed the risks (Wallentin et al.).

Patients frequently report dyspnea and, and less frequently bradycardia, during the first week of ticagrelor treatment. These side effects are benign and usually transient. Ticagrelor is contraindicated in patients with previous cerebral hemorrhage or liver failure (clopidogrel is recommended for those patients instead).

Ticagrelor does not require dose adjustment in patients with chronic kidney disease (CKD).

Anticoagulants in acute STEMI

• Unfractionated heparin (UFH) is the first-choice anticoagulant and should be administered to all patients with STEMI undergoing primary PCI (Class I recommendation).• Alternative anticoagulants (enoxaparin and bivalirudin) are used in patients undergoing primary PCI when UFH is unavailable.

Low molecular weight heparin (enoxaparin) and unfractionated heparin (UFH)

Low molecular weight heparin (enoxaparin) and unfractionated heparin (UFH) reduce mortality in patients with STEMI. UFH is preferred over enoxaparin. The loading dose of UFH is 70–100 U/kg, given as a bolus. If the patient is also given GP IIb/IIIa antagonists, UFH is reduced to 50–60 U/kg.

Bivalirudin

Bivalirudin was compared with a combination of UHF and GP IIb/IIIa antagonists in the HORIZONS-AMI trial. Bivalirudin caused fewer bleedings and resulted in lower mortality. Hence, bivalirudin is preferred over the combination UFH+GP IIb/IIIa antagonist in patients undergoing primary PCI. Bivalirudin is also preferred in patients with heparin-induced thrombocytopenia (HIT), as well as in cases with a high risk of bleeding.

Fondaparinux

Fondaparinux was evaluated in the OASIS-6 study and there were no beneficial effects in patients undergoing primary PCI. On the contrary, fondaparinux was associated with an increased risk of stent thrombosis.

Glycoprotein (GP) IIb/IIa receptor antagonists

• Gp IIb/IIIa antagonists may be considered during PCI if the procedure is not successful (slow or no-reflow) or if angiography shows massive thrombosis or complications of thrombosis.• Gp IIb/IIIa antagonists may accompany unfractionated heparin (which then must be dose-reduced) if there are no contraindications.• Gp IIb/IIIa antagonists may be administered during transport to high-risk patients who are referred to primary PCI.

These agents (abciximab, tirofiban, eptifibatide, elinogrel) block the GP IIb/IIIa receptor which is located on the membrane of platelets and connects platelets to fibrinogen and von Willebrand factor. This class of drugs is actually the most potent platelet inhibition available. However, the addition of these agents confers little benefit, which appears to be reserved for certain subgroups of patients.

Glycoprotein IIb/IIIa inhibitors are most frequently employed during percutaneous coronary intervention (PCI) when complications arise. They are particularly useful in the following scenarios:

Slow coronary flow (slow reflow) after PCI

Absence of coronary flow (no-reflow) after PCI

Extensive thrombosis

Long-term antithrombotic regimens in patients with STEMI

Figure 10 presents the antithrombotic regimens in patients without an indication for oral anticoagulation.

Patients without an indication for oral anticoagulation

Figure 10. Antithrombotic regimens in patients with ACS without an indication for oral anticoagulation.

Patients with an indication for oral anticoagulation

Figure 11 presents the antithrombotic regimens in patients with an indication for oral anticoagulation (e.g. patients with atrial fibrillation on oral anticoagulants).

Figure 11. Antithrombotic regimens in patients with ACS with an indication for oral anticoagulation.

Reperfusion in acute STEMI: PCI and fibrinolysis

Figure 12. Appropriate use of PCI and fibrinolysis in STEMI.

Reperfusion is accomplished by means of PCI or intravenous fibrinolysis. Successful reperfusion restores blood flow to the ischemic myocardium and halts the infarction process. PCI is superior to fibrinolysis if it can be performed early (within 120 minutes).

• Primary PCI is the recommended reperfusion strategy (Class Ia) for STEMI patients if the time from diagnosis to wire passage is <120 minutes.• If symptoms persist for more than 12 hours, primary PCI is still recommended (Class Ic) in patients with ongoing ischemic symptoms, hemodynamic instability, or life-threatening arrhythmias.• In patients presenting between 12 and 48 hours after symptom onset, PCI should be considered (Class IIa), even in the absence of symptoms.• If the time from diagnosis to PCI exceeds 120 minutes, fibrinolysis is recommended as the initial reperfusion strategy (Class Ia). Following fibrinolysis, transfer to a PCI-capable center is recommended for all patients, regardless of the initial outcome of fibrinolysis (Class Ia). Angiography and PCI of the infarct-related artery should be performed between 2 and 24 hours after successful fibrinolysis (Class Ia).

Figure 13. Reperfusion strategies in STEMI, NSTEMI, unstable angina.

Percutaneous coronary intervention (PCI)

PCI is the most effective means to restore blood flow in acute STEMI. Restoration of coronary blood flow is markedly better with PCI, as compared with fibrinolysis (re-flow is greater and the risk of re-stenosis is smaller). PCI is less dependent on symptom duration (fibrinolysis is dependent on symptom duration because the thrombus reorganizes gradually and becomes less susceptible to fibrinolytic agents).

Figure 14. Management of multivessel disease in patients with ACS undergoing PCI

If no clear culprit lesion is identified during angiography, intravascular imaging should be used for further assessment. Optical coherence tomography (OCT) is the preferred modality, while intravascular ultrasound (IVUS) is recommended as a Class IIb alternative. Treatment decisions should be based on the imaging findings. When a clear culprit lesion is identified, it should be treated with PCI.

Management of multivessel disease in patients with STEMI undergoing PCI

Complete revascularization is recommended during the index procedure or within 45 days (Class I recommendation). Treatment of non-infarct-related artery (non-IRA) lesions should be guided by angiographic findings (imaging and flow reserve calculations are not necessary).

Patient in cardiogenic shock

Initial management includes PCI of the infarct-related artery (IRA) only (Class I recommendation). Staged complete revascularization may be performed subsequently (Class IIa recommendation). Coronary artery bypass grafting (CABG) may be considered if PCI fails (Class IIb recommendation).

Fibrinolysis

Figure 15. Evaluation of fibrinolysis.

Fibrinolysis (tenecteplase, alteplase, reteplase) is very effective in lysing a thrombus if given early (within 2 hours of symptom onset). The effect of these agents diminishes gradually because of a reorganization in the thrombotic material. If fibrinolysis is administered in the prehospital setting, it may be as effective as PCI. However, fibrinolysis frequently fails to establish a patent blood flow and the risk of re-occlusion is significant. Moreover, fibrinolysis may cause serious bleeding and even death due to hemorrhage.

Fibrinolysis is considered unsuccessful if the magnitude of the ST elevations is not reduced by 50% within 60 minutes. In such cases, PCI (rescue PCI) should be considered.

Absolute contraindications to fibrinolysis

Previous cerebral hemorrhage

Stroke of unknown type

Ischemic stroke during the past 6 months

Tumors or injuries in the central nervous system

Arteriovenous malformation in the central nervous system

Aortic dissection

Recent surgery/trauma (within 3 weeks).

Gastrointestinal bleeding within 4 weeks

Coagulation disorders

Lumbar puncture, liver biopsy or similar procedures within 24 hours.

Relative contraindications to fibrinolysis

Transient Ischemic Attack (TIA) within 6 months.

Ongoing oral anticoagulation therapy

Pregnancy or 1 week post partum

Refractory hypertension (systolic blood pressure >180 mmHg and /or diastolic blood pressure >110 mmHg).

Severe liver disease

Infectious endocarditis

Active ulcer

Prolonged or traumatic resuscitation 

Coronary artery bypass grafting (CABG)

CABG has a limited role in the acute phase of STEMI. However, CABG should be considered if (1) PCI fails, (2) if coronary anatomy is not amenable to PCI, (3) if there are mechanical complications (e.g. free wall rupture) or (4) cardiogenic shock.

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