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.

 

Coronary artery disease (ischemic heart disease)

Ischemic heart disease, which is synonymous with coronary artery 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 heart disease peaked in the 1970s and has declined rather steadily ever since. The marked decline in death rates and case fatality due to coronary heart disease is most likely explained by successful primary preventive strategies; reduced smoking rates, aggressive lowering of blood lipids with statins and sophisticated treatments for hypertension are some of the primary explanations. However, coronary artery disease remains the number one killer in most regions worldwide.

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 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 the more risk factors, the more aggressive the atherosclerosis. Moreover, inflammation and risk factors also modify the risk of destabilization of the plaque. Indeed, the greatest risk emerges if the plaque ruptures.

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 work load (physical exercise) because the increased work load 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 work load and the symptoms disappear within minutes after stopping the activity. The greater the stenosis, the lower level of myocardial work load required to elicit ischemia and symptoms.

The diagnosis stable angina pectoris (stable coronary artery disease) is established if the ischemic heart disease is stable over time. This requires that that symptoms (typically angina pectoris) appear at the same level of myocardial work load; symptoms must cease within 1–2 minutes at rest and administering of nitroglycerin should alleviate symptoms. Moreover, the level of physical activity that elicits the angina must be stable during the past few weeks.

The size of coronary plaques tends to increase with time. This leads to increased stenosis and thus more pronounced symptoms (and symptoms at lower myocardial work loads). Notably, research conducted in the past few years have shown that statin treatment may slow, inhibit or even reverse this progression (The JUPITER Studies).

The most serious scenario emerge if the coronary plaque ruptures, or if the endothelium which covers the plaque becomes eroded (plaque erosion). This is generally a result of intensive inflammation inside the plaque. Inflammation destabilizes the plaque (the mechanisms may be studied in this article) which leads to plaque rupture and plaque erosion. As the plaque is damaged, thrombogenic substances (located within the artery wall, for example collagen) are exposed to the blood. Thrombocytes and coagulation factors passing by the plaque will react and become activated, which leads to a thrombus. formation of a thrombus only takes a few minutes, or even less. The thrombus will occlude the artery either completely or partially. In either case, the sudden reduction in myocardial blood flow will lead to myocardial ischemia. this type of ischemia is typically pronounced and causes persisting chest discomfort which is not alleviated by rest, and nitroglycerin does not have an adequate effect. The chest discomfort is typically accompanied by dyspnea, cold sweat, paleness and anxiety. This scenario, which is the result of a thrombus secondary to plaque rupture/erosion, is referred to as an acute coronary syndrome. Please refer to Figure 1.

 

Figure 1. Atherosclerotic plaque which has ruptured and lead to atherothrombosis.

Figure 1. Atherosclerotic plaque which has ruptured and lead to atherothrombosis.

 

Myocardial ischemia and infarction

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 occlusion is complete all ischemic myocardium will be dead within 2 to 12 hours. the size of the ischemic/infarcted area correlates strongly with the risk of heart failure, malignant ventricular arrhythmias and other complications. Indeed, the risk of malignant ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation) is highest in the hyperacute phase (the first hour). Because most patients delay before they seek medical attention, those who die from 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 heart disease to acute coronary syndromes – is not universal. The majority of patient never develop acute coronary syndromes, whereas some may have myocardial infarction as their first sign of ischemic heart 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 heart disease

Risk factors of ischemic heart disease is one of the most intensively researched areas of medicine. Thousands of studies, ranging from genomics and other cellular studies to nationwide epidemiological studies, have elucidated the risk factors of coronary heart 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 myocardial infarction was explained by nine modifiable risk factors. This was true for men and women, and throughout the world. 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 (read the INTERHEART study here). Importantly, hyperlipidemia (sometimes referred to as dyslipidemia) and smoking constitute 66% of the risk of myocardial infarction!

Blood lipids deserve special mention as the condition is both common and easy to treat. All levels of blood lipids are associated with risk of myocardial infarction. The lower the lipid levels, the lower the risk of myocardial infarction. There are numerous types of blood lipids. LDL (low density lipoprotein) cholesterol is the one with the strongest association with coronary heart disease. Moreover, studies in basic science have consistently shown a causal pathway between LDL cholesterol and coronary artery disease.

Body Mass Index (BMI) is not as strongly associated with the risk of acute myocardial infarction, as is abdominal obesity. Psychosocial stress (economic stress, work place stress, depression, domestic stress) are comparable to hypertension and abdominal obesity. Smokers have three times as great a risk of myocardial infarction, as non-smokers. Smoking one to five cigarettes per day increases the risk of infarction by 40%. Smoking 20 cigarettes per day increases 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 and cheap 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.

Because ischemia primarily affects the 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), flattening of the T-waves or T-waves with increased amplitude. One or several of these changes may occur. Which of these that occur depend on the localization, extent and time course of the ischemia. ECG changes seen in the early phase differ from those seen in the late phase of ischemia. Note that ST-T changes 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.

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 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.

The ECG is utilized in all phases of coronary artery disease to classify the condition. The following must be noted:

  • Stable coronary artery disease (Stable angina pectoris) do 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.
  • Stable coronary artery disease may, however display QRS changes (patholgocial Q-waves, fragmented QRS, reduced R-wave ampltiude), and this indicates previous myocardial infarction.
  • In case of acute coronary syndrome the ECG is used to classify the syndrome into STE-AKS and NSTE-AKS. This subdivision is fundamental because it affects the management and immediate treatment.
    • NSTE-AKS (Non-ST Elevation Acute Coronary Syndrome): acute coronary syndromes without ST-segment elevations on the ECG.
    • STE-AKS (ST Elevation Acute Coronary Syndrome): acute coronary syndromes with ST-segment elevations on the ECG.

 

There are aspects of acute coronary syndromes that are rather peculiar and interesting, but certainly not of relevance to most clinicians. These aspects will be discussed in the next section. Readers who are only interested in ECG interpretation may skip this section and continue to the next article.

 

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 an 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 which 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 damages.

A large body of science indicates that acute coronary syndromes only occur if the plaque damages coincides 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 fibrinogene, 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 in the coagulation factors and thrombocytes, such that 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 vary 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 cap) tend to revert to more stabile 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 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.

Read more: Arbab-Zadeh et al: Acute Coronary Events; Circulation 2012

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