Clinical Consequences of Coronary Artery Disease

Coronary artery disease can present in a variety of ways. The classical presentation is with chest discomfort. Chest discomfort resulting from myocardial ischemia secondary to coronary artery disease is called angina pectoris (squeezing of the chest). Discomfort is diffuse and not localized and may radiate down the arms, as low as the umbilicus and up to the lower jaw. This may be associated with shortness of breath (dyspnea). This
discomfort is the result of myocardial ischemia however it is one of the last manifestations to appear. Due to the myocardium’s complete reliance on coronary blood flow for energy supply, within a few beats of coronary occlusion, diastolic and systolic dysfunction set in and the electrocardiogram begins to register abnormalities before the patient begins to experience angina pectoris. This explains why patients may describe
associated shortness of breath when they experience angina. The association of both symptoms together indicates that the myocardium fed by the narrowed vessel is sizable. The following are the more frequent clinical consequences of coronary artery disease. These “scenarios” may progress from one to another and their recognition allows for their proper management to preclude any potential lethal consequence. The term acute coronary syndrome refers to unstable angina, non ST-segment elevation and STsegment elevation myocardial infarction. One fourth of acute coronary syndrome patients are diagnosed with ST-segment elevation myocardial infarction, the remainders have unstable angina or non ST-segment MI (NSTEMI).

1. Stable Angina: Angina occurring predictably after exertion and relieved by rest. This is due to increased oxygen demand in the face of limited coronary flow. The more severe the narrowing, the less the amount of exertion required to induce ischemia and angina pectoris. As the narrowing becomes more severe, the amount of exertion required to precipitate angina becomes less. Certain types of exertion are classical in reproducing angina such as climbing stairs/slopes, walking in cold weather especially if accompanied by wind and after meals. The discomfort is pressure-like and diffuse, it peaks over minutes and when relieved by rest or sublingual nitroglycerine, it does so within 5-10 minutes. Some patients display individual variability in the amount of effort required to precipitate angina. This is called variable threshold angina where a component of
vasoconstriction may play a role in lowering the threshold for angina. Cardiac catheterization has shown that 25% of patients with stable angina have single vessel disease, 25% have two and 25% have three-vessel disease (defined as luminal narrowing of > 70%). Five to ten percent have left main disease and 15% have no
discernible obstruction. Treatment is by using beta-blockers to reduce myocardial O2 requirements, Ca++ channel blockers to vasodilate and reduce preload and afterload. Nitrates also vasodilate and reduce preload. When medical therapy fails, percutaneous intervention with balloon angioplasty or surgical revascularization may be required. Risk factor modification is equally important addressing dyslipidemia, hypertension, smoking, obesity and physical inactivity. The annual risk of death in this patient population is 1.7%-3% with a 1.4%-2.4% risk of a major ischemic event.

2. Unstable Angina: The diagnosis of unstable angina is a clinical one where patients with UA can present in one of three clinical scenarios; A) An acceleration from stable angina to one that occurs with less activity with more intensity and lasting longer. B) Angina at rest C) New onset angina usually with severe discomfort. Whereas the pathogenesis of ST-segment elevation myocardial infarction is total occlusion of the coronary vessel, the pathogenesis of UA is severe but not total occlusion of the culprit vessel. This is usually due to 1. plaque disruption with clot formation and interruption of distal blood flow, 2. Vasoconstriction, 3. mechanical occlusion, 4. inflammation, and 5. increased myocardial oxygen demand due to extracardiac causes (anemia, thyrotoxicosis) play variable roles in the pathogenesis of unstable angina. One year progression to death or myocardial infarction is between 7% and 14%. Patients older than 70 yrs., diabetic patients, and patients with vascular disease have a worse prognosis. Electrocardiographic determinants of prognosis include the magnitude of STsegment deviation as well as the presence of a left bundle branch block. Elevated serum troponin and C-reactive protein also portend a worse prognosis. The existence of these features should prompt a more aggressive approach. Since thrombus formation is an integral component in the pathogenesis of unstable angina, anticoagulants such as aspirin, heparin and more recently glycoprotein IIB/IIIA inhibitors are critical ingredients of the therapeutic armamentarium. Reduction of oxygen consumption using beta-blockers and nitrates are also used. A rise in one of the serum cardiac markers, troponin, portends a worse prognosis. Such patients are treated more aggressively with glycoprotein IIB/IIIA inhibitors and early cardiac catheterization.

3. Non-ST Elevated Myocardial Infarction. If patients present with chest discomfort and / or symptoms of a myocardial infarction (nausea, vomiting, diaphoresis, shortness of breath), have positive biomarkers for myocardial necrosis (CPK, CPK-MB and troponin, but without ST-segment elevation in the electrocardiogram, the diagnosis is non ST-elevated myocardial infarction (NSTEMI). Recent studies have shown that patients with NSTEMI constitute the majority (54%) of acute MIs patients admitted to the hospital. This study also showed that patients with NSTEMI had higher 1 year mortality (31%) than patients with ST-elevation MI (21%). Patients with NSTEMI tend to be older, have worse LV function, multi vessel disease and a history of acute coronary events. The pathophysiology of NSTEMI shares many of the features of UA i.e. clot on plaque, vasoconstriction, increased O2 demand, inflammation and progression of occlusive thrombus.

Management includes the use of heparin and glycoprotein IIB/IIIA inhibitors in addition to aspirin and beta-blockers. The importance of distinguishing ST-segment elevation from non ST-segment elevation myocardial infarction is that thrombolytic agents are not administered in NSTEMI and percutaneous intervention may be used acutely if the patient does not respond to medical therapy. 4. ST-Segment Elevation Myocardial Infarction. This is the other end of the spectrum of coronary syndromes. The etiology is complete occlusion of a coronary vessel from a clot developing on a recently ruptured plaque. These plaques are usually < 50% in diameter and are lipid rich. The ensuing activation of platelets and the coagulation cascade results in thrombus formation and occlusion of the vessel. Patients describe chest discomfort that is severe and often associated with nausea and vomiting. Discomfort typically lasts more than twenty minutes and does not respond to nitroglycerine. Radiation may occur down either arm, the lower jaw and to the back. Discomfort due to an acute MI does not radiate below the umbilicus or above the earlobes. Shortness of breath may indicate a large sized infarction. Up to 25% of patients, may not experience any discomfort when they suffer an infarction. The elderly and diabetic patients are more prone to having a silent myocardial infarction. Acute MIs, particularly in patients not receiving beta blockers of aspirin, tend to cluster between 6AM and 12PM. This circadian variation is thought to be due to circadian variation in levels of circulating corticosteroids and catecholamines. On examination, patients are uncomfortable and diaphoretic. They may exhibit pallor indicating decreased peripheral perfusion due to a drop in cardiac output and / or heightened sympathetic tone. Blood pressure may be normal, elevated due to discomfort and anxiety or reduced due to low cardiac output (especially if the right ventricle is involved) or the medications used to treat the patient’s condition. Jugular venous distension indicates right sided heart failure, the commonest cause being left-sided heart failure. Râles heard over the lung bases suggests left heart failure and is an ominous finding in patients suffering a myocardial infarction.

The WHO criteria for diagnosing an acute myocardial infarction is: Chest pain, serial elevation of cardiac enzymes and typical electrocardiographic features. The fulfillment of two out of three of these criteria establishes the diagnosis. A more recent definition for an acute, evolving or recent myocardial infarction requires the typical rise and fall of cardiac enzymes (troponin, CK-MB) along with one of the four following criteria;
1. Typical ischemic symptoms
2. ST-segment elevation or depression
3. Development of Q waves
4. Acute percutaneous intervention

Myocardial necrosis results in the release of non-specific and more specific enzymes. An estimation of the magnitude of myocardial necrosis can be determined by the degree of enzyme elevation. One of the first enzymes to climb is myoglobin. It peaks and falls back to baseline within one day of the MI, however myoglobin is very non-specific. The more cardio specific enzymes CK-MB and Troponins then begin to rise, CK-MB reaches a peak in 1-1 ½ day and is down to baseline in 4 days. Troponins peak in two days and fall
to baseline in 5-7 days. Hence, for the diagnosis of an MI that may have occurred 4-5 days ago, troponins are more helpful than CK-MB. Cardiac enzymes should display a characteristic rise followed by a fall back to baseline. The electrocardiogram displays characteristic changes. One of the first changes seen is elevation of the ST-segment and peaking of the T wave. The T wave then begins to invert and once irreversible myocardial necrosis sets in, Q waves begin to show. The STsegment then descends to baseline and the T wave may or may not normalize with time. Persistent ST-segment elevation may indicate formation of an aneurysm in the underlying myocardium. Patients with angina of non ST-segment elevation myocardial infarction (NSTEMI) display ST-segment depression and T wave changes but not the characteristic ST-segment elevation. Where myocardial infarction is involved, time is salvageable myocardium and every minute from the inception of symptoms counts. Irreversible injury begins to set in < one hour after occlusion of the offending vessel takes place. However myocardium can be salvaged as late as 12 hours after symptoms begin. This sets the stage for prompt intervention by one of two available methods of revascularization; thrombolytic (fibrinolytic) therapy and percutaneous intervention.

Tissue plasminogen activator is released by endothelial cells in response to clot formation. Plasminogen is cleaved to plasmin which in turn lyses fibrinogen breaking up formed or forming clot. This agent is given intravenously, however it cannot discriminate between a clot causing a myocardial infarction and a clot preventing a catastrophic hemorrhage, in for instance, the GI tract or the central nervous system. The risk / benefit ratio increases as time goes by. It is most effective when given the first four hours however it may be administered as late as twelve hours after symptoms began. Up to 80% of occluded coronary vessels are reperfused with fibrinolytic therapy leading to enhanced survival, improving prognosis and lowering complication rates. Recent studies have shown that acute percutaneous intervention with balloon tipped catheters (primary angioplasty) to revascularize occluded coronary vessels is equally as good as if not safer than thrombolytic therapy as long as its employment does not lengthen the critical time to intervention. Up to 30% of patients with myocardial infarction have a contraindication to receive fibrinolytic therapy and may benefit from primary angioplasty.

Adjunctive treatment includes aspirin, heparin, analgesics and beta blockers. Recently administration of afterload reducing agents angiotensin converting enzyme inhibitors (ACE-inhibitors) and cholesterol reducing hydroxymethylglutaryl coenzyme-A reductase inhibitors (statins) has been shown to portend favorably on patients with acute MI. Mortality from ST-elevated MI has declined over the last 40 years. This is in part due to the introduction of coronary care units, use of invasive monitoring when appropriate, thrombolytic therapy and direct acute revascularization. Large studies report in-hospital mortalities of 6.5%-7% whereas community based observation yield a15%-20% mortality.

5. Silent Ischemia. Impaired coronary flow may occur without symptoms. This syndrome can be seen in up to 40% of patients with classical angina pectoris and in up to 10% of patients with no symptoms of angina at all. Diabetic patients have a higher incidence of silent ischemia. Angina is a warning symptom without which serious underlying coronary disease is often overlooked. Hence patients with silent ischemia have a worse prognosis than those with angina pectoris.

6. Sudden Cardiac Death. Patients with coronary artery disease can present for the first time with a lethal arrhythmia; ventricular fibrillation. The definition of Sudden Cardiac Death is natural death due to cardiac causes, heralded by abrupt loss of consciousness within one hour of the onset of acute symptoms. Preexisting heart disease may or may not have been known to be present, but the time and mode of death are unexpected. Ischemia plays an important role in generating ventricular fibrillation, the lethal arrhythmia that leads to sudden cardiac death. It may occur immediately as a result of plaque rupture and occlusion of a critical vessel or after the onset of a myocardial infarction. Patients with a history of a myocardial infarction and myocardial damage are also predisposed to ventricular arrhythmias (primary ventricular fibrillation arrest).