Epicardial coronary arteries are the major site of atherosclerotic disease. The major risk factors for atherosclerosis [high plasma low-density lipoprotein (LDL), low plasma high-density lipoprotein (HDL), cigarette smoking, hypertension, and diabetes mellitus] (Chap. 235) disturb the normal functions of the vascular endothelium. These functions include local control of vascular tone, maintenance of an antithrombotic surface, and impairment of inflammatory cell adhesion and diapedesis. The loss of these defenses leads to inappropriate constriction, luminal thrombus formation, and abnormal interactions with blood leukocytes, especially monocytes, and platelets. Monocyte interaction ultimately results in the subintimal collections of fat, smooth-muscle cells, fibroblasts, and intercellular matrix (i.e., atherosclerotic plaques), which develop at irregular rates in different segments of the epicardial coronary tree and lead eventually to segmental reductions in cross-sectional area.
There is also a predilection for atherosclerotic plaques to develop at sites of increased turbulence in coronary flow, such as at branch points in the epicardial arteries. When a stenosis reduces the diameter of an epicardial artery by 50%, there is a limitation on the ability to increase flow to meet increased myocardial demand. When the diameter is reduced by ~80%, blood flow at rest may be reduced, and further minor decreases in the stenotic orifice area can reduce coronary flow dramatically and cause myocardial ischemia.
Segmental atherosclerotic narrowing of epicardial coronary arteries is caused most commonly by the formation of a plaque, which is subject to rupture or erosion of the cap separating the plaque from the bloodstream. Upon exposure of the plaque contents to blood, two important and interrelated processes are set in motion: (1) platelets are activated and aggregate; and (2) the coagulation cascade is activated, leading to deposition of fibrin strands. A thrombus composed of platelet aggregates and fibrin strands traps red blood cells and can reduce coronary blood flow, leading to the clinical manifestations of myocardial ischemia.
The location of the obstruction influences the quantity of myocardium rendered ischemic and determines the severity of the clinical manifestations. Thus, critical obstructions in vessels, such as the left main coronary artery or the proximal left anterior descending coronary artery, are particularly hazardous. Severe coronary narrowing and myocardial ischemia are frequently accompanied by the development of collateral vessels, especially when the narrowing develops gradually. When well developed, such vessels can, by themselves, provide sufficient blood flow to sustain the viability of the myocardium at rest but not during conditions of increased demand.
With progressive worsening of a proximal epicardial artery stenosis, the distal resistance vessels (when they function normally) dilate to reduce vascular resistance and maintain coronary blood flow. A pressure gradient develops across the proximal stenosis, and poststenotic pressure falls. When the resistance vessels are maximally dilated, myocardial blood flow becomes dependent on the pressure in the coronary artery distal to the obstruction. In these circumstances, ischemia, manifest clinically by angina or electrocardiographically by ST-segment deviation, can be precipitated by increases in myocardial oxygen demand caused by physical activity, emotional stress, and/or tachycardia. Changes in the caliber of the stenosed coronary artery due to physiologic vasomotion, loss of endothelial control of dilation (as occurs in diabetes mellitus), pathologic spasm (Prinzmetal's angina), or small platelet-rich plugs can also upset the critical balance between oxygen supply and demand and thereby precipitate myocardial ischemia.
Effects of Ischemia
During episodes of inadequate perfusion caused by coronary atherosclerosis, myocardial tissue oxygen tension falls and may cause transient disturbances of the mechanical, biochemical, and electrical functions of the myocardium. Coronary atherosclerosis is a focal process that usually causes nonuniform ischemia. Regional disturbances of ventricular contractility cause segmental akinesia or, in severe cases, bulging (dyskinesia), which can greatly reduce myocardial pump function.
The abrupt development of severe ischemia, as occurs with total or subtotal coronary occlusion, is associated with almost instantaneous failure of normal muscle contraction and relaxation. The relatively poor perfusion of the subendocardium causes more intense ischemia of this portion of the wall (compared with the subepicardial region). Ischemia of large portions of the ventricle causes transient LV failure, and if the papillary muscle apparatus is involved, mitral regurgitation can occur. When ischemia is transient, it may be associated with angina pectoris; when it is prolonged, it can lead to myocardial necrosis and scarring with or without the clinical picture of acute MI (Chap. 239).
A wide range of abnormalities in cell metabolism, function, and structure underlie these mechanical disturbances during ischemia. The normal myocardium metabolizes fatty acids and glucose to carbon dioxide and water. With severe oxygen deprivation, fatty acids cannot be oxidized, and glucose is degraded to lactate; intracellular pH is reduced, as are the myocardial stores of high-energy phosphates, i.e., ATP and creatine phosphate. Impaired cell membrane function leads to the leakage of potassium and the uptake of sodium by myocytes, as well as an increase in cytosolic calcium. The severity and duration of the imbalance between myocardial oxygen supply and demand determine whether the damage is reversible (
20 min for total occlusion in the absence of collaterals) or whether it is permanent, with subsequent myocardial necrosis (>20 min).
20 min for total occlusion in the absence of collaterals) or whether it is permanent, with subsequent myocardial necrosis (>20 min).Ischemia also causes characteristic changes in the electrocardiogram (ECG) such as repolarization abnormalities, as evidenced by inversion of T waves and, when more severe, by displacement of ST segments (Chap. 221). Transient T-wave inversion likely reflects nontransmural, intramyocardial ischemia; transient ST-segment depression often reflects subendocardial ischemia; and ST-segment elevation is thought to be caused by more severe transmural ischemia. Another important consequence of myocardial ischemia is electrical instability, which may lead to isolated ventricular premature beats or even ventricular tachycardia or ventricular fibrillation (Chap. 226). Most patients who die suddenly from IHD do so as a result of ischemia-induced ventricular tachyarrhythmias (Chap. 267).
Asymptomatic versus Symptomatic IHD
Postmortem studies on accident victims and military casualties in western countries have shown that coronary atherosclerosis often begins to develop prior to age 20 and is widespread even among adults who were asymptomatic during life. Exercise stress tests in asymptomatic persons may show evidence of silent myocardial ischemia, i.e., exercise-induced ECG changes not accompanied by angina pectoris; coronary angiographic studies of such persons may reveal coronary artery plaques and previously unrecognized obstructions (Chap. 223). Postmortem examination of patients with such obstructions without a history of clinical manifestations of myocardial ischemia often shows macroscopic scars secondary to MI in regions supplied by diseased coronary arteries, with or without collateral circulation. According to population studies, ~25% of patients who survive acute MI may not come to medical attention, and these patients carry the same adverse prognosis as those who present with the classic clinical picture of acute MI (Chap. 239). Sudden death may be unheralded and is a common presenting manifestation of IHD (Chap. 267).
Patients with IHD can also present with cardiomegaly and heart failure secondary to ischemic damage of the LV myocardium that may have caused no symptoms prior to the development of heart failure; this condition is referred to as ischemic cardiomyopathy. In contrast to the asymptomatic phase of IHD, the symptomatic phase is characterized by chest discomfort due to either angina pectoris or acute MI (Chap. 239). Having entered the symptomatic phase, the patient may exhibit a stable or progressive course, revert to the asymptomatic stage, or die suddenly.
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