Porth's Essentials of Pathophysiology, 4e

446

Circulatory Function

U N I T 5

network or plexus of subendocardial vessels. Although there are no connections between the large coro- nary arteries, there are anastomotic channels that join the small arteries. If larger vessels gradually become occluded, the smaller collateral vessels increase in size and provide alternative channels for blood flow. One of the reasons individuals with CAD may not experience any symptoms until the disease is advanced is due to the development of collateral channels occurring in concert with atherosclerotic changes (see Chapter 18). Physical, metabolic, and neural factors control blood flow in the coronary arteries. The openings for the coro- nary arteries originate in the root of the aorta just out- side the aortic valve. Thus, aortic blood pressure is the main factor controlling the perfusion pressure in the coronary arteries; aortic pressure is generated by the heart itself. Myocardial blood flow, in turn, is largely regulated by the metabolic activity of the myocardium and autoregulatory mechanisms that control vessel dila- tion. In addition to generating the aortic pressure that propels blood through the coronary vessels, the con- tracting heart muscle influences its own blood supply by compressing the intramyocardial and subendocardial blood vessels during systole. Coronary blood flow is regulated by oxygen demand of the cardiac muscle. Under resting conditions, the heart extracts and utilizes 60% to 80% of oxygen in the blood flowing through the coronary arteries, as compared with the 25% to 30% extracted by skeletal muscle. 4 There is little oxygen reserve in the blood, and therefore, the coronary arteries vasodilate to meet the metabolic needs of the myocardium during periods of increased activity. Metabolic activity is a major deter- minant of coronary blood flow. Numerous substances (i.e., metabolites), which include potassium ions, lactic acid, carbon dioxide, and adenosine, are released from working myocardial cells and mediate the vasodilation that accompanies increased cardiac work. Of these sub- stances, adenosine has the greatest vasodilator effect and is perhaps the most critical mediator of local blood flow in coronary circulation. 4 Endothelial cells, which make up the inner lining of all blood vessels including the coronary arteries, play an active role in the control of blood flow. These cells function as a selectively permeable barrier, which allows for the movement of small and large molecules from the blood to the tissues and also from the tissues to the blood. In addition, endothelial cells synthesize and release substances that affect relaxation or constriction of the vascular smooth muscle cells in the arterial wall. Potent vasodilators produced by the endothelium include nitric oxide (NO), prostacyclin, and endothe- lium-dependent hyperpolarizing factor (EDHF). The most important of these is nitric oxide. Most vasodi- lating stimuli exert their effects through nitric oxide pathways. 7,8 The endothelium also is the source of endo- thelium-dependent constricting factors, the best known of which are the endothelins. Coagulation factors (e.g., thrombin), inflammatory mediators (e.g., histamine), and mechanical factors (e.g., increased shear force exerted on the vessel wall) and ischemia contribute to

flow-mediated vasodilation, and stimulate the synthesis and release of nitric oxide. 5

Pathogenesis of Coronary Artery Disease The most common cause of CAD is atherosclerosis (dis- cussed in Chapter 18). Atherosclerosis may affect one or all three of the major epicardial coronary arteries and their branches. Clinically significant lesions may be located anywhere in these vessels, but tend to predomi- nate in the first several centimeters of the left anterior descending and left circumflex artery or along the entire length of the right coronary artery. 6 In some cases the major secondary branches also are involved. Coronary heart disease is commonly divided into two broad disorders: acute coronary syndromes and chronic ischemic heart disease. The acute coronary syndromes represent a spectrum ranging from unstable angina to myocardial infarction that is caused by acute plaque dis- ruption, whereas chronic ischemic heart disease is caused by atherosclerosis or vasospasm of the coronary arteries. Plaque Disruption andThrombus Formation There are two types of atherosclerotic lesions: (1) the fixed or stable plaque , which obstructs blood flow, and (2) the vulnerable or unstable plaque, which can rup- ture, activating a cascade of events leading to thrombus formation. The fixed or stable plaque is commonly associated with stable angina, and the unstable plaque is impli- cated in unstable angina and myocardial infarction (MI). In most cases the myocardial ischemia underlying unstable angina and acute MI is precipitated by plaque disruption, followed by thrombosis. The major deter- minants of plaque vulnerability to disruption include the size of its lipid-rich core, lack of stabilizing smooth muscle cells, presence of inflammation with plaque deg- radation, and stability and thickness of its fibrous cap 6,9 (Fig. 19-2). Plaques with a thin fibrous cap overlying a large lipid core are at high risk for rupture. 10 Although plaque disruption may occur spontane- ously, this event is often triggered by hemodynamic factors, such as blood flow characteristics and vessel tension. For example, an elevated risk for plaque dis- ruption may result from physiologic events including increased sympathetic activity elicited by rising blood pressure, heart rate, or cardiac contractility. 6 Plaque disruption is also associated with diurnal variation, which commonly occurs within an hour of rising. This phenomenon suggests that physiologic factors (e.g., coronary artery tone and blood pressure) may promote atherosclerotic plaque disruption and subsequent plate- let deposition. 6 The elevated sympathetic activity associ- ated with wakefulness and being active may promote platelet aggregation and fibrinolytic activity that favor plaque disruption and thrombosis. Local thrombosis occurring after plaque disruption results from a complex interaction among the contents