Knowledge about mechanisms of plaque formation in the coronary arteries has rapidly accumulated in recent years. Epidemiologic studies reported in the 1960s suggested associations among certain traits and habits and the development of CHD. More recent studies have confirmed and expanded on these risk factors, which include several major risks (e.g., age, family history, abnormal lipid levels, cigarette smoking, hypertension, diabetes, and obesity) and numerous probable risks (Box 18-1).² Although males and females succumb to heart disease in equal numbers, male gender is a risk factor for earlier development of heart disease, on average about 10 years earlier. The risk factors for CHD are the same as those for atherosclerosis in other arteries and are discussed in Chapter 15.

The observation that atherosclerotic plaque is composed primarily of lipid prompted the idea that abnormal lipid metabolism was a probable culprit in the development of CHD, and a great deal of attention has been focused on therapies to reduce levels of serum cholesterol in individuals with dyslipidemia. Lipids are transported through the bloodstream in combination with specific proteins (apoproteins). Certain lipid-protein molecules (lipoproteins) are associated with a greater risk of atherosclerosis. The five major kinds of lipoproteins are shown in Figure 18-1. High levels of low-density lipoproteins (LDLs), which are high in cholesterol, have been associated with the highest risk. Very-low-density lipoproteins, which have large amounts of triglycerides, also appear to increase the risk. High-density lipoproteins, on the other hand, have been correlated with a decreased risk of atherosclerosis.²

High-density lipoproteins are thought to transport cholesterol from the peripheral tissues back to the liver, thus removing atheromatous plaque. The role of low-density and, indirectly, very-low-density lipoproteins is to transport cholesterol to the peripheral tissues (Figure 18-2). Cholesterol uptake by peripheral cells is mediated by LDL receptors on cell surfaces that bind and promote endocytosis of cholesterol. The liver normally binds and internalizes about 75% of the circulating LDL cholesterol.

Extreme cases of hyperlipidemia occur in individuals who have genetic derangements in lipid metabolism. These disorders run in families, and some are associated with the development of severe coronary atherosclerosis at a young age unless aggressively managed. The most common form of genetic hyperlipidemia (familial hypercholesterolemia) is associated with a defect in the LDL receptor on liver cells.3 Inability of the liver to efficiently remove cholesterol from the bloodstream results in hyperlipidemia. Genetic disorders of lipid metabolism are described in Table 18-1. Even when lipid metabolism is normal, a high-fat diet can overwhelm the liver’s ability to clear LDL cholesterol from the circulation and results in hyperlipidemia. Dietary fat restriction may be beneficial in reducing cholesterol level in this case.

Atherosclerotic plaque formation is initiated by injury to the coronary artery endothelium. The specific cause of endothelial dysfunction in the early stage of atherosclerosis is uncertain; however, several potential mechanisms have been described. These include chronic hemodynamic wall stress, which may explain the typical localization of plaques at arterial branch points and the role of hypertension as a risk factor; toxins from cigarette smoke; circulating inflammatory cytokines; and hyperlipidemia. Once the injury occurs, the endothelium may become more permeable and recruit leukocytes (Figure 18-3). LDLs leak through the endothelium and into the vessel wall (insudation) where they are oxidized by endothelial cells and macrophages.⁴ Oxidized lipids are damaging to the endothelial and smooth muscle cells, and stimulate the recruitment of macrophages into the vessel wall, where they engulf the lipids. Lipid-filled macrophages are called foam cells. The macrophages and foam cells release inflammatory mediators and growth factors that attract more leukocytes and stimulate smooth muscle proliferation. Excess lipid and debris begins to accumulate within the vessel wall and to coalesce into a pool called the lipid core (Figure 18-4). Atherosclerotic plaques with large lipid cores are fragile and prone to rupture. Rupture of a plaque exposes subendothelial proteins and initiates platelet aggregation and thrombus formation. Thrombi may be asymptomatic if they are small and do not occlude the artery. Components of the thrombus may be incorporated into the plaque, causing it to enlarge. Older plaques have significant collagen and fibrin, which form a cap and tend to make the plaque more stable. Numerous therapies aimed at stabilizing vulnerable plaques and preventing thrombus formation have been studied in clinical trials. Lipid-lowering therapy is a mainstay of treatment and prevention for atherosclerosis. Targets for serum LDL cholesterol levels have been developed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (NCEP III) based on the presence of known CHD or risk factors (Table 18-2).⁵ An update to the NCEP III is expected in 2012. In addition to risk factor modification, therapies to reduce plaque inflammation, inhibit lipid oxidation, and prevent thrombosis are in common use (Table 18-3). A major aim of therapy is to stabilize the plaques, making them less prone to rupture.

Atherosclerotic coronary lesions have been characterized and attempts made to correlate the anatomic descriptions with plaque development and behavior. Typically atherosclerotic lesions begin as fatty streaks and progress to small regions of medial wall thickening with scattered macrophages at a young age. These lesions are considered to be precursor lesions and are not symptomatic.6 As the plaques acquire more free lipid within the arterial wall, they are more vulnerable to rupture, thrombus formation, and progressive plaque growth. These are considered to be advanced lesions and carry a significant risk of producing disruptions in coronary blood flow. Critical narrowing of the coronary lumen over time or sudden rupture of a plaque followed by thrombus formation causes the clinical syndromes of CHD, including angina, infarction, ischemic cardiomyopathy, and sudden cardiac arrest.

Stable plaques usually are asymptomatic or may be associated with exercise-induced angina pain (stable angina pectoris). However, plaques are vulnerable to rupture or erosion, which can initiate thrombus formation and acute coronary occlusion. A variety of factors have been identified as markers of increased plaque vulnerability. These factors include (1) active inflammation within the plaque; (2) a large lipid core with a thin cap; (3) endothelial denudation (erosion) with superficial platelet adherence; (4) fissured or ruptured cap; and (5) severe stenosis predisposing to high shear stress.⁷ Acute coronary syndrome (ACS), or unstable angina or MI, as well as sudden cardiac arrest, is nearly always associated with acute disruption of a vulnerable plaque. Because the types of plaques that are most vulnerable often do not significantly obstruct the lumen before they rupture, ACS frequently occurs in individuals whose disease had been asymptomatic. Patients with a high risk for or known presence of vulnerable plaques benefit from therapies such as lipid-lowering agents (to stabilize plaques) and antiplatelet agents (to prevent thrombosis).⁸

Myocardial workload depends on heart rate, preload, afterload, and contractility (see Chapter 17). An increase in any of these variables increases myocardial oxygen requirements and may precipitate ischemia. However, even conditions resulting in very high myocardial oxygen consumption will seldom lead to ischemia unless some underlying impairment in coronary perfusion is present.

One or more of the aforementioned mechanisms are operative in producing clinically significant myocardial ischemia resulting in the acute or chronic coronary syndromes. Advanced fibrous plaque is thought to produce intermittent ischemia when 75% or more of the arterial lumen is occluded.⁹ Because fibrous plaque progresses slowly over many years, the heart can develop alternative pathways for myocardial blood flow. This collateral circulation can preserve blood flow despite almost total occlusion of the coronary artery. Thus, stable fibrous plaque may produce no symptoms of ischemia unless the demand of the heart for oxygen is suddenly elevated, as occurs in exercise or stress. When the onset of ischemia is predictable with certain activities and subsides with rest, the patient is said to have a chronic coronary syndrome, called classic or stable angina pectoris.

ACS occurs when sudden obstruction of coronary blood flow results in acute myocardial ischemia. Acute obstruction is usually associated with the formation of a clot in the coronary artery at the site of a vulnerable plaque. Rupture of the plaque exposes a rough area composed of collagen and other molecules that are thrombogenic. A high fibrinogen level, as occurs in smokers, and enhanced platelet adhesiveness, as occurs in hyperlipidemia, may enhance the risk of thrombus formation. Clot formation begins with adherence of platelets to the ruptured plaque. The platelets that initially attach release chemicals that attract more platelets, which aggregate and form a plug. The coagulation cascade may also be initiated and result in the formation of a platelet-fibrin clot that may occlude the vessel or break loose and travel farther along the vessel. Chemicals released by activated platelets include several vasoactive products (e.g., serotonin, thromboxane) that may contribute to spasm of the coronary vessel, further reducing blood flow.

Thrombosis occurs suddenly and may partially or completely obstruct the artery and cause acute ischemia. The ACS may present as unstable angina, MI, or sudden cardiac arrest. Appreciation of the role thrombus formation plays in coronary obstruction has resulted in the prophylactic use of antithrombotics, such as aspirin. Research indicates that the long-term use of small doses of aspirin reduces mortality from ischemic heart disease.¹⁰

Vasospasm usually occurs in areas of atherosclerotic plaque, but is also proposed as a mechanism of ischemia in patients who have anginal signs and symptoms but no significant amount of fibrous plaque in the coronary arteries. Variant, or Prinzmetal, angina is the term applied to vasospasm-initiated anginal symptoms. The etiology of spasm in vessels having no significant atherosclerotic plaques is unclear, but usually responds promptly to vasodilating agents. Intense vasospasm can occur in response to certain drugs, such as cocaine.

As previously mentioned, endothelial cells are important regulators of vascular tone. They secrete variable amounts of constricting and relaxing factors to control tissue perfusion. This autoregulation of blood flow allows the microvasculature to dilate when the need for oxygen in a particular area is increased. Failure of endothelial cells to appropriately regulate flow is a potential mechanism of myocardial ischemia.¹¹ Endothelial cells can be damaged by circulating toxins from cigarette smoke, immune cells, and infectious agents. Inflammatory disorders that may alter endothelial cell function include lupus erythematosus, Kawasaki syndrome, and polyarteritis nodosa. The importance of inflammatory processes in the pathogenesis of CHD has been recognized, resulting in efforts to find markers (e.g., serum high-sensitivity C-reactive protein) and methods to reduce inflammation in those at risk.

Even if the coronary arteries and microcirculation are functioning properly, coronary perfusion may still be inadequate if perfusion pressure is low. Recall from Chapter 17 that coronary blood flow occurs primarily during diastole and depends on the driving pressure in the aorta. A fall in aortic blood pressure can significantly reduce coronary perfusion, particularly in vessels with high resistance to flow. Conditions such as shock, hemorrhage, and anesthesia may be associated with a decline in blood pressure, which decreases driving pressure and coronary perfusion and results in myocardial ischemia. However, the most common cause of cardiac ischemia is atherosclerotic coronary arteries.