Pathobiology of Atherosclerosis and Therapeutic Targets

Atherosclerosis is a systemic disease of the aorta, coronary, carotid, and peripheral arteries in response to endothelial injury by one or more risk factors (e.g., hypertension, oxidized LDL, tobacco, homocysteine, infection). The earliest lesions, fatty streaks, can be found in children and young men and women who die of noncardiac causes. Diffuse nonocclusive coronary plaque has been found in 25% to 50% of young adult men postmortem. The amount of fatty streak and plaque correlates with the prevalence of classic coronary risk factors even in children. The duration of exposure to risk factors (age) and genetics (family history of premature disease) are major determinants of how and when clinical manifestations may occur.

Atherosclerosis is primarily an inflammatory response to injury. At least six major processes occur in the development of atherosclerotic plaques (atheroma). Each is a potential therapeutic target that can be influenced by drugs, particularly the statin family of lipid-lowering drugs:

Histological evidence suggests that plaque growth may be gradual over years, with bursts of growth from periodic intraplaque hemorrhage and repair. Gradual buildup of plaque over decades can lead to the gradual narrowing of coronary and other conduit arteries (carotid, femoral, popliteal), and, alternatively, can rupture, leading to sudden occlusion, resulting in an acute ischemic syndrome (unstable angina, myocardial infarction, stroke, death, critical limb ischemia). Fibrous plaques are prevalent in the 4th and 5th decades of life, and symptoms (angina, claudication) from occlusive plaques peak in the 7th decade. Ruptures and fissures of plaques, which can lead to sudden occlusion with a superimposed thrombus resulting in acute ischemic events, occur predominantly in nonocclusive lesions. The prevalence of acute coronary syndromes in healthy men and women increases with age, from very rare in the 30s to more than 1% in men over 60 years and women over 70 years of age.

The type of plaque is a major determinant for risk of acute coronary events. Angina pectoris and claudication are usually caused by flow-limiting partially occlusive coronary or peripheral artery stenosis (>50% to 70%). The latter are composed of fibrocalcific plaques abundant in smooth muscle and fibrous tissue with or without a lipid core. Most people with hemodynamically significant stenosis remain asymptomatic until an acute event occurs. Most acute coronary events are the result of an occluding or partially occluding thrombus at the site of rupture of the fibrous cap in a nonocclusive (20% to 75%) coronary segment or intraplaque hemorrhage.

Most heart attacks and sudden cardiac deaths occur in persons without a history of angina or previous symptoms. Intraplaque hemorrhage from weakening of the walls of the vasa vasorum (small adventitial arteries supplying arteries with O₂ and nutrients) can lead to plaque progression and sudden occlusion. Characteristics of vulnerable plaques include:

The endothelium, or luminal layer of cells of the arterial wall, provides a protective barrier and produces a wide variety of substances involved in regulating vascular tone, thrombosis, and cellular adhesion, migration, and growth. Coronary risk factors, including age, elevated LDL-C, low HDL-C, smoking, hypertension, and diabetes are associated with impaired endothelial function. Nitric oxide and prostacyclin are released in response to shear stress and autonomic tone. Each is a vasodilator with antithrombotic, antiplatelet, and antioxidant functions. Formation and release of prostacyclin and nitric oxide by the endothelium is impaired after a high-fat diet and in all stages of atherosclerosis in coronary and conduit vessels with or without plaque.

Lipid-lowering therapy can improve endothelial function, reduce coronary events and strokes, relieve symptoms, prevent new plaque formation, reduce rate of progression, and even induce regression of focal narrowing. Raising HDL-C enhances endothelial function and results in removal of cholesterol from cells and lipid pools, known as reverse cholesterol transport. In established coronary heart disease and for primary prevention, serum lipids are one of many interactive risk factors requiring lifestyle changes and drug therapy (see Fig. 25-1). Aspirin and other platelet antagonists (see Chapter 26) reduce risks of acute coronary syndrome and strokes by reducing thrombosis. Antihypertensive strategies (see Chapter 20) reduce wall stress and plaque rupture by various mechanisms.

Therapeutic uses of lipid-lowering drugs are summarized in the Therapeutic Overview Box.

Cholesterol Balance

The dynamics of cholesterol ingestion, synthesis, and elimination are depicted in Figure 25-2. The sole sources of exogenous cholesterol are ingested animal-based food substances, including meats and dairy products. Dietary intake can vary from 0 to 1000 mg/day, with 30% to 75% typically absorbed.

FIGURE 25–2 Total body balance of cholesterol, showing input by ingestion and liver synthesis, output by nonabsorption into feces, conversion into bile salts, delivery in bile salts to small intestine, partial reabsorption from bile, and delivery as lipoproteins into systemic circulation. Quantities shown are approximate daily amounts.

Although cholesterol can be synthesized de novo in most cells, its main endogenous sources are the adrenals and liver. Because of the greater liver mass, hepatic synthesis is a major source of cholesterol. The normal rate of endogenous cholesterol synthesis varies from 600 to 1000 mg/day, with approximately 750 to 1250 mg secreted daily in bile. One half to two thirds of biliary cholesterol is reabsorbed, and the remainder is excreted in the stool. Total body cholesterol is estimated to be in excess of 125 g, of which greater than 90% is in cell membranes.

Synthesis of cholesterol originates with a reaction between acetyl coenyzmeA (acetyl-CoA), a key intermediate for glycolysis, the citric acid cycle, and fatty acid degradation, and acetoacetyl-CoA to produce HMG-CoA. The next step is rate-limiting for cholesterol synthesis and involves the irreversible conversion of HMG-CoA to mevalonic acid (Fig. 25-3). The rate of this reaction is influenced by several factors, including time of day (predominantly at night), diet composition, excessive food intake, or obesity. Diets rich in saturated fats increase serum cholesterol primarily by down regulating hepatic clearance, whereas a diet of predominantly unsaturated fats or carbohydrates is generally associated with lower serum cholesterol. In addition, many other factors affect the rate of cholesterol synthesis, including a dynamic equilibrium with certain lipoproteins.

FIGURE 25–3 Sequence for in vivo synthesis of cholesterol from acetyl-CoA.

The liver is the primary organ for cholesterol uptake and degradation. Most cholesterol is converted to bile acids, which are secreted into the intestine to emulsify ingested fats, and are then reabsorbed and recycled. The total bile pool mass is estimated to be 2 to 3 g and is recycled approximately six times per day. Approximately half the cholesterol secreted in bile is reabsorbed, and the remainder is excreted. Rapid recycling normally limits the need for rapid synthesis of bile acids. Cholesterol is also secreted in bile as free cholesterol, which is fairly insoluble, requiring large amounts of bile. The enhanced synthesis and increased excretion of cholesterol in bile is a likely cause of cholesterol-containing gallstones in obese patients.

Lipoproteins and Lipids

Cholesterol, triglycerides, and phospholipids are transported in plasma and other fluids as lipoproteins, which have a lipid core encased in a protein coat. Triglycerides are assembled in the liver from fatty acids and glycerol. The largest plasma lipoprotein is the chylomicron, composed of triglyceride:cholesterol in 10:1 ratio. The shell is composed of phospholipid, cholesterol, and several apolipoproteins (Apo). Chylomicrons are usually present only after eating, especially a meal with a high fat content, but may be present in fasting persons with inadequate chylomicron metabolism. They are synthesized in the intestine, and their principal role is to transport dietary fats to adipose tissue, muscle, and liver. The apolipoproteins associated with chylomicrons in the intestine are ApoB-48 and ApoA-I (Fig. 25-4). After chylomicrons have been secreted and enter the plasma, they acquire ApoE, ApoC-I, ApoC-II, and ApoC-III. ApoC-II is critical and acts with insulin to activate lipoprotein lipase in the capillary wall, liberating free fatty acids and glycerol from released triglycerides. The chylomicron remnants, containing ApoA, ApoB, and ApoE, but having lost ApoC-II and ApoC-III, continue to circulate and are eventually removed by specific hepatic remnant receptors. This is the principal route by which dietary fat is transported and is referred to as the exogenous pathway. Fasting chylomicronemia resulting from inherited or acquired deficiency of lipoprotein lipase is usually associated with triglyceride levels greater than 2000 mg/dL, which may result in life-threatening pancreatitis.

FIGURE 25–4 Lipoprotein metabolism depicting: (1) the exogenous pathway where ingested free fatty acids are converted to triglycerides, combined with ApoB-48, and covered by phospholipid to form chylomicrons in intestinal lymph; and (2) the endogenous pathway where triglycerides synthesized in the liver combine with ApoB-100 to form VLDLs in the liver. Both chylomicrons and VLDLs acquire ApoC from HDLs. ApoC serves as a cofactor to activate lipoprotein lipase in the vascular epithelium, delivering fatty acids to target tissues such as fat and muscle. HDLs recover ApoC for reuse as the chylomicrons and VLDLs are metabolized. Remnant particles are removed by the liver and secreted as LDLs, which contain cholesterol ester as their predominant component.

The endogenous formation and transport of triglycerides is accomplished by very-low-density lipoprotein (VLDL) particles (see Fig. 25-4). Synthesized principally by the liver and to a lesser extent by the intestine, these particles are much smaller than chylomicrons. In contrast to chylomicrons, triglycerides in VLDL are obtained from fatty acids synthesized by the liver or released by adipose tissue and circulate to the liver. In addition to cholesterol and phospholipid, the wall of VLDL particles contains ApoB-100, ApoE, and ApoC-I, ApoC-II, and ApoC-III, the latter obtained from HDL. The internal composition is 5:1, triglyceride:cholesterol. ApoC-II on the VLDL surface results in lipoprotein lipase activation, releasing free fatty acids to muscle and adipose tissues and resulting in smaller, increasingly dense intermediate-density lipoprotein (IDL) particles. The surface ApoE on these VLDL remnants results in clearance of some particles via the same hepatic remnant receptors that bind chylomicron remnants.

Other IDL particles continue to lose triglycerides via lipoprotein lipase and hepatic lipase, resulting in contracted particles known as LDLs, which are approximately 2% the size of VLDL particles and 0.02% the volume of a chylomicron. LDL particles contain 50% to 60% cholesterol and less than 10% triglyceride and have one molecule of ApoB-100 on their surface. LDL particles vary in density and size. The small, dense particles are usually found in association with higher levels of serum triglycerides, are highly atherogenic because they readily cross the endothelial barrier, are more easily oxidized, and are more readily taken up by scavenger receptors. Atherogenicity is related to both LDL particle number and size. Every 1% increase in LDL-C increases the rate of coronary events by approximately 2%. In addition, both VLDL remnants and IDL particles have been found in atheroma. Lipoprotein(a) [Lp(a)] is a small particle formed in the liver, the size of LDL particles, containing Apo(a) linked to ApoB-100. Apo(a) has a homology with plasminogen, resulting in competition for plasminogen receptors and decreasing thrombolysis.

The LDL surface protein ApoB-100 is recognized by LDL receptors located in pits on membranes of hepatocytes and other cells. When LDL particles bind, they and their receptors are endocytosed, and the LDL particle is incorporated into lysosomes and separated from its receptor, which is recycled. The coating of the particle is removed, and esterified cholesterol is hydrolyzed and released. The released cholesterol has three major effects on its own metabolism:

The HDL lipoprotein particle