68 WHAT IS ATHEROSCLEROSIS?
Craig H. Selzman M.D.

1. Are elderly individuals the only ones who have atherosclerosis?

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No. The initial (or type I) lesion, consisting of lipid deposits in the intima, has been well characterized in infants and children.

2. What is a fatty streak?

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Fatty streaks or type II lesions are visible as yellow-colored streaks, patches, or spots on the intimal surface of arteries. Microscopically, they are characterized by the intracellular accumulation of lipid.

3. What is a foam cell?

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A foam cell is any cell that has ingested lipids, thus giving the histologic appearance of a sudsy vacuole. In general, a foam cell refers to a lipid-laden macrophage; however, other cells that uptake lipids, particularly vascular smooth muscle cells, also may be considered foam cells.

4. Describe the progression of atherosclerosis.

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Although the sequence of events is not always consistent, fatty streaks progress to type III or intermediate lesions. This growth is characterized by extracellular pools of lipid, which are generally clinically occult. However, when the pools coalesce to create a core of extracellular lipid (type IV lesion or atheroma), the blood vessel architecture has been altered sufficiently to become clinically overt. With smooth muscle cell (SMC) proliferation and collagen deposition, the atheroma becomes a fibroatheroma (type V). The fibroatheroma is characterized by thrombogenic surface defects that provoke intramural hemorrhage or intraluminal thrombus (type V lesion), resulting in vessel occlusion, which, in the case of a coronary artery, results in myocardial infarction.

5. Of the 100 medical students in your class, how many have significant atherosclerosis?

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In 1953, Enos reported autopsy findings from 300 American male battle casualties in Korea (average age, 22 years). He noted that 77% of the hearts had some gross evidence of coronary atherosclerosis. About 39% of the men had luminal narrowing, estimated at 10-90%, and 3% had plaques causing complete occlusion of one or more coronary vessels. However, a subsequent study evaluating 105 combat casualties in Vietnam demonstrated that only 45% exhibited atherosclerosis, and fewer than 5% were considered severe. Finally, a recent study looking at 105 trauma victims corroborated the Korean War study by demonstrating a 78% incidence of atherosclerosis, with left main or significant two- and three-vessel involvement in 20%.

6. What are the classic risk factors for atherosclerotic cardiovascular disease?

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Tobacco use, hyperlipidemia, hypertension, diabetes mellitus, and family history of cardiovascular disease.

7. How do such diverse risk factors produce similar disease?

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That is the million-dollar question. Do parallel pathways lead to a final atherosclerotic lesion, or do the apparently dissimilar risk factors activate signals that converge to a few dominant events, promoting the development of atherosclerosis? Certainly, this question has broad therapeutic implications. It would be a lot easier to inhibit a single proximal point in this process rather than to treat multiple divergent, more distal cellular pathologic events.

8. What is the response to injury?

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The premise that atherogenesis represents an exaggerated inflammatory, fibroproliferative response to injury has evolved into an attractive unifying hypothesis of vascular disease and repair. Mechanical, metabolic, and toxic insults may injure the vessel wall. The common denominator is endothelial injury. Disruption of the endothelium not only results in endothelial cell dysfunction but also allows adhesion and transmigration of circulating monocytes, platelets, and T lymphocytes. Within the developing lesion, the activated cells release potent growth-regulatory molecules that may act in both a paracrine and autocrine manner. Under the influence of cytokines and growth factors, vascular smooth muscle cells (VSMCs) adapt to a synthetic phenotype and begin proliferation and migration across the internal elastic lamina into the intimal layer. Stimulated VSMCs allow the deposition of extracellular matrix, thus converting the initial lesion to a fibrous plaque.

9. What is C-reactive protein? Is it just another random, nonclinically relevant marker of inflammation?

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C-reactive protein (CRP) is one of many acute phase proteins elaborated from hepatocytes upon inflammatory stimulation. Originally isolated from the serum of patients with pneumonia, it has a high binding affinity for pneumococcal C-polysaccharide. Although CRP is best known as an active peptide by neutralizing foreign antigens, controlling tissue damage, and promoting tissue repair, it is increasingly considered a sensitive marker of inflammation.
Unlike other markers of inflammation, CRP levels are stable over long periods of time, have no diurnal variation, can be measured inexpensively with available high-sensitivity assays, and have shown specificity in predicting risk of cardiovascular events. Indeed, elevation of CRP levels might be more predictive of cardiac events than elevation of low-density lipoprotein (LDL) levels. These observations may influence therapy because nonhyperlipidemic patients with elevated CRP levels might benefit from aggressive statin (HMG-reductase inhibitors) therapy.

10. Does vascular injury mean only direct physical injury, as with an angioplasty catheter?

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No. Injury is a catch-all word that includes physical injury such as angioplasty, hypertension, and shear forces (atherosclerotic lesions typically occur at bifurcations) as well as other diverse insults, including viruses, bacteria, nicotine, homocysteine, and oxidized LDLs.

11. Are lipids important?

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The lipid hypothesis of atherosclerosis suggests that the cellular changes in atherosclerosis are reactive events in response to lipid infiltration. Indeed, antilipid therapy is one of the few strategies that has induced regression of atherosclerosis in randomized, prospective clinical trials. Strong evidence also derives from patients with genetic hyperlipidemias; homozygotes rarely live beyond age 26 years.

12. What is syndrome X?

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Syndrome X is a metabolic phenomenon in healthy, nonobese, nondiabetic people who have hyperinsulinemia associated with elevated blood sugar, high blood pressure, and increased triglycerides with decreased high-density lipoprotein (HDL) cholesterol levels. Clinically, such patients develop premature cardiovascular disease. Insulin resistance with elevated insulin levels, with or without overt diabetes, fuels important aspects of atherogenesis, including dyslipidemias, endothelial dysfunction, hypertension, and SMC proliferation.

13. Why would vitamin E be (even theoretically) protective against cardiovascular disease?

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Antioxidant therapy with vitamins C and E as well as beta-carotene is intuitively sound. In vitro, these agents afford resistance of LDL to oxidation and reduce elaboration of vessel-injuring reactive oxygen species. Reactive oxygen metabolites (as much as 5% of oxygen), such as superoxide and hydrogen peroxide, directly injure vascular cells, impair endothelial vasomotor function, promote platelet aggregation and leukocyte adhesion, and stimulate vascular SMC proliferation. Although descriptive, case-control, and prospective cohort studies have found inverse associations between the frequency of coronary artery disease and dietary intake of antioxidant vitamins, randomized therapeutic trials thus far have exhibited no benefit of doing so.

14. What is homocysteine?

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This amino acid intermediate in the metabolism of methionine is an essential amino acid in the synthesis of both animal and plant proteins. Excessive homocysteine in the vessel wall reacts with LDPs to create damaging reactive oxygen species. Epidemiologic evidence correlates elevated levels of homocysteine and decreased levels of folate with cardiovascular disease.

15. How does homocysteine rank as a risk factor for atherosclerosis?

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It is estimated that 10% of the risk of coronary artery disease in the general population is attributable to homocysteine. An increase in 5 μmol/L in plasma homocysteine concentration (normal, 5-15 μmol/L) raises the risk of coronary disease by as much as an increase of 20 mg/dL in the cholesterol concentration.

16. Should everyone take folate supplements?

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Folic acid, vitamins B12 and B6, and pyridoxine are important cofactors for the enzymatic processing of homocysteine. Indeed, the reduction in mortality from cardiovascular causes since 1960 has been correlated with the increase in vitamin B6 supplementation in the food supply. Furthermore, the Food and Drug Administration recently mandated folic acid fortification in flour and cereal products as a method of preventing atherosclerotic-related death. Although these supplements may decrease homocysteine levels, the expected decrease in cardiovascular events has not yet been documented in prospective, randomized clinical trials.

17. What microorganisms have been implicated in atherosclerosis?

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Bacteria include Chlamydia pneumoniae, Helicobacter pylori, streptococci, and B. typhosus. Viruses include influenza, herpes virus, adenovirus, and cytomegalovirus.

KEY POINTS: ATHEROSCLEROSIS

1. The classic risk factors for atherosclerotic cardiovascular disease include tobacco use, hyperlipidemia, hypertension, diabetes mellitus, and family history of cardiovascular disease.
2. It is estimated that 10% of the coronary artery disease in the general population is attributable to homocysteine.
3. The bacteria implicated in atherosclerosis include Chlamydia pneumoniae, Heliobacter pylori, streptococci, and B. typhosus.

18. Are individuals with sexually transmitted diseases (STDs) at greater risk for cardiovascular disease? Show answer

The initial epidemiologic description linking Chlamydia species to atherosclerosis was reported by venerologists in South America in the 1940s. Chlamydia pneumoniae, a ubiquitous respiratory organism, is the predominant species subsequently identified in cardiovascular lesions. More than 50% of the population has antichlamydial antibodies (ACAs) by age 50 years; yet this 50% of the population does not have this STD.

19. Is there an Helicobacter pylori peptic ulcer equivalent in atherosclerosis? Should we all take a macrolide a day?

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The jury is still out. It is unlikely that eradication of Chlamydia species will have the same profound effect on disease as eradication of H. pylori. However, C. pneumoniae may be another factor, exacerbating the response to injury. Evidence suggests that antibiotic therapy decreases the number of cardiovascular events in patients with elevated antichlamydial antibody titers.

20. What is the role of the endothelium?

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A healthy blood vessel wall is lined by a monolayer of phenomenally metabolically active endothelial cells. The surface area of the endothelium is approximately 5000 m2 but comprises only 1% of the total body weight. While acting as a physical barrier to protect the underlying vessel and allowing formed blood elements to flow freely, thus preventing thrombosis, this seemingly bucolic layer is a central control center of vascular physiology. The endothelium is a key docking point for monocytes, neutrophils, and lymphocytes by virtue of its ability to express sticky, cell-specific adhesion molecules. The endothelium is a source for cytokines and peptide growth factors that act in both autocrine and paracrine fashion to promote atherogenesis.

21. What are some of the products of endothelial cells that govern vasomotor tone?

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Factors that favor vascular relaxation include nitric oxide and prostacyclin. Conversely, factors favoring vascular constriction include thromboxane, leukotrienes, free radicals, endothelins, and cytokines (e.g., tumor necrosis factor and interleukin-1).

22. What is the importance of vascular thrombosis?

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Thrombosis is central to the pathogenesis of acute arterial insufficiency and acute coronary or cerebrovascular syndromes, including unstable angina, non-Q-wave myocardial infarction, acute (ST-elevation) myocardial infarction, and vessel occlusion after vascular intervention (angioplasty).

23. Describe the three main phases of platelet activation involved with thrombus formation.

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The three main phases of platelet activation include adhesion, aggregation, and secretion. With exposure of the subendothelial space after vascular injury, platelets adhere to basement membrane proteins, especially collagen. This adhesion depends on binding of endothelial or circulating von Willebrand factor (vWF) to the platelet membrane glycoprotein 1b receptor. Platelet aggregation is an energy-dependent process that requires adenosine triphosphate (ATP). The predominant mechanism of aggregation involves binding of fibrinogen to the platelet glycoprotein IIb/IIIa receptor. Platelet secretion usually follows aggregation. Released products include the contents of dense bodies (serotonin, calcium, ATP) and alpha granules (vWF, fibrinogen, growth factors, platelet factor 4, and coagulation factors).

24. Is atherosclerosis an inflammatory disease?

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Yes.

25. Would taking an aspirin a day help?

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Maybe. Strategies aimed at limiting the inflammatory cascade offer promise as antiatherosclerosis therapy. Examples in daily use include aspirin, fibrinolytics, 3-hydroxyl-3-methylglutaryl (HMG)-reductase inhibitors, and estrogens. Others in the preclinical arena include gene therapy, anticytokine therapy, and antigrowth factor therapy. Certainly, primary prevention is important in limiting the initial injury stimulus. However, the smoldering inflammation involved with atherosclerosis may best be attacked by modifying the vascular cells’ response to these insults.

References
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BIBLIOGRAPHY
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