Pathobiology of Atherosclerosis

Cholesterol

Experimental data have repeatedly shown a link between plasma cholesterol levels and the formation of atheromas. Pioneering work performed in Russia in the early 20th century showed that consumption by rabbits of a cholesterol-rich diet caused the formation of arterial lesions that shared features with human atheromas. By midcentury, application of the ultracentrifuge to the analysis of plasma proteins led to the recognition that various classes of lipoproteins transported cholesterol and other lipids through the aqueous medium of the blood. Multiple epidemiologic studies verified a link between one cholesterol-rich lipoprotein particle in particular, low-density lipoprotein (LDL), and risk for coronary heart disease (CHD). The characterization of familial hypercholesterolemia as a genetic disease provided further evidence linking LDL cholesterol levels with CHD. Heterozygotes for this condition had a markedly elevated risk for atherosclerotic disease. Individuals homozygous for familial hypercholesterolemia commonly develop CHD within the first decade of life.

The elucidation of the LDL-receptor pathway and findings that mutations in the LDL receptor cause familial hypercholesterolemia provided proof positive of LDL’s role in atherogenesis. Yet the cholesterol hypothesis of atherogenesis still encountered skepticism. Many critics—some lay people and some respected professionals—questioned aspects of the theory, pointing out that dietary cholesterol levels did not always correlate with cholesterolemia. The lack of proof that either dietary or drug intervention could modify outcomes dogged proponents of the cholesterol hypothesis of atherogenesis.

Ultimately, controlled clinical trials that lowered LDL by interventions including partial intestinal bypass, bile acid–binding resins, and statin drugs showed reductions in coronary events and vindicated the cholesterol hypothesis. In appropriately powered trials conducted with sufficiently potent agents, lipid lowering also reduced overall mortality. Yet the very success of these interventions suggested that there must be more to atherogenesis than cholesterol, because a majority of events still occurred despite increasingly aggressive control of LDL cholesterol levels. The identification of proprotein convertase subtilisin/kexin type 9 (PCSK9) as the gene involved in autosomal dominant hypercholesterolemia has furnished new insight in this regard. Reduced function of this enzyme raises cellular LDL receptor numbers and hence augments LDL clearance, leading to lower plasma LDL levels. Individuals with reduced function variants of PCSK9 who experience lifelong lower exposure to LDL show protection from atherosclerotic events even in the presence of other cardiovascular risk factors. These observations strengthen the case for the involvement of LDL in atherogenesis and for the aggressive management of LDL in practice.

Of course aspects of the lipoprotein profile other than LDL can influence atherogenesis (see later). Yet as atherosclerotic events commonly occur in individuals with average levels of the major lipoprotein classes, a full understanding of atherogenesis requires consideration of factors other than blood lipids.

Systemic arterial hypertension

The relationship between arterial blood pressure and mortality emerged early from actuarial studies. Insurance underwriters had a major financial stake in mortality prediction. A simple measurement of blood pressure with a cuff sphygmomanometer powerfully predicted longevity. Data emerging from the Framingham Study and other observational cohorts verified a relationship between systemic arterial pressure and CHD events. Concordant observations from experimental animals and epidemiologic studies bolstered the link between hypertension and atherosclerosis.

As in the case of high cholesterol, clinical evidence that the pharmacologic reduction of blood pressure could reduce CHD events proved fairly elusive. Early intervention studies readily showed decreases in stroke and congestive heart failure endpoints following the administration of antihypertensive drugs. Studies indicating clear-cut reductions in CHD events with antihypertensive treatment have accumulated much more recently.

Mechanistically, antihypertensive drug therapy likely benefits atherosclerosis and its complications principally by lowering blood pressure, although some have posited other beneficial actions of various antihypertensive agents. A large randomized clinical trial, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), showed no advantage over a 5-year period over a thiazide diuretic of an angiotensin receptor blocker, a calcium channel antagonist, or a β-adrenergic blocking agent. Recent studies affirm the benefits of antihypertensive therapy in reducing the risk of atherosclerosis.

Clinical observations provide strong additional support for the concept that hypertension itself can promote atherogenesis. Atherosclerosis of the pulmonary arteries seldom occurs in individuals with normal pulmonary artery pressures, but even in relatively young patients with pulmonary hypertension, pulmonary artery atheromas occur quite commonly. This “experiment of nature” supports the direct proatherogenic effect of hypertension in humans.

Cigarette smoking

Tobacco abuse, and cigarette smoking in particular, accentuates the risk of cardiovascular events. In the context of noncoronary artery disease, cigarette smoking appears particularly important. The rapid return toward baseline rates of cardiovascular events after smoking cessation suggests that tobacco use alters the risk of thrombosis as much or more than it may accentuate atherogenesis per se. Classic studies in nonhuman primates have shown little effect of 2 to 3 years of cigarette smoke inhalation on experimental atherosclerosis in the presence of moderate hyperlipidemia.

Smoking has many adverse systemic effects, including eliciting the chronic inflammatory response implicated in atherothrombosis. Cigarette smoking seems to contribute particularly to the formation of abdominal aortic aneurysms. The mechanistic link between cigarette smoking and arterial aneurysm formation may resemble that invoked in the pathogenesis of smoking-related emphysema. Studies in genetically altered mice that inhale tobacco smoke have delineated a role for elastolytic enzymes such as matrix metalloproteinase (MMP)-12 in the destruction of lung extracellular matrix. Smoke-induced inflammation appears to release tumor necrosis factor-α (TNF-α) from macrophages, which can elevate the activity of elastolytic enzymes and promote pulmonary emphysema. A similar mechanism might well promote the destruction of elastic laminae in the tunica media of the abdominal aorta, which characterizes aneurysm formation.

Age

Multiple observational studies have identified age as a potent risk factor for atherosclerotic events. Indeed, age contributes substantially to risk calculation in most algorithms. Demographic trends portend a marked expansion in the elderly population, particularly women, in coming years. Although age-adjusted rates of cardiovascular disease may appear stable or even be declining in men, the actual burden of disease in the elderly will increase because of their sheer number. In view of the expanding elderly population, evidence supporting the mutability of atherosclerosis assumes even greater importance (see later). Recent studies have established that somatic mutations in bone marrow stem cells give rise to clones of leukocytes that accumulate with age and confer substantial cardiovascular risk. This new field of clonal hematopoiesis should provide new insights and links between age and atherosclerosis.

Sex

Male sex contributes to heightened cardiovascular risk in numerous observational studies. The mechanisms for this increased burden of disease may reflect male-related proatherogenic factors and/or lack of protection conferred by female sex. As cardiovascular risk increases after menopause in women, many previously attributed the vascular protection enjoyed by premenopausal women to estrogen. But estrogen therapy in women (in recent large-scale clinical trials) and in men (in the older Coronary Drug Project study) seems to confer hazard rather than benefit in the circumstances studied. Thus estrogen, certainly in combination with progesterone, does not provide a panacea for protection against cardiovascular events, although the timing of intervention may influence outcomes.

High-density lipoprotein and triglyceride-rich lipoproteins

High-density lipoprotein (HDL) indubitably relates inversely to cardiovascular risk; however, current genetic data suggest that HDL does not protect against atherosclerotic risk. Moreover, numerous attempts to raise HDL pharmacologically have failed to improve outcomes. Although various functional properties of HDL are still considered possibly beneficial, there is currently no actionable information regarding the therapeutic modification of HDL. Indeed, low HDL concentrations associated with increased cardiovascular risk probably reflect the inverse relationship between HDL and triglycerides ( Fig. 6.1 ). In contrast to HDL, current genetic evidence strongly supports a causal role for triglyceride-rich lipoproteins in atherosclerotic risk.