Etiology and Pathogenesis

Atherosclerotic plaques lead to clinical events (angina, MI) by two mechanisms. First, with gradual enlargement, plaques may obstruct blood flow within epicardial vessels, resulting in ischemia to the myocardial tissue dependent on the affected vessel’s blood supply. Alternatively, plaques may become symptomatic because of acute rupture or thrombosis, resulting in catastrophic acute occlusion of a vessel, the hallmark of MI. Indeed, the two mechanisms are apt to be linked, because less catastrophic (and subclinical) episodes of plaque rupture are probably one of the mechanisms by which nonocclusive plaques enlarge to become symptomatic.

The concept that endothelial injury is an inciting event in atherosclerosis is common to most theories of pathogenesis. Endothelial injury is a component of the earliest stages of atherosclerosis, the formation of lesions that can be detected only at autopsy, the fatty streak (Fig. 2-1A). Most of the well-characterized risk factors for atherosclerosis (hypertension, diabetes mellitus, cigarette smoking, hyperlipidemia, advanced age, elevated plasma homocysteine concentrations) injure the endothelium, initiating a chain of events, all attributes of atherosclerosis: smooth muscle cell (SMC) proliferation, inflammatory cell recruitment, and lipid deposition within the blood vessel (Fig. 2-1B). Though still early in development, potential diagnostic and/or therapeutic approaches based upon inflammatory signaling pathways now known to be important in atherogenesis hold promise.

Figure 2-1 Atherogenesis: (A) Fatty streak formation. (B) Fibrous plaque formation.

LDL-C, low-density lipoprotein cholesterol.

Endothelial injury and the subsequent events that occur in the vessel wall initiate the progression from stable to unstable atherosclerotic plaques, ultimately leading to the rupture of unstable plaques, thrombosis of the vessel, and, in many cases, MI (Fig. 2-2). Lesion development in the medium and small vessels of cerebral vessels leads to stroke, and in renal and mesenteric vasculature contributes to diabetic complications.

Figure 2-2 Atherogenesis: Unstable plaque formation.

An abundance of evidence suggests that atherosclerotic lesions, at least in part, result from an excessive inflammatory response. For example, although elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for premature atherosclerosis, the LDL-C must undergo oxidative modification to cause damage to the arterial wall. Cytokines, growth factors, and oxidative stress may also contribute to atherosclerosis by mechanisms that are independent of LDL-C oxidation. Any of these mediators can rapidly react with and inactivate nitric oxide, enhancing proatherogenic mechanisms such as leukocyte adhesion to endothelium, impaired vasorelaxation, and platelet aggregation (Fig. 2-3).

Figure 2-3 Classical risk factors in coronary artery disease: Relationship to excessive inflammatory responses.

LDL-C, low-density lipoprotein cholesterol.

Numerous adaptive changes in vascular structure occur with aging in healthy individuals. These changes include increases in arterial stiffening, aortic root size, and aortic wall thickness (which resembles the increased intimal medial thickness during early atherogenesis) and measurable abnormalities in vascular function, such as enhanced arterial systolic and pulse pressure. Collagen content is increased, but elastin content is decreased.

Throughout the spectrum of atherogenesis, SMCs play a pivotal role. SMCs are not terminally differentiated and can undergo phenotypic modulation, reverting to cells capable of proliferation, migration, and secretion of mediators involved in these processes. These modulated SMC phenotypes have potentially opposing functions because they can repair vascular damage but can also contribute to vascular disease such as hypertension and atherosclerosis. In arteries prone to develop atherosclerosis, and in the sites of plaque destabilization and rupture, the terminal events in lesion progression—the number of SMCs—is often decreased. Because SMCs are important in maintaining plaque stability (most of the interstitial collagen fiber deposition important for tensile strength of the fibrous cap is secreted by SMCs), the paucity of SMCs increases the likelihood of plaque rupture. Therefore, it is likely that SMC proliferation is deleterious in the early stages of atherosclerotic lesion formation, whereas loss of SMCs (and decreased capacity for proliferation) in later stages increases the likelihood of plaque destabilization and clinical outcomes such as MI and stroke.

A large body of data now implicates both circulating and resident stem cells in the pathogenesis of and protection against atherosclerosis. Although the biology and contribution of stem cells to progression and regression of atherosclerosis remains incompletely understood, some data suggest that depletion of stem cells during the process of aging serves as a trigger for progression of atherosclerotic lesions.

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