Atherosclerosis is the leading cause of mortality and morbidity in the developed world. Through its major manifestations of cardiovascular disease and stroke, it likely will become the leading global killer by the year 2020. Commonly known as “hardening of the arteries,” atherosclerosis derives its name from the Greek roots athere-, meaning “gruel,” and -skleros, meaning “hardness.”
Recent evidence has demonstrated that atherosclerosis is a chronic inflammatory condition and that its pathogenesis involves lipids, thrombosis, elements of the vascular wall, and immune cells. The process of atherogenesis can smolder throughout adulthood, punctuated by acute cardiovascular events.
This chapter consists of two sections. The first part describes the normal arterial wall, the pathogenesis of atherosclerotic plaque formation, and pathologic complications that lead to clinical symptoms. The second section relates findings from population studies to attributes that lead to this condition, thereby offering opportunities for prevention and treatment.
Vascular Biology of Atherosclerosis
Normal Arterial Wall
The arterial wall consists of three layers ( Fig. 5.1): the intima, closest to the arterial lumen and therefore most “intimate” with the blood; the media, which is the middle layer; and the outer layer, the adventitia. The intimal surface consists of a single layer of endothelial cells that acts as a metabolically active barrier between circulating blood and the vessel wall. The media is the thickest layer of the normal artery. Boundaries of elastin, known as the internal and external elastic laminae, separate this middle layer from the intima and adventitia, respectively. The media consists of smooth muscle cells and extracellular matrix, and subserves the contractile and elastic functions of the vessel.
The elastic component, more prominent in large arteries (e.g., the aorta and its primary branches), stretches during the high pressure of systole and then recoils during diastole, propelling blood forward. The muscular component, more prominent in smaller arteries such as arterioles, constricts or relaxes to alter vessel resistance and therefore luminal blood flow (flow = pressure/resistance; see Chapter 6). The adventitia contains the nerves, lymphatics, and blood vessels (vasa vasorum) that nourish the cells of the arterial wall.
Figure 5.1. Schematic diagram of the arterial wall.
The intima, the innermost layer, overlies the muscular media demarcated by the internal elastic lamina. The external elastic lamina separates the media from the outer layer, the adventitia.
Far from an inert conduit, the living arterial wall is a scene of dynamic interchange between its cellular components—most importantly, endothelial cells, vascular smooth muscle cells, and their surrounding extracellular matrix. An understanding of the dysfunction that leads to atherosclerosis requires knowledge of the normal function of these components.
In a healthy artery, the endothelium performs structural, metabolic, and signaling functions that maintain homeostasis of the vessel wall. The tightly adjoined endothelial cells form a barrier that contains blood within the lumen of the vessel and limits the passage of large molecules from the circulation into the subendothelial space.
As blood traverses the vascular tree, it encounters antithrombotic molecules produced by the normal endothelium that prevent it from clotting. Some of these molecules reside on the endothelial surface (e.g., heparan sulfate, thrombomodulin, and plasminogen activators; see Chapter 7), while other antithrombotic products of the endothelium enter the circulation (e.g., prostacyclin and nitric oxide [NO]; see Chapter 6). Although a net anticoagulant state normally prevails, the endothelium can also produce prothrombotic molecules when subjected to various stressors.
Endothelial cells also secrete substances that modulate contraction of smooth muscle cells in the underlying medial layer. These substances include vasodilators (e.g., NO and prostacyclin) and vasoconstrictors (e.g., endothelin) that alter the resistance of the vessel and therefore luminal blood flow. In a normal artery, the predominance of vasodilator substances results in net smooth muscle relaxation. Several of the aforementioned endothelial products also function within the vessel wall to inhibit proliferation of smooth muscle cells into the intima, thus enforcing their normal residence within the media.
Endothelial cells can also modulate the immune response. In the absence of pathologic stimulation, healthy arterial endothelial cells resist leukocyte adhesion and thereby oppose local inflammation. However, endothelial cells in postcapillary venules respond to local injury or infection by secreting chemokines—chemicals that attract white blood cells to the area. Such stimulation also causes endothelial cells to produce cell surface adhesion molecules, which anchor mononuclear cells to the endothelium and facilitate their migration to the site of injury. These effects may be mediated in part via Kruppellike factor 2 (KLF2), a gene regulator in endothelial cells. As described later, under the adverse influences present during atherogenesis, endothelial cells similarly recruit leukocytes to the vessel wall.
Thus, the normal endothelium provides a protective, nonthrombogenic surface with homeostatic vasodilatory and anti-inflammatory properties ( Fig. 5.2).
Figure 5.2. Endothelial and smooth muscle cell activation by inflammation.
Normal endothelial and smooth muscle cells maintain the integrity and elasticity of the normal arterial wall while limiting immune cell infiltration. Inflammatory activation of these vascular cells corrupts their normal functions and favors proatherogenic mechanisms that drive plaque development.
Vascular Smooth Muscle Cells
Smooth muscle cells within the vessel wall have both contractile and synthetic capabilities. Various vasoactive substances modulate the contractile function, resulting in vasoconstriction or vasodilation. Such agonists include circulating molecules (e.g., angiotensin II), those released from local nerve terminals (e.g., acetylcholine), and others originating from the overlying endothelium (e.g., endothelin and NO).
Normal biosynthetic functions of smooth muscle cells include production of the collagen, elastin, and proteoglycans that form the vascular extracellular matrix (see Fig. 5.2). Smooth muscle cells can also synthesize vasoactive and inflammatory mediators, including interleukin-6 (IL-6) and tumor necrosis factor-? (TNF-?), which promote leukocyte proliferation and induce endothelial expression of leukocyte adhesion molecules (LAM). These synthetic functions become more prominent at sites of atherosclerotic plaque and may contribute to their pathogenesis.
In healthy arteries, fibrillar collagen, proteoglycans, and elastin make up most of the extracellular matrix in the medial layer. Interstitial collagen fibrils, constructed from intertwining helical proteins, possess great biomechanical strength, while elastin provides flexibility. Together these components maintain the structural integrity of the vessel, despite the high pressure within the lumen. The extracellular matrix also regulates the growth of its resident cells. Native fibrillar collagen, in particular, can inhibit smooth muscle cell proliferation in vitro. Furthermore, the matrix influences cellular responses to stimuli—matrix-bound cells respond in a specific manner to growth factors and are less likely to undergo apoptosis (programmed cell death).
Atherosclerotic Arterial Wall
The arterial wall is a dynamic and regulated system, but noxious elements can disturb normal homeostasis and pave the way for atherogenesis. For example, as described later, vascular endothelial and smooth muscle cells react readily to inflammatory mediators such as IL-1 and TNF-?. These inflammatory agents can also activate vascular cells to produce IL-1 and TNF-?—contrary to past dogma stating that only cells of the immune system synthesize such cytokines.
Realizing that immune cells were not the only source of proinflammatory agents, investigations into the role of “activated” endothelial and smooth muscle cells in atherogenesis burgeoned. This fundamental research has identified several key components that contribute to the atherosclerotic inflammatory process, including endothelial dysfunction, accumulation of lipids within the intima, recruitment of leukocytes and smooth muscle cells to the vessel wall, formation of foam cells, and deposition of extracellular matrix ( Fig. 5.3), as described in the following sections.
Rather than follow a sequential path, the cells of atherosclerotic lesions continuously interact and compete with each other, shaping the plaque over decades into one of many possible profiles. This section categorizes these mechanisms into three pathologic stages: the fatty streak, plaque progression, and plaque disruption ( Fig. 5.4).
Figure 5.3. Schematic diagram of the evolution of atherosclerotic plaque.
(1) Accumulation of lipoprotein particles in the intima. The darker color depicts modification of the lipoproteins (e.g., by oxidation or glycation). (2) Oxidative stress, including constituents of mLDL, induces local cytokine elaboration. (3) These cytokines promote increased expression of adhesion molecules that bind leukocytes and of chemoattractant molecules (e.g., monocyte chemoattractant protein 1 [MCP-1]) that direct leukocyte migration into the intima. (4) After entering the artery wall in response to chemoattractants, blood monocytes encounter stimuli such as macrophage colony–stimulating factor (M-CSF) that augment their expression of scavenger receptors. (5) Scavenger receptors mediate the uptake of modified lipoprotein particles and promote the development of foam cells. Macrophage foam cells are a source of additional cytokines and effector molecules such as superoxide anion () and matrix metalloproteinases. (6) Smooth muscle cells migrate into the intima from the media. Note the increasing intimal thickness. (7) Intimal smooth muscle cells divide and elaborate extracellular matrix, promoting matrix accumulation in the growing atherosclerotic plaque. In this manner, the fatty streak evolves into a fibrofatty lesion. (8) In later stages, calcification can occur (not depicted) and fibrosis continues, sometimes accompanied by smooth muscle cell death (including programmed cell death, or apoptosis), yielding a relatively acellular fibrous capsule surrounding a lipid-rich core that may also contain dying or dead cells. IL-1, interleukin 1; LDL, low-density lipoprotein.
(Modified from Zipes D, Libby P, Bonow RO, et al., eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia, PA: Elsevier Saunders; 2005:925.)
Figure 5.4. Stages of plaque development.
A. The fatty streak develops as a result of endothelial dysfunction, lipoprotein entry and modification, leukocyte recruitment, and foam cell formation. B. Plaque progression is characterized by migration of smooth muscle cells into the intima, where they divide and elaborate extracellular matrix. The fibrous cap contains a lipid core. C. Hemodynamic stresses and degradation of extracellular matrix increase the susceptibility of the fibrous cap to rupture, allowing superimposed thrombus formation.
(Modified from Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1136.)
Fatty streaks represent the earliest visible lesions of atherosclerosis. On gross inspection, they appear as areas of yellow discoloration on the artery’s inner surface, but they neither protrude substantially into the arterial lumen nor impede blood flow. Surprisingly, fatty streaks exist in the aorta and coronary arteries of most people by age 20. They do not cause symptoms, and in some locations in the vasculature, they may regress over time.
Although the precise initiation of fatty streak development is not known, observations in animals suggest that various stressors cause early endothelial dysfunction, as described in the next section. Such dysfunction allows entry and modification of lipids within the subendothelial space, where they serve as proinflammatory mediators that initiate leukocyte recruitment and foam cell formation—the pathologic hallmarks of the fatty streak ( Fig. 5.5).
Figure 5.5. Endothelial dysfunction is the primary event in plaque initiation.
Physical and chemical stressors alter the normal endothelium, allowing lipid entry into the subintima and promoting inflammatory cytokine release. This cytokine- and lipid-rich environment promotes recruitment of leukocytes to the subintima, where they may become foam cells—a promi nent inflammatory participant.
Injury to the arterial endothelium represents a primary event in atherogenesis. Such injury can result from exposure to diverse agents, including physical forces and chemical irritants.
The predisposition of certain regions of arteries (e.g., branch points) to develop atheromata supports the role of hydrodynamic stress. In straight sections of arteries, the normal laminar (i.e., smooth) shear forces favor the endothelial production of NO, which is an endogenous vasodilator, an inhibitor of platelet aggregation, and an anti-inflammatory substance (see Chapter 6).
Moreover, laminar flow not only activates KLF-2 as described above, but also accentuates expression of the antioxidant enzyme superoxide dismutase, which protects against reactive oxygen species produced by chemical irritants or transient ischemia. Conversely, disturbed flow occurs at arterial branch points, which impairs these locally atheroprotective endothelial functions. Accordingly, arteries with few branches (e.g., the internal mammary artery) show relative resistance to atherosclerosis, whereas bifurcated vessels (e.g., the common carotid and left coronary arteries) are common sites for atheroma formation.
Endothelial dysfunction may also result from exposure to a “toxic” chemical environment. For example, tobacco smoking, abnormal circulating lipid levels, and diabetes—all known risk factors for atherosclerosis—can promote endothelial dysfunction. Each of these states increases endothelial production of reactive oxygen species—notably, superoxide anion—which interact with other intracellular molecules to influence the metabolic and synthetic functions of the endothelium. In such an environment, the cells promote local inflammation.
When physical and chemical stressors interrupt normal endothelial homeostasis, an activated state ensues, manifested by impairment of the endothelium’s role as a permeability barrier, release of inflammatory cytokines, increased production of cell surface adhesion molecules that recruit leukocytes, altered release of vasoactive substances (e.g., prostacyclin and NO), and interference with normal antithrombotic properties. These undesired effects of endothelial dysfunction lay the groundwork for subsequent events in the development of atherosclerosis (see Fig. 5.2).