Atherosclerosis, Inflammation, and Acute Coronary Syndrome
Bradley E. Aouizerat
Polly E. Gardner
Gaylene Altman
Acute coronary syndrome encompasses the clinical entities of myocardial ischemia and myocardial infarction. The diagnosis of acute coronary syndrome is based on history, risk factors, diagnostic laboratory tests, functional studies, and, to a lesser extent, the electrocardiogram (ECG). This chapter focuses primarily on the incidence, mechanisms, causes, and pathophysiology, including the cellular and metabolic changes of myocardial ischemia and infarction. Hemodynamic mechanisms affecting the balance of oxygen supply and demand are addressed. The role of inflammation in myocardial ischemia and myocardial infarction is also addressed. Clinical manifestations are briefly discussed and are fully detailed in Chapter 22.
INTRODUCTIONMany factors affect the pathophysiologic events that lead to ischemia, infarction, and injury of myocardial muscle. Injury to the myocardium can range from reversible to permanent damage of cellular components in localized tissue. Ischemia occurs from a transient imbalance of blood supply to an area of tissue, with the chief result being tissue hypoxia. Ischemia can be a sudden event or a gradual occurrence from a partial or totally occluded coronary vessel or vessels. The burden of the ischemic event depends on the sensitivity of the tissue to hypoxia, the degree and duration of ischemia, and the ability of the tissue to regenerate when conditions improve.1,2
Myocardial ischemia is a condition that results from diminished oxygen supply coupled with inadequate removal of metabolites because of reduced perfusion to the heart muscle.3,4 Pure anoxia or hypoxia, without metabolic clearance, can occur in patients with congenital heart disease, severe anemia, asphyxiation, carbon monoxide poisoning, or cor pulmonale.5 Myocardial ischemia can occur as a result of reduced oxygen and nutrient supply or increased metabolic demand to meet tissue demands6 (Fig. 5-1). In the presence of coronary artery occlusion, an increase in oxygen demand requirements from exercise or emotional stress can cause a transitory imbalance known as demand ischemia. Angina pectoris is a condition characterized by chest pain or discomfort, which results from myocardial ischemia. Patients with chronic stable angina experience this demand ischemia when they exert themselves yet obtain relief with rest. An abrupt or acute reduction in blood flow to myocardium is termed supply ischemia. This abrupt imbalance is caused by an increase in coronary vascular tone, such as coronary vasospasm, or by a marked reduction or cessation of blood flow caused by thrombi or platelet aggregation. Supply ischemia is seen in patients with unstable angina or myocardial infarction.7 Unstable angina is not relieved with rest. Crescendo angina, a worsening chest pain that may lead to myocardial infarction or preinfarct angina, can develop in some patients with unstable angina.3,8,9
The coronary arteries supply blood flow to meet the specific demands of the myocardium under varying workloads such as stress, sleep, or exercise. If oxygen needs are not met, then normal coronary arteries dilate to increase delivery of oxygenated blood to the myocardium.5 Various pathologic states can affect the endothelium of the epicardial arteries impairing and impacting the normal vasomotor response of vasodilatation when myocardial demand increases. Atherosclerotic plaques (discussed later in this chapter) are the primary cause of endothelial injury and dysfunction, interfering with normal vasomotor response causing a paradoxical response of vasoconstriction.10, 11, 12, 13, 14, 15
The heart is an aerobic organ that relies on oxidation of substrates for maximal efficiency. The myocardium has a small margin of oxygen debt to maintain normal function. Myocardial oxygen consumption (M[V with dot above]O2) is a measure of the heart’s total metabolism and is used to determine myocardial oxygen consumption.16 Factors that determine myocardial oxygen consumption are heart rate, contractility, systolic wall tension, and metabolic and vasomotor regulations of coronary blood flow.4,16
Heart rate has a linear relationship with myocardial oxygen consumption. The faster the heart rate, the greater the myocardial oxygen consumption. Myocardial contractility is influenced by different stimuli. Positive inotropes such as epinephrine or dobutamine augment the contractile forces of the myocardium, increasing myocardial oxygen consumption. Researchers believe the increase in M[V with dot above]O2 may result from enhanced excitation-contraction coupling or more rapid uptake of calcium by the sarcoplasmic reticulum.5,16
Evans and Matsuoka, who concluded that a relationship exists between myocardial tension during systole and metabolism of contractile tissue, described myocardial systolic wall tension in 1915 (as cited in Braunwald, 2000).16 For every heart beat there is a generated ventricular tension or pressure, as measured in the area under the left ventricular curve. See Chapter 1 for discussion of the Starling mechanism. Increases in myocardial tension or pressure increase myocardial oxygen consumption.
Low blood pressure causing decreased blood return can lead to imbalances of oxygen supply and demand. Examples are hypotension or hypovolemia. Increased oxygen demand is caused by conditions such as hyperthyroidism, anemia, or hyperviscosity of the blood.
MECHANISMS THAT REGULATE CORONARY BLOOD FLOWMechanisms that determine coronary blood flow can be divided into mechanical factors and metabolic mediators. Mechanical
factors affect blood flow by a driving force or resistance to pressure. Blood flow is directly related to the driving pressure and inversely related to the arteriolar resistance. Driving pressure, the mean arterial pressure less the central venous pressure, is influenced by volume, contractility, heart rate, and, hence, cardiac output. Any clinical state that reduces cardiac output to below the tissue’s ability to compensate leads to ischemia. Examples are hypovolemia (reduction in the total vascular volume), decreased pumping efficiency of the heart, or increased vascular space secondary to systemic vasodilatation. Pumping action of the heart is decreased in the presence of ventricular arrhythmias, heart failure, and direct trauma to the myocardium. In addition, the circular events of ischemia to the myocardium, decreased perfusion, and decreased contractility lead to decreased output. Vascular resistance is the result of obstruction of vessels, shunting of blood flow, or increased vascular resistance. Local trauma, vasoconstriction, calcific changes, or thrombus can enhance resistance. Obstruction can result from vasospastic stimuli, such as thermal changes, tissue edema, or injury leading to compression of vessels. Shunting of blood flow is the result of vasoactive substances that cause shunting, congenital malformations, or trauma to vessels. Arteriolar resistance is dependence on the effects of systemic mediators, which are locally released in response to the tissue energy, and oxygen needs.
factors affect blood flow by a driving force or resistance to pressure. Blood flow is directly related to the driving pressure and inversely related to the arteriolar resistance. Driving pressure, the mean arterial pressure less the central venous pressure, is influenced by volume, contractility, heart rate, and, hence, cardiac output. Any clinical state that reduces cardiac output to below the tissue’s ability to compensate leads to ischemia. Examples are hypovolemia (reduction in the total vascular volume), decreased pumping efficiency of the heart, or increased vascular space secondary to systemic vasodilatation. Pumping action of the heart is decreased in the presence of ventricular arrhythmias, heart failure, and direct trauma to the myocardium. In addition, the circular events of ischemia to the myocardium, decreased perfusion, and decreased contractility lead to decreased output. Vascular resistance is the result of obstruction of vessels, shunting of blood flow, or increased vascular resistance. Local trauma, vasoconstriction, calcific changes, or thrombus can enhance resistance. Obstruction can result from vasospastic stimuli, such as thermal changes, tissue edema, or injury leading to compression of vessels. Shunting of blood flow is the result of vasoactive substances that cause shunting, congenital malformations, or trauma to vessels. Arteriolar resistance is dependence on the effects of systemic mediators, which are locally released in response to the tissue energy, and oxygen needs.
 ▪ Figure 5-1 Myocardial oxygen balance. The major determinants in the normal heart are heart rate, afterload, preload and contractility. When the myocardial oxygen demand increases and blood flow is not concomitantly increased or even reduced, as in exercising patients with coronary stenosis, the result is the chest pain called angina pectoris. Clinically, the heart rate increase during exercise is one of the major determinants of myocardial oxygen uptake. (From Opie, L. H. [2004]. Heart physiology: From cell to circulation [4th ed., p. 526]. New York: Lippincott Williams & Wilkins.) |
Metabolic and vasoactive mediators influence the regulation of coronary blood flow. These metabolic mediators include adenosine, serotonin, acetylcholine, carbon dioxide, bradykinin, histamine, substance P, and prostaglandins.5,13,17 Stimulation of the metabolic mediators induces arterial vasodilatation, thereby increasing coronary blood flow and subsequent increase in myocardial oxygen consumption.5,17,18 An imbalance of oxygen supply and demand of less than 1 second leads to changes in coronary vascular resistance or tone. When a coronary vessel is occluded and then released, coronary blood flow increases, causing a response called coronary reactive hyperemia.19 Metabolic mediators are released to relax vasomotor tone and improve blood flow to re-establish homeostasis. The vascular endothelium located between the vascular lumen and smooth muscle cells also releases vasoactive substances that ultimately regulate vascular tone. These substances are known as prostacyclin, nitric oxide, endothelial-derived relaxing factor, and hyperpolarizing factor are potent vasodilators.6,13,20, 21, 22, 23 In addition, endothelin-1, a potent vasoconstrictor, causes a reduction of Na+-/K+-ATPase activity. ATPases are impaired by anoxia and produce superoxides and free radicals. Thus, decreased oxygen leads to a production of superoxides and hydrogen peroxide, which are highly diffusible and induce cell damage. Early or chronic atherosclerosis and factors such as dyslipidemia, hypertension, diabetes mellitus, cigarette smoking, menopause, hyperhomocystinemia, and mutations in nitric oxide synthetase, may inhibit mediator effects and impair arterial endothelial function, causing increased permeability of blood lipids and monocytes.6,17,21,22,24 Further discussion of atherosclerosis is mentioned below.
CAUSES OF MYOCARDIAL ISCHEMIA AND INFARCTIONThe leading cause of myocardial ischemia is atherosclerotic plaque or atheroma disease.7,15,22,25,26 Atherosclerosis is a disease of the large and medium arteries, especially the aorta and arteries supplying the heart, brain, kidneys, and lower extremities.22 The intima or innermost arterial layer is thickened by the development of fibrous tissue and the accumulation of lipid-forming atheromatous plaques.27 These plaques or atheromas continue to develop and grow over the years, resulting in a narrowed arterial lumen. Blood flow through the coronary arteries is lessened, and some patients may begin to experience angina.
Atherosclerosis is a thickening or hardening of arteries. It is a progressive disease that evolves from deposits of lipids, cellular debris, calcium, and fibrin (a clotting agent) that accumulate in the lining of large arteries, all of which initiates and is compounded by a progressive inflammatory component. The later stages of these lesions are termed plaques. While atherosclerosis is primarily a disease of the large arteries, medium-size vessels can also be affected, with significant interindividual variation in the sites and rate of plaque formation. Plaques can enlarge to partially or completely impede blood flow through an artery. Some plaques may hemorrhage within the plaque or rupture, initiating thrombus formation at the site with possible embolic consequences. Occlusion of arterial blood flow can lead to angina, myocardial infarction, or stroke.
Deposition of lipids, platelets, cellular debris, and calcium stimulate cells in the locale of the damaged artery wall to produce still other substances that contribute further to the atherosclerotic process. This results in recruitment of immune cells into the lesion as well as proliferation of arterial smooth muscle cells in an attempt to “heal” the lesion. As a result, the innermost layer of the artery, the intima, thickens, enlarges, and eventually encroaches on the vessel lumen, progressively restricting the flow of blood (and thus oxygen) to the vascular bed. Critical reductions in the supply of oxygen to the heart can result in angina or myocardial infarction or ischemic stroke in the brain, often exacerbated by arterial thrombus formation.
Atherosclerosis is a slow progressive disease that may start in childhood. In some persons, this condition may progress rapidly to cause symptoms in their third decade, whereas in others it does not become clinically significant until the fifth or sixth decades. In industrialized nations, it accounts for more than 50% of all cause adult
mortality. However, the underlying complexity of the disease has made precise delineation of the cellular and molecular mechanisms involved difficult. Over the past decade, new investigative tools have contributed to a clearer picture of the molecular mechanisms underlying the development of atherosclerotic plaque. It is clear that atherosclerosis is not simply an inevitable consequence of ageing.
mortality. However, the underlying complexity of the disease has made precise delineation of the cellular and molecular mechanisms involved difficult. Over the past decade, new investigative tools have contributed to a clearer picture of the molecular mechanisms underlying the development of atherosclerotic plaque. It is clear that atherosclerosis is not simply an inevitable consequence of ageing.
American Heart Association Lesion Classification System
More than a decade ago, the American Heart Association (AHA) endeavored to provide an organized system for the categorization of lesions based on histological and morphological data.28 This system has helped standardize research in atherosclerosis, though modifications have been proposed.29
Coronary artery lesions can be grouped into seven major types (I to VII).28,30, 31, 32, 33 Consistent morphologic data would seem to indicate that each lesion type is relatively stable and will not progress to the next lesion type without additional factors or pressures. While the advanced lesions (types IV to VII) can manifest clinically, the early lesions (types I to III) are clinically silent and can be organized temporally. Types I and II are generally found in children, whereas type III tends to occur later and bridges early and advanced lesions. Perhaps the most important observation is that the clinically silent lesions (types I to III) have been shown capable of regression in animal models. Advanced lesions are generally disorganized and lead to thickening and eventual compromise of the vessel wall. Lipid-laden macrophages (termed “foam cells”) are the predominant cellular components of type I lesions. In types II and III lesions, intimal smooth muscle cells dominate, with minimal involvement of lymphocytes, plasma cells, and mast cells in the pathological processes. This group of inflammatory cells becomes quite active in advanced (types IV and V) lesions. Figures 5-2 and 5-3 summarize the essential characteristics and temporal occurrence of atherosclerotic lesions.
Type I Lesions
Type I lesions, often termed the “initial lesion,” are the earliest detectable lesion type. The lesion can only be observed microscopically and histochemically (by staining for lipid deposits) in the intima. Type I lesions are most often observed in infants and children,34 although they are readily identifiable in adults with little atherosclerosis or in areas of the vasculature not prone to arteriosclerosis. These lesions occur in regions of the intima that display adaptive intimal thickening caused by the hemodynamic force of blood flow. These regions eventually evolve into types II and III lesions. Although more common in early adulthood, the occurrence of type III lesions has been reported as early as the first year of life.34,35 The accumulation of intimal foam cells is a consequence and a marker of pathological accumulation of atherogenic lipoproteins.
 ▪ Figure 5-2 Progression of atheromatous plaque from initial lesion to complex and ruptured plaque. (Modified from Grech, E. D. [2003]. ABC of interventional cardiology: Pathophysiology and investigation of coronary artery disease. BMJ, 326[7397], 1027-1030.) |
Type II Lesions
Type II lesions, also known as fatty streaks that are visible on gross inspection, are yellow spots or streaks on arterial intima. The transmigration of macrophages into the subendothelial space and their subsequent transformation into foam cells produces an adaptive intimal thickening, which may obscure the fatty streak, potentially leading to an underestimate of the extent of these lesions. Recruitment of macrophages to the intima marks one of the defining events in the initiation of the atherosclerotic lesion. Specific adhesion molecules expressed on the surface of vascular endothelial cells mediate leucocyte adhesion. In addition, modified lipoproteins contain oxidized phospholipids that induce the expression of adhesion molecules and cytokines implicated in early atherogenesis.22
Progression of atheroma involves accumulation of smooth muscle cells that elaborate extracellular matrix macromolecules. Microscopic examination of type II lesions reveals that the foam cells are more organized, stratifying into layers, and that smooth muscle cells also begin to show signs of intracellular lipid accumulation. The properties of these lesions results in continued recruitment of macrophage and evidence suggests that T-lymphocytes and mast cells (components of the immune system) begin to invade the lesion.30,36,37 At this stage, the preponderance of the lipid in type II lesions resides in cells, with the majority found in foam cells. A limited amount of extracellular lipid (droplets) can also be detected.
Consistent colocalization of type II lesions to specific portions of the arterial tree is characteristic.38 Additionally, subgroups of type II lesions can be described dependent on their location and the lipoprotein profile of the individual. Type IIa lesions represent the subset of lesions that may potentially progress to type III lesions over time or with increases in atherogenic (triglyceride- and cholesterol-enriched) lipoproteins. This smaller subgroup of type II lesions occurs in predictable locations in the arterial tree (proximal to bifurcations), where adaptive intimal thickenings occur, and are also termed progression-prone or advanced lesion-prone. Type IIb (progression-resistant or advanced lesion-resistant) lesions consist of the larger subset of type II lesions that are less likely to progress and are located in regions with relatively normal intima with little subendothelial smooth muscle cell invasion or proliferation. Type IIb lesions do have the potential to progress, particularly in persons with high plasma levels of atherogenic lipoproteins. Type IIb lesions are further distinguished from IIa by the presence of smooth muscle cells that produce intercellular matrix in the region of adaptive thickening. In type IIb lesions, macrophages without lipid are found mostly near the endothelial surface, foam cells are found deeper within the intima, and the extracellular lipid accumulates even deeper within the adaptive thickening.
The fate of a type II lesion, to become progression-prone or progression-resistant, is dependent not only on the relative atherogenicity of one’s plasma lipoprotein profile but also on the direct
mechanical forces that act on the vessel wall. The flow of blood through the vasculature causes nonuniform distributions of mechanical force, particularly immediately distal to vessel bifurcations. Lesion-prone regions experience greater shear stress, which increases the opportunity for blood-borne components (e.g., lipids) and the vessel wall to interact, facilitating greater transendothelial diffusion.39 Clearly, individuals with greater plasma concentrations of atherogenic lipoproteins will provide the opportunity for accelerated influx and early accumulation of lipid in the lesion-prone areas. In individuals with very high plasma levels of atherogenic lipoproteins, such as those with familial hypercholesterolemia, type II lesions rapidly evolve into advanced lesions, even in arterial locations outside the progression-prone zones. It is noteworthy that by middle age, the development of advanced lesions outside the progression-prone areas occurs even in the absence of high plasma cholesterol (i.e., even in individuals free of premature risk factors).
mechanical forces that act on the vessel wall. The flow of blood through the vasculature causes nonuniform distributions of mechanical force, particularly immediately distal to vessel bifurcations. Lesion-prone regions experience greater shear stress, which increases the opportunity for blood-borne components (e.g., lipids) and the vessel wall to interact, facilitating greater transendothelial diffusion.39 Clearly, individuals with greater plasma concentrations of atherogenic lipoproteins will provide the opportunity for accelerated influx and early accumulation of lipid in the lesion-prone areas. In individuals with very high plasma levels of atherogenic lipoproteins, such as those with familial hypercholesterolemia, type II lesions rapidly evolve into advanced lesions, even in arterial locations outside the progression-prone zones. It is noteworthy that by middle age, the development of advanced lesions outside the progression-prone areas occurs even in the absence of high plasma cholesterol (i.e., even in individuals free of premature risk factors).
 ▪ Figure 5-3 Schematic representation of normal coronary artery wall (top) and development of atheroma (bottom). (Modified from Grech, E. D. [2003]. ABC of interventional cardiology: Pathophysiology and investigation of coronary artery disease. BMJ, 326[7397], 1027-1030.) |
Type III Lesions
Type III lesions are also known as intermediate or transitional lesions or preatheroma. Type III lesions contain more free cholesterol, fatty acid, sphingomyelin, lysolecithin, and triglyceride than type II lesions.36,40 Fatty acid composition differs between type II and more advanced lesions and may be explained by the overall increase in lipids and the change from intracellular to predominantly extracellular storage. Type III lesions contain extracellular lipid deposits (droplets and particles) among the layers of smooth muscle cells that tend to occur adjacent to areas of adaptive intimal thickening. These dispersed droplets accumulate beneath the macrophage/foam cell layer, replace cellular matrix proteoglycans and fibers, and also divide smooth muscle cells. This lipidvariegation destabilizes the integrity of intimal smooth muscle cells and is characteristic of type III lesions.
Type IV Lesions
This lesion, referred to as atheroma is the first “advanced” lesion of atherosclerosis, characterized histologically by a lipid core, intimal disorganization, and arterial deformity, which predispose this lesion type to sudden progression that may precipitate clinical symptoms. Macrophages within the lesions are primed for immune and/or inflammatory responses, expressing major histocompatibility complex receptors, and a variety of cytokines and growth regulatory molecules. These lesions possess a large, well-defined intimal pool of extracellular lipid known as the lipid core. The type IV lesion is also known as an atheroma. The continued growth of these extracellular lipid pools is a result of continued
transmigration from the plasma, encouraged by the areas of decreased local blood flow (called eddies) at lesion-prone sites. Initially, these lesions colocalize with adaptive intimal thickenings. Lipid cores thicken the artery wall and are clearly visible when the luminal surface of the lesion is examined, although thickening usually occurs at the external boundary and contributes little to narrowing of the vessel lumen at this stage.39
transmigration from the plasma, encouraged by the areas of decreased local blood flow (called eddies) at lesion-prone sites. Initially, these lesions colocalize with adaptive intimal thickenings. Lipid cores thicken the artery wall and are clearly visible when the luminal surface of the lesion is examined, although thickening usually occurs at the external boundary and contributes little to narrowing of the vessel lumen at this stage.39
This lesion type is characterized by the displacement of the intimal smooth muscle cells and the intercellular matrix of the deep intima by accumulating pools of extracellular lipid. The dispersed cells appear attenuated and elongated with thickening of the basement membranes. Calcium particles are often found within the lipid cores and even within the organelles of some of the smooth muscle cells. In addition, capillaries may be readily identified around the lipid core and are most common at the lateral margins and facing the lumen. Macrophages, smooth muscle cells, and even mast cells and lymphocytes, populate the region between the lipid core and the endothelial surface. Coalescence of the lipid core leads to a subsequent increase in fibrous tissue (mainly collagen), which will in turn alter the intima above the lipid core. When the fibrous tissue enrichment of the intima covering the lipid core occurs, the lesion is classified as type V. In either conventional histological sections, or by examination by the unaided eye, the upper intimal layer of a type IV lesion is indistinguishable from the fibrotic cover (also known as the fibrous cap) of a type V lesion. This explains why both types IV and V lesions are referred to as fibrous plaques.
Although this lesion class only minimally contributes to luminal narrowing, type IV lesions have important clinical significance. Enrichment of the region between the lipid core and the lesion surface with proteoglycans, foam cells, and dispersed smooth muscle cells with decreased collagen content renders the lesion susceptible to fissures or ulceration. Ominously, localization and accumulation of macrophages in the periphery of advanced lesions, particularly type IV, makes them vulnerable to sudden rupture.
Type V Lesions
This stage in lesion progression is referred to as a fibroatheroma, because of the intimal accumulation of abundant fibrous connective tissue adjacent to a lipid core. When a type V lesion has both a lipid core and calcification within the lesion, it is referred to as a type Vb lesion. Type Vc lesions are devoid of a lipid core and contain minimal lipid deposition. Type V lesions tend to cause a more noticeable narrowing of arteries than type IV lesions and are particularly clinically relevant given their susceptibility to fissure, hemorrhage, and rupture with hematoma and/or thrombus formation.
Population studies of advanced lesion histology reveal that reparative smooth muscle cells infiltrate regions of the intima in which lipid cores disturb or disrupt the cell and intercellular matrix structure. This fibrous tissue often accounts for more of the thickness of the lesion than its underlying lipid core. The new tissue is composed of both collagen and smooth muscle cells. These new smooth muscle cells are distinct from their older counterparts in that they are enriched in rough-surfaced endoplasmic reticulum. Previous thrombi appear to result in thicker lesions and surrounding tissue as they are incorporated into the growing lesion. Type V lesions also contain large, numerous, and newly formed vessel capillaries at the periphery of the lipid core. The media adjacent to the intima of type V lesions are characterized by depletion and disorganization of smooth muscle cells. The surrounding media and adjacent adventitia are enriched in lymphocytes, macrophages, and macrophage foam cells.
Type Va lesions can form larger compound lesions, composed of irregular intercalating lipid cores separated by thick layers of fibrous connective tissue (variably termed multilayered fibroatheroma). Both hemodynamic and tensile forces may contribute to the formation of such compound lesions; as lesions impinge on the circulation, alterations in blood flow promote asymmetric vascular narrowing and a redistribution of the regions of predisposition to lesion formation.39 An alternate explanation may be the serial rupture of the lesion surface, hematoma formation, and thrombosis followed by fibrious organization.
Although type Vb lesions are primarily differentiated by calcification, they tend to possess greater fibrous connective tissue compared to earlier lesion types. Mineral deposits may eventually replace a lesion’s core (an accumulation of dead cells and extracellular lipid). Such calcified lesions are variably also termed a type VII lesion.28,31
The type Vc lesions, being fibrotic and largely devoid of lipid core, often occur in the arteries in the lower extremities24 and have been referred to as a type VIII lesion by some investigators.28,33 These lesions may form by one of several mechanisms including thrombus organization, extension of the fibrous component of an adjacent fibroatheroma, or resorption of lipid cores. Although fibrotic lesions rarely possess a lipid core, a positive stain for lipids is not uncommon in this lesion type. It is noteworthy that wall shear stress caused by increased hydrostatic pressure is common in the lower extremities and could conceivably provide another mechanism for this lesion formation.
Type VI Lesions
Lesion types V and VI may undergo disruption of the lesion surface or develop hematoma, hemorrhage, or thrombotic deposits. They account for the majority of atherosclerotic morbidity and mortality. Any one of these complications is sufficient to recategorize type IV or V lesions as type VI lesions; they are also referred to as complicated lesions. Moreover, the particular complicating event permits subdivision of type VI lesions into three subtypes according to (a) disruption, (b) hemorrhage, or (c) thrombosis; although practically, lesions are often complex and rarely conform perfectly to the lesion classification criteria. Indeed, instances of surface disruptions, hematoma, and thrombosis superimposed on other lesions types or even on intima without a noticeable lesion are not uncommon. The composition of blood, the integrity of the intima, the sensitivity of the inflammatory response, and the dynamic range of shear and tensile forces to which the lesion or intima is exposed varies greatly between persons. While physiological and biochemical studies aimed at characterizing both the determinants and mechanisms resulting in the spectrum of lesion types is ongoing, continued innovation in clinical imaging of lesions has contributed much to the more accurate identification of lesion types and their associated clinical syndromes.
In the past, clinical assessment of atherosclerotic lesions was confined to advanced, gross vascular abnormalities, including aneurysms and vascular stenoses. But the integration of newer and emerging technologies has permitted more accurate depiction of lesion morphology, which in turn informs more specific interventions (Table 5-1). Targeting of treatment has been honed further by the growing understanding of the pathophysiology of lesion progression and associated clinical events. This has permitted clinicians to move beyond simple diagnosis to proactive prevention of complicated lesions through detection of earlier lesions and more accurate lesion characterization. Morphological, immunohistochemical, and
epidemiological data have supported the construction of a lesion classification system, which has helped clinical decision making and research into the underlying pathophysiology and potential therapeutic intervention (Table 5-2).
epidemiological data have supported the construction of a lesion classification system, which has helped clinical decision making and research into the underlying pathophysiology and potential therapeutic intervention (Table 5-2).
Table 5-1 ▪ TECHNOLOGIES PERMITTING EARLIER DETECTION AND ESTIMATION OF LESION VOLUME ARE LISTED | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||
Vascular Surface Defects and Hematoma
The degree of luminal narrowing by an atheroma has little relation to whether thrombosis will occur. Myocardial infarctions of most patients often result from atheromas of less than 50% luminal narrowing or occlusion.11,18,41 Fissuring and disruption of atherosclerotic plaque can occur at any time during this chronic process.12,14 The ability of the plaque to disrupt is a major factor in future ischemic events. Plaque composition, rather than the amount of narrowing, is a major determinant of the vulnerability of the plaque formation. Both mechanical and inflammatory changes affect the vulnerability of the plaque and propensity for thrombosis.10 Superimposed thrombosis on the ruptured, ulcerated plaque can impede blood flow and the delivery of nutrients to the myocardium.
Table 5-2 ▪ TERMS USED TO DESIGNATE DIFFERENT TYPES OF HUMAN ATHEROSCLEROTIC LESIONS IN PATHOLOGY | ||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||
As lesions progress, disruptions of the lesion surface may present as fissures or even ulcerations and are highly variable in their severity and scope. Fissures of the lesion surface vary in length and depth and most likely reseal, leading to lesion progression by incorporating hematoma and thrombus.42,43 Ulcerations can range from minor focal loss of a microscopic portion of the endothelial cell layer to deep ulcerations that can expose lipid cores and release lipid and other components that activate the coagulation cascade. Atheromatous lesions (types IV and Va) are particularly prone to intimal disruptions and ultimately thrombosis.42, 43, 44, 45 This susceptibility is caused in part by the presence of activated inflammatory cells within the lesions,46,47 the release of proteolytic enzymes by macrophages within the lesions,42,48,49 coronary spasm,50 structural weakness related to lesion composition,45 the release of toxic factors from cell death (necrosis), and shear stress.39,51 In addition to intimal hematoma caused by tearing of the lesion surface, some hemorrhage may begin internally from disruption of newly formed vessels within the lesion.52
Thrombosis
Although plaque disruption and thrombosis can be separate processes, they appear to be interrelated. Thrombosis formation may be exacerbated by changes in the endothelium. Contractility, secretory, and mitogenic activities of the vessel wall all are factors that affect ischemia.10 A dysfunctional endothelium leads to the potential for thrombosis and the development of atherosclerotic lesions. Platelets migrate quickly to the site of plaque rupture and adhere. Platelet aggregation releases metabolic substances that cause vasoconstriction.53 Thrombin formation is activated by factor XII, and the coagulation pathway results in the formation of fibrin. A fibrin mesh binds with the platelets and leads to formation of a clot.3,11,25,26,54
Advanced atherosclerotic lesions containing thrombi or their remnants become common by the fourth decade of life, ranging in size from microscopic to grossly visible deposits, with some consisting of stratified layers of lesions of different ages.55 Incorporation of recurrent hematomas and thrombi over time (months
to years) results in the progressive narrowing of the arterial lumen. Thrombus remnants contain increasing numbers of smooth muscle cells derived by ingrowth from the intima. These smooth muscle cells synthesize collagen, providing the stratum for overgrowth of endothelial cells at the lumen. Ultimately, thrombi may continue to enlarge, with the potential to rapidly occlude the lumen of a medium-sized artery (within days or even hours).
to years) results in the progressive narrowing of the arterial lumen. Thrombus remnants contain increasing numbers of smooth muscle cells derived by ingrowth from the intima. These smooth muscle cells synthesize collagen, providing the stratum for overgrowth of endothelial cells at the lumen. Ultimately, thrombi may continue to enlarge, with the potential to rapidly occlude the lumen of a medium-sized artery (within days or even hours).
Several mechanisms can influence the location, frequency, concentration, and size of thrombi. Shear stress participates in lesion progression, with thrombotic occlusions being common at vessel bifurcations and locations of arterial angulation.56 Increased levels of low-density lipoproteins (LDLs) (demonstrated to impair platelet function),57,58 nutrition,59 contents of cigarette smoke,60 and elevated lipoprotein(a) levels61,62 have been associated with greater risk for clinical coronary artery disease. Taken together, systemic factors play a significant role in modulating the development of thrombi.
Atherosclerotic Aneurysms
A common sequela of advanced lesions (types IV, V, and VI) is the development of distensions in the entire vascular wall. These aneurysms are most commonly associated with type VI lesions, when the intimal surface is eroded. Both old and new mural thrombi permeate atherosclerotic aneurysms, and the thrombi become layered in older aneurysms. Whereas the thrombi can form large masses that can fill an aneurysm, the underlying lumen remains generally well preserved and approximates the dimensions of the original vessel. The evolution of atherosclerotic aneurysms is preceded by a series of changes in the locale of the lesion. Matrix fibers are continuously degraded and resynthesized,63 causing a progressive decay of matrix architecture that results in dilation and potentially rupture.64 Susceptibility to atherosclerotic aneurysm is modulated by secondary risk factors resulting in increased hemodynamic and/or tensile stress (e.g., hypertension) and by genetic variation. The search for genetic factors predisposing to atherosclerotic aneurysm development is ongoing.
Severity of Stenosis
The severity of lesion stenosis modulates the degree of impaired blood flow. The degree of stenosis is estimated by the ratio of the maximum diameter of a stenosed artery in comparison to an adjacent normal arterial diameter. Coronary artery blood flow begins to decrease to a clinically significant degree with 50% stenosis and blood flow decreases rapidly when stenosis exceeds 70%,65 and the determination of stenosis is of particular clinical benefit above and below these cutoffs. However, this physiological marker (decrease in blood flow) is technically difficult to measure accurately and fails to account for other factors that can influence the clinical impact of stenosis on a patient (e.g., rate of lesion growth and lesion length and/or geometry).66 Nevertheless, percent stenosis measured by a variety of means provides a powerful tool with significant clinical usefulness in the evaluation of coronary disease.67, 68, 69
Cells and Extracellular Matrix of Lesions
A host of changes exist in the cellular compartment and extracellular matrix composition of lesions. Interaction of the apolipoprotein B on LDL with cell surface glycosaminoglycans appears to be a mechanism for trapping LDL in the arterial intima. Moreover, production of glycosaminoglycans increases during the early stages of atherosclerosis, which contribute to more avid cellular lipoprotein recruitment.70, 71, 72 Dermatan sulfate proteoglycans are another surface moiety hypothesized to increase the rate of progression of atherosclerosis.72 This class of molecules also binds plasma LDL under physiological conditions with increased affinity in comparison with other molecules of this class.73 In vitro studies of smooth muscle cells exposed to conditioned media from cultured macrophages provides evidence for a role for macrophages in modulating the type and amount of proteoglycans found in the developing lesion.74 Macrophage accumulation in type II lesions leads to the production of enzymes capable of degrading proteoglycans within the lesion locale. Enzymatic digestion of the chondroitin sulfate proteoglycan, versican, leads to progression of the lesion because of its role in maintaining the viscoelasticity and the integrity of the vessel wall against the passage of plasma materials.
Although there are significant decreases in elastin content in advanced atherosclerotic lesions, few changes are reported in initial and fatty streak lesions. A variety of elastases attack elastic fibers, and the possibility exists for macrophages75 and smooth muscle cells76 to produce such proteases. This results in a decrease in structural integrity. Moreover, degradation of elastic fibers may have significant consequences in early lesions, because elastin-derived peptides are extremely chemotactic for macrophages. The component cells and extracellular matrix of the atherosclerotic lesion are reviewed briefly below.
Smooth Muscle Cells
Alterations in the functional properties and amount of smooth muscle cells are a central feature of atherogenesis. Changes result from stimuli, including lipid accumulation, disruption of intimal structure, damage to intimal cells and matrix, and deposits of platelets and fibrinogen. These stimuli activate resident cells to produce mitogenic factors, spurring smooth muscle cell proliferation, and ultimately contributing to lesion progression.
Macrophages
Whereas macrophages are generally located proximal to the lumen, foam cells are trapped within the intima. However, this distribution becomes less obvious in complicated lesions or regions in which the intima is relatively thin. When a lipid core is present, macrophage foam cells are usually most evident along the luminal aspect and at the lateral margins of the core. Macrophage foam cells are more numerous and found closer to the surface of the lesion boarder, largely because of a lack of intimal thickening at the lesion periphery. Foam cells eventually die as the lesion develops, contributing to the growth of what is more appropriately termed a “necrotic” core, being composed of extracellular lipid and necrotizing cells. Unfortunately, there are currently no appropriate biomarkers for defining this type of cellular injury.
An accumulating body of evidence indicates that in addition to lipid accumulation, macrophages contribute to atherogenesis by secretion of a range of factors modulating the formation and modeling of advanced lesions, including monocyte chemotactic protein-1 and tumor necrosis factor (TNF).77 Lesions laden with monocytes and macrophage foam cells42,43 are more prone to rupture because of the release of proteolytic enzymes (e.g., collagenase and elastase) by the macrophages. It is not clear yet if macrophages secrete these enzymes throughout lesion formation or only as they die. The capacity of macrophages to express cytokines and growth regulatory molecules was reviewed earlier.31
Lymphocytes
Monoclonal antibodies against CD antigens reveal the presence of T (CD4+ T helper and CD8+ T killer) and B lymphocytes in advanced lesions.78 It is yet unclear to what extent these immune cells participate in the atherogenic process. Macrophage foam cellderived oxidized lipids constitute a significant but variable component of the core of advanced lesions.79, 80, 81 Autoantibodies that recognize oxidized LDL have been isolated from human sera,82 and the titers of these antibodies may potentially be diagnostic of advanced atherosclerosis.83 In addition, viral and bacterial (e.g., chlamydia) antigens have been found in advanced human lesions using molecular and immunocytochemical techniques.84
Lipid and Lipoprotein in the Extracellular Matrix
While the transfer of lipoproteins from the plasma into the intima is a physiological process, the concentrations of these particles are particularly elevated in advanced lesions.33 Definitive identification of the types and amounts of extracellular lipid are difficult and depend largely on methods of tissue preparation and study. More extracellular lipid is observed in lesion types III, IV, Va, and VI. In addition, extracellular lipid accumulates and pools, forming “lipid cores,” in lesion types IV, Va, and VI. Lesions contain many lipid-laden cells that die or can be found in various stages of disintegration, evidence that much of the extracellular lipid is derived from cells and lipoproteins originally internalized by cells.79,80 In addition, intracytoplasmic lipid can also be expelled from intact cells into the extracellular space.85 Extracellular lipid is also derived in part by direct coalescence of plasma-derived lipoproteins.86,87
Fibrinogen
The degree and extent to which fibrinogen accumulates in advanced lesions or parts of advanced lesions varies. Immunohistochemical techniques show that the cores of advanced lesions stain for fibrinogen more than any other part of advanced lesions, except superimposed thrombi. It must be recalled that immunohistochemical staining alone cannot distinguish thrombus-associated fibrinogen from physiological infiltration of fibrinogen from the plasma. However, it is generally accepted that intensely fibrinogen-positive bands found in the majority of advanced lesions constitute evidence of incorporated past thrombi.55 Fibrinogen contributes directly and indirectly (by promoting smooth muscle cell growth) to the volume of most advanced lesions.
Proteoglycans
Proteoglycans are a class of glycosylated proteins that have covalently linked sulfated glycosaminoglycans, (i.e., chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin). The protein component of proteoglycans is a core protein that is modified by the addition of a complex set of sugar groups. Glycosaminoglycans are sulfated polysaccharides made of repeating disaccharides (40 to 100 repeats, on average). These complex groups endow proteoglycans with unique properties. In contrast to arterial glycosaminoglycans, little is known about qualitative changes in specific proteoglycan molecules in atherosclerotic lesions. Large extracellular proteoglycans, mainly chondroitin sulfate-containing molecules, function in arterial permeability, ion exchange, transport, and deposition of plasma materials such as LDL. Extracellular heparin sulfate proteoglycans possessing particular oligosaccharide or carbohydrate sequences have different functional properties. Functions attributed to specific oligosaccharides include antiproliferative effects on arterial smooth muscle cells,88 fibroblast growth factor binding,89,90 lipoprotein lipase binding,91 and antithrombin III binding.92 While hypotheses regarding the concentrations, composition, and function of various proteogyclans are currently being evaluated, the lack of clinical studies to inform the clinical relevance of such hypotheses makes discussion of these molecules premature in this venue.
Collagen
Second only to lipids, collagen is the major extracellular component of type V lesions. The increased collagen of atherosclerotic lesions is produced by intimal smooth muscle cells. The major collagen type of advanced lesions is the fibrillar collagen type I. Type I collagen is particularly prevalent in the fibrous cap and in vascularized regions of advanced lesions.93 A significant and consistent change in the minor collagen types of advanced atherosclerotic lesions includes type V collagen, which increases with advancing fibrosis94, 95, 96 and plays a role in cell migration97; and type IV collagen, which is associated with the basement membranes of smooth muscle cells. The exact stimulus for collagen accumulation in atherosclerosis is unknown, although redistribution of mechanical stress has been shown to produce changes in matrix production.
Elastin
The relative concentration and localization of elastin fibers varies with the location and type of lesion. De novo synthesis of subendothelial, medial, and adventitial elastin is common in type V lesions, along with collagen. Whereas the smooth muscle cells of advanced lesions produce elastin, integration of the protein into a functional elastic fiber may be impaired.
Split or frayed elastic fibers tend to associate closely with lipid and calcium deposits. Lipid bound to elastic fibers may change elasticity of tissue by modifying the functionality of the elastin fibers and increase their susceptibility to proteolytic degradation.98,99 Both calcium and magnesium may increase the degradation of elastin,100 the degradation products of which have been reported to produce chemotactic derivatives, which recruit macrophages.101
Calcium
Mineralization of atherosclerotic lesions is a well-substantiated phenomenon. Accumulation of calcium in the arterial wall in the course of the atherogenic process is considered to be a manifestation of advanced atherosclerosis. Unfortunately, very little is known about the factors controlling the quantity of calcium in the lesions. Vesicles in the extracellular matrix of advanced lesions may serve as sites for calcification.102 Mineral deposits in atherosclerosis may also be associated with elastic fibers.103
Inflammation
Epidemiological research in cohort studies over the past three decades (e.g., the Framingham Heart Study and the Multiple Risk Factor Intervention Trial) has resulted in the elucidation of several risk factors for cardiovascular disease (CVD).104,105 Such studies have established the following risk factors for CVD: age, male gender, hypertension, diabetes mellitus, dyslipidemia, and smoking. Strong evidence also exists to implicate lack of physical activity, obesity, and alcohol intake. While recognition and control of these risk factors have engendered a substantial reduction in
CVD-related morbidity and mortality, more than 35% of CVD occurs among those without any known risk factors.106 This observation motivates a large part of the medical research community to identify novel markers of disease, including inflammatory markers of CVD.
CVD-related morbidity and mortality, more than 35% of CVD occurs among those without any known risk factors.106 This observation motivates a large part of the medical research community to identify novel markers of disease, including inflammatory markers of CVD.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
