Harrison's Cardiovascular Medicine 2 ed.


Peter Libby


Atherosclerosis remains the major cause of death and premature disability in developed societies. Moreover, current predictions estimate that by the year 2020 cardiovascular diseases, notably atherosclerosis, will become the leading global cause of total disease burden. Although many generalized or systemic risk factors predispose to its development, atherosclerosis affects various regions of the circulation preferentially and has distinct clinical manifestations that depend on the particular circulatory bed affected. Atherosclerosis of the coronary arteries commonly causes myocardial infarction (MI) (Chap. 35) and angina pectoris (Chap. 33). Atherosclerosis of the arteries supplying the central nervous system frequently provokes strokes and transient cerebral ischemia. In the peripheral circulation, atherosclerosis causes intermittent claudication and gangrene and can jeopardize limb viability. Involvement of the splanchnic circulation can cause mesenteric ischemia. Atherosclerosis can affect the kidneys either directly (e.g., renal artery stenosis) or as a common site of atheroembolic disease (Chap. 38).

Even within a particular arterial bed, stenoses due to atherosclerosis tend to occur focally, typically in certain predisposed regions. In the coronary circulation, for example, the proximal left anterior descending coronary artery exhibits a particular predilection for developing atherosclerotic disease. Similarly, atherosclerosis preferentially affects the proximal portions of the renal arteries and, in the extracranial circulation to the brain, the carotid bifurcation. Indeed, atherosclerotic lesions often form at branching points of arteries which are regions of disturbed blood flow. Not all manifestations of atherosclerosis result from stenotic, occlusive disease. Ectasia and the development of aneurysmal disease, for example, frequently occur in the aorta (Chap. 38). In addition to focal, flow-limiting stenoses, nonocclusive intimal atherosclerosis also occurs diffusely in affected arteries, as shown by intravascular ultrasound and postmortem studies.

Atherogenesis in humans typically occurs over a period of many years, usually many decades. Growth of atherosclerotic plaques probably does not occur in a smooth, linear fashion but discontinuously, with periods of relative quiescence punctuated by periods of rapid evolution. After a generally prolonged “silent” period, atherosclerosis may become clinically manifest. The clinical expressions of atherosclerosis may be chronic, as in the development of stable, effort-induced angina pectoris or predictable and reproducible intermittent claudication. Alternatively, a dramatic acute clinical event such as MI, stroke, or sudden cardiac death may first herald the presence of atherosclerosis. Other individuals may never experience clinical manifestations of arterial disease despite the presence of widespread atherosclerosis demonstrated postmortem.


An integrated view of experimental results in animals and studies of human atherosclerosis suggests that the “fatty streak” represents the initial lesion of atherosclerosis. These early lesions most often seem to arise from focal increases in the content of lipoproteins within regions of the intima. This accumulation of lipoprotein particles may not result simply from increased permeability, or “leakiness,” of the overlying endothelium (Fig. 30-1). Rather, the lipoproteins may collect in the intima of arteries because they bind to constituents of the extracellular matrix, increasing the residence time of the lipid-rich particles within the arterial wall. Lipoproteins that accumulate in the extracellular space of the intima of arteries often associate with glycosaminoglycans of the arterial extracellular matrix, an interaction that may slow the egress of these lipid-rich particles from the intima. Lipoprotein particles in the extracellular space of the intima, particularly those retained by binding to matrix macromolecules, may undergo oxidative modifications. Considerable evidence supports a pathogenic role for products of oxidized lipoproteins in atherogenesis. Lipoproteins sequestered from plasma antioxidants in the extracellular space of the intima become particularly susceptible to oxidative modification, giving rise to hydroperoxides, lysophospholipids, oxysterols, and aldehydic breakdown products of fatty acids and phospholipids. Modifications of the apoprotein moieties may include breaks in the peptide backbone as well as derivatization of certain amino acid residues. Local production of hypochlorous acid by myeloperoxidase associated with inflammatory cells within the plaque yields chlorinated species such as chlorotyrosyl moieties. High-density lipoprotein (HDL) particles modified by HOCl-mediated chlorination function poorly as cholesterol acceptors, a finding that links oxidative stress with impaired reverse cholesterol transport, which is one likely mechanism of the antiatherogenic action of HDL (see later). Considerable evidence supports the presence of such oxidation products in atherosclerotic lesions. A particular member of the phospholipase family, lipoprotein-associated phospholipase A2 (LpPL A2), can generate proinflammatory lipids, including lysophosphatidyl choline-bearing oxidized lipid moieties from oxidized phospholipids found in oxidized low-density lipoproteins (LDLs). An inhibitor of this enzyme is in clinical development.



Cross-sectional view of an artery depicting steps in development of an atheroma,
 from left to right. The upper panel shows a detail of the boxed area below. The endothelial monolayer overlying the intima contacts blood. Hypercholesterolemia promotes accumulation of LDL particles (light spheres) in the intima. The lipoprotein particles often associate with constituents of the extracellular matrix, notably proteoglycans. Sequestration within the intima separates lipoproteins from some plasma antioxidants and favors oxidative modification. Such modified lipoprotein particles (darker spheres) may trigger a local inflammatory response that signals subsequent steps in lesion formation. The augmented expression of various adhesion molecules for leukocytes recruits monocytes to the site of a nascent arterial lesion.

Once adherent, some white blood cells migrate into the intima. The directed migration of leukocytes probably depends on chemoattractant factors, including modified lipoprotein particles themselves and chemoattractant cytokines (depicted by the smaller spheres), such as the chemokine macrophage chemoattractant protein-1 produced by vascular wall cells in response to modified lipoproteins. Leukocytes in the evolving fatty streak can divide and exhibit augmented expression of receptors for modified lipoproteins (scavenger receptors). These mononuclear phagocytes ingest lipids and become foam cells, represented by a cytoplasm filled with lipid droplets. As the fatty streak evolves into a more complicated atherosclerotic lesion, smooth-muscle cells migrate from the media (bottom of lower panel hairline) through the internal elastic membrane (solid wavy line) and accumulate within the expanding intima, where they lay down extracellular matrix that forms the bulk of the advanced lesion (bottom panelright side).

Leukocyte recruitment

Accumulation of leukocytes characterizes the formation of early atherosclerotic lesions (Fig. 30-1). Thus, from its very inception, atherogenesis involves elements of inflammation, a process that now provides a unifying theme in the pathogenesis of this disease. The inflammatory cell types typically found in the evolving atheroma include monocyte-derived macrophages and lymphocytes. A number of adhesion molecules or receptors for leukocytes expressed on the surface of the arterial endothelial cell probably participate in the recruitment of leukocytes to the nascent atheroma. Constituents of oxidatively modified low-density lipoprotein can augment the expression of leukocyte adhesion molecules. This example illustrates how the accumulation of lipoproteins in the arterial intima may link mechanistically with leukocyte recruitment, a key event in lesion formation.

Laminar shear forces such as those encountered in most regions of normal arteries also can suppress the expression of leukocyte adhesion molecules. Sites of predilection for atherosclerotic lesions (e.g., branch points) often have disturbed flow. Ordered, pulsatile laminar shear of normal blood flow augments the production of nitric oxide by endothelial cells. This molecule, in addition to its vasodilator properties, can act at the low levels constitutively produced by arterial endothelium as a local anti-inflammatory autacoid, e.g., limiting local adhesion molecule expression. Exposure of endothelial cells to laminar shear stress increases the transcription of Krüppel-like factor 2 (KLF2) and reduces the expression of a thioredoxin-interacting protein (Txnip) that inhibits the activity of the endogenous antioxidant thioredoxin. KLF2 augments the activity of endothelial nitric oxide synthase, and reduced Txnip levels boost the function of thioredoxin. Laminar shear stress also stimulates endothelial cells to produce super-oxide dismutase, an antioxidant enzyme. These examples indicate how hemodynamic forces may influence the cellular events that underlie atherosclerotic lesion initiation and potentially explain the favored localization of atherosclerotic lesions at sites that experience disturbance to laminar shear stress.

Once captured on the surface of the arterial endothelial cell by adhesion receptors, the monocytes and lymphocytes penetrate the endothelial layer and take up residence in the intima. In addition to products of modified lipoproteins, cytokines (protein mediators of inflammation) can regulate the expression of adhesion molecules involved in leukocyte recruitment. For example, interleukin 1 (IL-1) or tumor necrosis factor α (TNF-α) induce or augment the expression of leukocyte adhesion molecules on endothelial cells. Because products of lipoprotein oxidation can induce cytokine release from vascular wall cells, this pathway may provide an additional link between arterial accumulation of lipoproteins and leukocyte recruitment. Chemoattractant cytokines such as monocyte chemoattractant protein 1 appear to direct the migration of leukocytes into the arterial wall.

Foam-cell formation

Once resident within the intima, the mononuclear phagocytes mature into macrophages and become lipid-laden foam cells, a conversion that requires the uptake of lipoprotein particles by receptor-mediated endocytosis. One might suppose that the well-recognized “classic” receptor for LDL mediates this lipid uptake; however, humans or animals lacking effective LDL receptors due to genetic alterations (e.g., familial hypercholesterolemia) have abundant arterial lesions and extraarterial xanthomata rich in macrophage-derived foam cells. In addition, the exogenous cholesterol suppresses expression of the LDL receptor; thus, the level of this cell-surface receptor for LDL decreases under conditions of cholesterol excess. Candidates for alternative receptors that can mediate lipid loading of foam cells include a growing number of macrophage “scavenger” receptors, which preferentially endocytose modified lipoproteins, and other receptors for oxidized LDL or very low-density lipoprotein (VLDL). Monocyte attachment to the endothelium, migration into the intima, and maturation to form lipid-laden macrophages thus represent key steps in the formation of the fatty streak, the precursor of fully formed atherosclerotic plaques.


Although the fatty streak commonly precedes the development of a more advanced atherosclerotic plaque, not all fatty streaks progress to form complex atheromata. By ingesting lipids from the extracellular space, the mono-nuclear phagocytes bearing such scavenger receptors may remove lipoproteins from the developing lesion. Some lipid-laden macrophages may leave the artery wall, exporting lipid in the process. Lipid accumulation, and hence the propensity to form an atheroma, ensues if the amount of lipid entering the artery wall exceeds that removed by mononuclear phagocytes or other pathways.

Export by phagocytes may constitute one response to local lipid overload in the evolving lesion. Another mechanism, reverse cholesterol transport mediated by high-density lipoproteins, probably provides an independent pathway for lipid removal from atheroma. This transfer of cholesterol from the cell to the HDL particle involves specialized cell-surface molecules such as the ATP binding cassette (ABC) transporters. ABCA1, the gene mutated in Tangier disease, a condition characterized by very low HDL levels, transfers cholesterol from cells to nascent HDL particles and ABCG1 to mature HDL particles. “Reverse cholesterol transport” mediated by these ABC transporters allows HDL loaded with cholesterol to deliver it to hepatocytes by binding to scavenger receptor B 1 or other receptors. The liver cell can metabolize the sterol to bile acids that can be excreted. This export pathway from macrophage foam cells to peripheral cells such as hepatocytes explains part of the antiatherogenic action of HDLs. (Anti-inflammatory and antioxidant properties also may contribute to the atheroprotective effects of HDLs.) Thus, macrophages may play a vital role in the dynamic economy of lipid accumulation in the arterial wall during atherogenesis.

Some lipid-laden foam cells within the expanding intimal lesion perish. Some foam cells may die as a result of programmed cell death, or apoptosis. This death of mononuclear phagocytes results in the formation of the lipid-rich center, often called the necrotic core, in established atherosclerotic plaques. Macrophages loaded with modified lipoproteins may elaborate cytokines and growth factors that can further signal some of the cellular events in lesion complication. Whereas accumulation of lipid-laden macrophages characterizes the fatty streak, buildup of fibrous tissue formed by extracellular matrix typifies the more advanced atherosclerotic lesion. The smooth-muscle cell synthesizes the bulk of the extracellular matrix of the complex atherosclerotic lesion. A number of growth factors or cytokines elaborated by mononuclear phagocytes can stimulate smooth-muscle cell proliferation and production of extracellular matrix. Cytokines found in the plaque, including IL-1 and TNF-α, can induce local production of growth factors, including forms of platelet-derived growth factor (PDGF), fibroblast growth factors, and others, which may contribute to plaque evolution and complication. Other cytokines, notably interferon γ (IFN-γ) derived from activated T cells within lesions, can limit the synthesis of interstitial forms of collagen by smooth-muscle cells. These examples illustrate how atherogenesis involves a complex mix of mediators that in the balance determines the characteristics of particular lesions.

The arrival of smooth-muscle cells and their elaboration of extracellular matrix probably provide a critical transition, yielding a fibrofatty lesion in place of a simple accumulation of macrophage-derived foam cells. For example, PDGF elaborated by activated platelets, macrophages, and endothelial cells can stimulate the migration of smooth-muscle cells normally resident in the tunica media into the intima. Such growth factors and cytokines produced locally can stimulate the proliferation of resident smooth-muscle cells in the intima as well as those that have migrated from the media. Transforming growth factor β (TGF-β), among other mediators, potently stimulates interstitial collagen production by smooth-muscle cells. These mediators may arise not only from neighboring vascular cells or leukocytes (a “paracrine” pathway), but also, in some instances, may arise from the same cell that responds to the factor (an “autocrine” pathway). Together, these alterations in smooth-muscle cells, signaled by these mediators acting at short distances, can hasten transformation of the fatty streak into a more fibrous smooth-muscle cell and extracellular matrix-rich lesion.

In addition to locally produced mediators, products of blood coagulation and thrombosis likely contribute to atheroma evolution and complication. This involvement justifies the use of the term atherothrombosis to convey the inextricable links between atherosclerosis and thrombosis. Fatty streak formation begins beneath a morphologically intact endothelium. In advanced fatty streaks, however, microscopic breaches in endothelial integrity may occur. Microthrombi rich in platelets can form at such sites of limited endothelial denudation, owing to exposure of the thrombogenic extracellular matrix of the underlying basement membrane. Activated platelets release numerous factors that can promote the fibrotic response, including PDGF and TGF-β. Thrombin not only generates fibrin during coagulation, but also stimulates protease-activated receptors that can signal smooth-muscle migration, proliferation, and extracellular matrix production. Many arterial mural microthrombi resolve without clinical manifestation by a process of local fibrinolysis, resorption, and endothelial repair, yet can lead to lesion progression by stimulating these profibrotic functions of smooth-muscle cells (Fig. 30-2D).



Plaque rupture, thrombosis, and healing. A.
 Arterial remodeling during atherogenesis. During the initial part of the life history of an atheroma, growth is often outward, preserving the caliber of the lumen. This phenomenon of “compensatory enlargement” accounts in part for the tendency of coronary arteriography to underestimate the degree of atherosclerosis. B. Rupture of the plaque’s fibrous cap causes thrombosis. Physical disruption of the atherosclerotic plaque commonly causes arterial thrombosis by allowing blood coagulant factors to contact thrombogenic collagen found in the arterial extracellular matrix and tissue factor produced by macrophage-derived foam cells in the lipid core of lesions. In this manner, sites of plaque rupture form the nidus for thrombi. The normal artery wall has several fibrinolytic or antithrombotic mechanisms that tend to resist thrombosis and lyse clots that begin to form in situ. Such antithrombotic or thrombolytic molecules include thrombomodulin, tissue- and urokinase-type plasminogen activators, heparan sulfate proteoglycans, prostacyclin, and nitric oxide. C. When the clot overwhelms the endogenous fibrinolytic mechanisms, it may propagate and lead to arterial occlusion. The consequences of this occlusion depend on the degree of existing collateral vessels. In a patient with chronic multivessel occlusive coronary artery disease (CAD), collateral channels have often formed. In such circumstances, even a total arterial occlusion may not lead to myocardial infarction (MI), or it may produce an unexpectedly modest or a non-ST-segment elevation infarct because of collateral flow. In a patient with less advanced disease and without substantial stenotic lesions to provide a stimulus for collateral vessel formation, sudden plaque rupture and arterial occlusion commonly produces an ST-segment elevation infarction. These are the types of patients who may present with MI or sudden death as a first manifestation of coronary atherosclerosis. In some cases, the thrombus may lyse or organize into a mural thrombus without occluding the vessel. Such instances may be clinically silent. D. The subsequent thrombin-induced fibrosis and healing causes a fibroproliferative response that can lead to a more fibrous lesion that can produce an eccentric plaque that causes a hemodynamically significant stenosis. In this way, a nonocclusive mural thrombus, even if clinically silent or causing unstable angina rather than infarction, can provoke a healing response that can promote lesion fibrosis and luminal encroachment. Such a sequence of events may convert a “vulnerable” atheroma with a thin fibrous cap that is prone to rupture into a more “stable” fibrous plaque with a reinforced cap. Angioplasty of unstable coronary lesions may “stabilize” the lesions by a similar mechanism, producing a wound followed by healing.


As atherosclerotic lesions advance, abundant plexuses of microvessels develop in connection with the artery’s vasa vasorum. Newly developing microvascular networks may contribute to lesion complications in several ways. These blood vessels provide an abundant surface area for leukocyte trafficking and may serve as the portal for entry and exit of white blood cells from the established atheroma. Microvessels in the plaques may also furnish foci for intraplaque hemorrhage. Like the neovessels in the diabetic retina, microvessels in the atheroma may be friable and prone to rupture and can produce focal hemorrhage. Such a vascular leak can provoke thrombosis in situ, yielding local thrombin generation, which in turn can activate smooth-muscle and endothelial cells through ligation of protease-activated receptors. Atherosclerotic plaques often contain fibrin and hemosiderin, an indication that episodes of intraplaque hemorrhage contribute to plaque complications.

image Calcification

As they advance, atherosclerotic plaques also accumulate calcium. Proteins usually found in bone also localize in atherosclerotic lesions (e.g., osteocalcin, osteopontin, and bone morphogenetic proteins). Mineralization of the atherosclerotic plaque recapitulates many aspects of bone formation, including the regulatory participation of transcription factors such as Runx2.

Plaque evolution

Although atherosclerosis research has focused much attention on proliferation of smooth-muscle cells, as in the case of macrophages, smooth-muscle cells also can undergo apoptosis in the atherosclerotic plaque. Indeed, complex atheromata often have a mostly fibrous character and lack the cellularity of less advanced lesions. This relative paucity of smooth-muscle cells in advanced atheromata may result from the predominance of cytostatic mediators such as TGF-β and IFN-γ (which can inhibit smooth-muscle cell proliferation), and also from smooth-muscle cell apoptosis. Some of the same proinflammatory cytokines that activate atherogenic functions of vascular wall cells can also sensitize these cells to undergo apoptosis.

Thus, during the evolution of the atherosclerotic plaque, a complex balance between entry and egress of lipoproteins and leukocytes, cell proliferation and cell death, extracellular matrix production, and remodeling, as well as calcification and neovascularization, contribute to lesion formation. Multiple and often competing signals regulate these various cellular events. Many mediators related to atherogenic risk factors, including those derived from lipoproteins, cigarette smoking, and angiotensin II, provoke the production of proinflammatory cytokines and alter the behavior of the intrinsic vascular wall cells and infiltrating leukocytes that underlie the complex pathogenesis of these lesions. Thus, advances in vascular biology have led to increased understanding of the mechanisms that link risk factors to the pathogenesis of atherosclerosis and its complications.


Atherosclerotic lesions occur ubiquitously in Western societies. Most atheromata produce no symptoms, and many never cause clinical manifestations. Numerous patients with diffuse atherosclerosis may succumb to unrelated illnesses without ever having experienced a clinically significant manifestation of atherosclerosis. What accounts for this variability in the clinical expression of atherosclerotic disease?

Arterial remodeling during atheroma formation (Fig. 30-2A) represents a frequently overlooked but clinically important feature of lesion evolution. During the initial phases of atheroma development, the plaque usually grows outward, in an abluminal direction. Vessels affected by atherogenesis tend to increase in diameter, a phenomenon known as compensatory enlargement, a type of vascular remodeling. The growing atheroma does not encroach on the arterial lumen until the burden of atherosclerotic plaque exceeds ~40% of the area encompassed by the internal elastic lamina. Thus, during much of its life history, an atheroma will not cause stenosis that can limit tissue perfusion.

Flow-limiting stenoses commonly form later in the history of the plaque. Many such plaques cause stable syndromes such as demand-induced angina pectoris or intermittent claudication in the extremities. In the coronary circulation and other circulations, even total vascular occlusion by an atheroma does not invariably lead to infarction. The hypoxic stimulus of repeated bouts of ischemia characteristically induces formation of collateral vessels in the myocardium, mitigating the consequences of an acute occlusion of an epicardial coronary artery. By contrast, many lesions that cause acute or unstable atherosclerotic syndromes, particularly in the coronary circulation, may arise from atherosclerotic plaques that do not produce a flow-limiting stenosis. Such lesions may produce only minimal luminal irregularities on traditional angiograms and often do not meet the traditional criteria for “significance” by arteriography. Thrombi arising from such nonocclusive stenoses may explain the frequency of MI as an initial manifestation of coronary artery disease (CAD) (in at least one-third of cases) in patients who report no prior history of angina pectoris, a syndrome usually caused by flow-limiting stenoses.

Plaque instability and rupture

Postmortem studies afford considerable insight into the microanatomic substrate underlying the “instability” of plaques that do not cause critical stenoses. A superficial erosion of the endothelium or a frank plaque rupture or fissure usually produces the thrombus that causes episodes of unstable angina pectoris or the occlusive and relatively persistent thrombus that causes acute MI (Fig. 30-2B). In the case of carotid atheromata, a deeper ulceration that provides a nidus for the formation of platelet thrombi may cause transient cerebral ischemic attacks.

Rupture of the plaque’s fibrous cap (Fig. 30-2C) permits contact between coagulation factors in the blood and highly thrombogenic tissue factor expressed by macrophage foam cells in the plaque’s lipid-rich core. If the ensuing thrombus is nonocclusive or transient, the episode of plaque disruption may not cause symptoms or may result in episodic ischemic symptoms such as rest angina. Occlusive thrombi that endure often cause acute MI, particularly in the absence of a well-developed collateral circulation that supplies the affected territory. Repetitive episodes of plaque disruption and healing provide one likely mechanism of transition of the fatty streak to a more complex fibrous lesion (Fig. 30-2D). The healing process in arteries, as in skin wounds, involves the laying down of new extracellular matrix and fibrosis.

Not all atheromata exhibit the same propensity to rupture. Pathologic studies of culprit lesions that have caused acute MI reveal several characteristic features. Plaques that have caused fatal thromboses tend to have thin fibrous caps, relatively large lipid cores, and a high content of macrophages. Morphometric studies of such culprit lesions show that at sites of plaque rupture, macrophages and T lymphocytes predominate and contain relatively few smooth-muscle cells. The cells that concentrate at sites of plaque rupture bear markers of inflammatory activation. In addition, patients with active atherosclerosis and acute coronary syndromes display signs of disseminated inflammation. For example, atherosclerotic plaques and even microvascular endothelial cells at sites remote from the “culprit” lesion of an acute coronary syndrome can exhibit markers of inflammatory activation.

Inflammatory mediators regulate processes that govern the integrity of the plaque’s fibrous cap and, hence, its propensity to rupture. For example, the T cell-derived cytokine IFN-γ, which is found in atherosclerotic plaques, can inhibit growth and collagen synthesis of smooth-muscle cells, as noted earlier. Cytokines derived from activated macrophages and lesional T cells can boost production of proteolytic enzymes that can degrade the extracellular matrix of the plaque’s fibrous cap. Thus, inflammatory mediators can impair the collagen synthesis required for maintenance and repair of the fibrous cap and trigger degradation of extracellular matrix macromolecules, processes that weaken the plaque’s fibrous cap and enhance its susceptibility to rupture (so-called vulnerable plaques). In contrast to plaques with these features of vulnerability, those with a dense extracellular matrix and relatively thick fibrous cap without substantial tissue factor–rich lipid cores seem generally resistant to rupture and unlikely to provoke thrombosis.

Features of the biology of the atheromatous plaque, in addition to its degree of luminal encroachment, influence the clinical manifestations of this disease. This enhanced understanding of plaque biology provides insight into the diverse ways in which atherosclerosis can present clinically and the reasons why the disease may remain silent or stable for prolonged periods, punctuated by acute complications at certain times. Increased understanding of atherogenesis provides new insight into the mechanisms linking it to the risk factors discussed later, indicates the ways in which current therapies may improve outcomes, and suggests new targets for future intervention.



The systematic study of risk factors for atherosclerosis emerged from a coalescence of experimental results, as well as from cross-sectional and ultimately longitudinal studies in humans. The prospective, community-based Framingham Heart Study provided rigorous support for the concept that hypercholesterolemia, hypertension, and other factors correlate with cardiovascular risk. Similar observational studies performed worldwide bolstered the concept of “risk factors” for cardiovascular disease.

From a practical viewpoint, the cardiovascular risk factors that have emerged from such studies fall into two categories: those modifiable by lifestyle and/or pharmacotherapy, and those that are immutable, such as age and sex. The weight of evidence supporting various risk factors differs. For example, hypercholesterolemia and hypertension certainly predict coronary risk, but the magnitude of the contributions of other so-called nontraditional risk factors, such as levels of homocysteine, levels of lipoprotein (a) (Lp[a]), and infection, remains controversial. Moreover, some biomarkers that predict cardiovascular risk may not participate in the causal pathway for the disease or its complications. For example, recent genetic studies suggest that C-reactive protein (CRP) does not itself mediate atherogenesis, despite its ability to predict risk. Table 30-1 lists the risk factors recognized by the current National Cholesterol Education Project Adult Treatment Panel III (ATP III). The later sections will consider some of these risk factors and approaches to their modification.

TABLE 30-1



Lipid disorders

Abnormalities in plasma lipoproteins and derangements in lipid metabolism rank among the most firmly established and best understood risk factors for atherosclerosis. Chapter 31 describes the lipoprotein classes and provides a detailed discussion of lipoprotein metabolism. Current ATP III guidelines recommend lipid screening in all adults >20 years of age. The screen should include a fasting lipid profile (total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol) repeated every 5 years.

ATP III guidelines strive to match the intensity of treatment to an individual’s risk. A quantitative estimate of risk places individuals in one of three treatment strata (Table 30-2). The first step in applying these guidelines involves counting an individual’s risk factors (Table 30-1). Individuals with fewer than two risk factors fall into the lowest treatment intensity stratum (LDL goal <4.1 mmol/L [<160 mg/dL]). In those with two or more risk factors, the next step involves a simple calculation that estimates the 10-year risk of developing coronary heart disease (CHD) (Table 30-2); see http://www.nhlbi.nih.gov/guidelines/cholesterol/ for the algorithm and a downloadable risk calculator. Those with a 10-year risk ≤20% fall into the intermediate stratum (LDL goal <23.4 mmol/L [<130 mg/dL]). Those with a calculated 10-year CHD risk of >20%, any evidence of established atherosclerosis, or diabetes (now considered a CHD risk equivalent) fall into the most intensive treatment group (LDL goal <2.6 mmol/L [<100 mg/dL]). Members of the ATP III panel recently suggested <1.8 mmol/L (<70 mg/dL) as a goal for very high-risk patients and an optional goal for high-risk patients based on recent clinical trial data (Table 30-2). Beyond the Framingham algorithm, there are multiple risk calculators for various countries or regions. Risk calculators that incorporate family history of premature (CAD) and a marker of inflammation (CRP) have been validated for U.S. women and men.

TABLE 30-2



The first maneuver to achieve the LDL goal involves therapeutic lifestyle changes (TLC), including specific diet and exercise recommendations established by the guidelines. According to ATP III criteria, those with LDL levels exceeding goal for their risk group by >0.8 mmol/L (>30 mg/dL) merit consideration for drug therapy. In patients with triglycerides >2.6 mmol/L (>200 mg/dL), ATP III guidelines specify a secondary goal for therapy: “non-HDL cholesterol” (simply, the HDL cholesterol level subtracted from the total cholesterol). Cut points for the therapeutic decision for non-HDL cholesterol are 0.8 mmol/L (30 mg/dL) more than those for LDL.

An extensive and growing body of rigorous evidence now supports the effectiveness of aggressive management of LDL. Addition of drug therapy to dietary and other nonpharmacologic measures reduces cardiovascular risk in patients with established coronary atherosclerosis and also in individuals who have not previously experienced CHD events (Fig. 30-3). As guidelines often lag the emerging clinical trial evidence base, the practitioner may elect to exercise clinical judgment in making therapeutic decisions in individual patients.



Lipid lowering reduces coronary events,
 as reflected on this graph showing the reduction in major cardiovascular events as a function of low-density lipoprotein level in a compendium of clinical trials with statins. (Adapted from CTT Collaborators, Lancet 366:1267, 2005.) The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA), Treating to New Targets (TNT), and Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL) studies have been added.

LDL-lowering therapies do not appear to exert their beneficial effect on cardiovascular events by causing a marked “regression” of stenoses. Angiographically monitored studies of lipid lowering have shown at best a modest reduction in coronary artery stenoses over the duration of study, despite abundant evidence of event reduction. These results suggest that the beneficial mechanism of lipid lowering does not require a substantial reduction in the fixed stenoses. Rather, the benefit may derive from “stabilization” of atherosclerotic lesions without decreased stenosis. Such stabilization of atherosclerotic lesions and the attendant decrease in coronary events may result from the egress of lipids or from favorably influencing aspects of the biology of atherogenesis discussed earlier. In addition, as sizable lesions may protrude abluminally rather than into the lumen due to complementary enlargement, shrinkage of such plaques may not be apparent on angiograms. The consistent benefit of LDL lowering by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) observed in many risk groups may depend not only on their salutary effects on the lipid profile but also on direct modulation of plaque biology independent of lipid lowering.

A new class of LDL-lowering medications reduces cholesterol absorption from the proximal small bowel by targeting an enterocyte cholesterol transporter denoted Niemann-Pick C1-like 1 protein (NPC1L1). The NPC1L1 inhibitor ezetimibe provides a useful adjunct to current therapies to achieve LDL goals; however, no clinical trial evidence has yet demonstrated that ezetimibe improves CHD outcomes.

As the mechanism by which elevated LDL levels promote atherogenesis probably involves oxidative modification, several trials have tested the possibility that antioxidant vitamin therapy might reduce CHD events. Rigorous and well-controlled clinical trials have failed to demonstrate that antioxidant vitamin therapy improves CHD outcomes. Therefore, the current evidence base does not support the use of antioxidant vitamins for this indication.

The clinical use of effective pharmacologic strategies for lowering LDL has reduced cardiovascular events markedly, but even their optimal utilization in clinical trials prevents only a minority of these endpoints. Hence, other aspects of the lipid profile have become tempting targets for addressing the residual burden of cardiovascular disease that persists despite aggressive LDL lowering. Indeed, in the “poststatin” era, patients with LDL levels at or below target not infrequently present with acute coronary syndromes. Low levels of HDL present a growing problem in patients with CAD as the prevalence of metabolic syndrome and diabetes increases. Blood HDL levels vary inversely with those of triglycerides, and the independent role of triglycerides as a cardiovascular risk factor remains unsettled. For these reasons, approaches to raising HDL have emerged as a prominent next hurdle in the management of dyslipidemia. Weight loss and physical activity can raise HDL. Nicotinic acid, particularly in combination with statins, can robustly raise HDL. Some clinical trial data support the effectiveness of nicotinic acid in cardiovascular risk reduction. However, flushing and pruritus remain a challenge to patient acceptance, even with improved dosage forms of nicotinic acid. A combination of nicotinic acid with an inhibitor of prostaglandin D receptor, a mediator of flushing, may limit this unwanted effect of nicotinic acid and is currently in clinical trials, but it has not received regulatory approval.

Agonists of nuclear receptors provide another potential avenue for raising HDL levels. Yet patients treated with peroxisome proliferator–activated receptors alpha and gamma (PPAR-α and -γ) agonists have not consistently shown improved cardiovascular outcomes, and at least some PPAR-agonists have been associated with worsened cardiovascular outcomes. Other agents in clinical development raise HDL levels by inhibiting cholesteryl ester transfer protein (CETP). The first of these agents to undergo large-scale clinical evaluation showed increased adverse events, leading to cessation of its development. Clinical studies currently underway will assess the effectiveness of other CETP inhibitors that lack some of the adverse off-target actions encountered with the first agent.


(See also Chap. 37) A wealth of epidemiologic data support a relationship between hypertension and atherosclerotic risk, and extensive clinical trial evidence has established that pharmacologic treatment of hypertension can reduce the risk of stroke, heart failure, and CHD events.

Diabetes mellitus, insulin resistance, and the metabolic syndrome

Most patients with diabetes mellitus die of atherosclerosis and its complications. Aging and rampant obesity underlie a current epidemic of type 2 diabetes mellitus. The abnormal lipoprotein profile associated with insulin resistance, known as diabetic dyslipidemia, accounts for part of the elevated cardiovascular risk in patients with type 2 diabetes. Although diabetic individuals often have LDL cholesterol levels near the average, the LDL particles tend to be smaller and denser and, therefore, more atherogenic. Other features of diabetic dyslipidemia include low HDL and elevated triglyceride levels. Hypertension also frequently accompanies obesity, insulin resistance, and dyslipidemia. Indeed, the ATP III guidelines now recognize this cluster of risk factors and provide criteria for diagnosis of the “metabolic syndrome” (Table 30-3). Despite legitimate concerns about whether clustered components confer more risk than an individual component, the metabolic syndrome concept may offer clinical utility.

TABLE 30-3



Therapeutic objectives for intervention in these patients include addressing the underlying causes, including obesity and low physical activity, by initiating TLC. The ATP III guidelines provide an explicit step-by-step plan for implementing TLC, and treatment of the component risk factors should accompany TLC. Establishing that strict glycemic control reduces the risk of macrovascular complications of diabetes has proved much more elusive than the established beneficial effects on microvascular complications such as retinopathy and renal disease. Indeed, “tight” glycemic control may increase adverse events in patients with type 2 diabetes, lending even greater importance to aggressive control of other aspects of risk in this patient population. In this regard, multiple clinical trials, including the Collaborative Atorvastatin Diabetes Study (CARDS) that addressed specifically the diabetic population, have demonstrated unequivocal benefit of HMG-CoA reductase inhibitor therapy in diabetic patients over all ranges of LDL cholesterol levels (but not those with end-stage renal disease). In view of the consistent benefit of statin treatment for diabetic populations and the thus far equivocal results with PPAR agonists, the current stance of the American Diabetic Association that statins be considered for persons with diabetes older than age 40 who have a total cholesterol level ≥135 appears amply justified. Among the oral hypoglycemic agents, metformin possesses the best evidence base for cardiovascular event reduction.

Diabetic populations appear to derive particular benefit from antihypertensive strategies that block the action of angiotensin II. Thus, the antihypertensive regimen for patients with the metabolic syndrome should include angiotensin converting-enzyme inhibitors or angiotensin receptor blockers when possible. Most of these individuals will require more than one antihypertensive agent to achieve the recently updated American Diabetes Association blood pressure goal of 130/80 mmHg.

Male sex/postmenopausal state

Decades of observational studies have verified excess coronary risk in men compared with premenopausal women. After menopause, however, coronary risk accelerates in women. At least part of the apparent protection against CHD in premenopausal women derives from their relatively higher HDL levels compared with those of men. After menopause, HDL values fall in concert with increased coronary risk. Estrogen therapy lowers LDL cholesterol and raises HDL cholesterol, changes that should decrease coronary risk.

Multiple observational and experimental studies have suggested that estrogen therapy reduces coronary risk. However, a spate of clinical trials has failed to demonstrate a net benefit of estrogen with or without progestins on CHD outcomes. In the Heart and Estrogen/Progestin Replacement Study (HERS), postmenopausal female survivors of acute MI were randomized to an estrogen/progestin combination or to placebo. This study showed no overall reduction in recurrent coronary events in the active treatment arm. Indeed, early in the 5-year course of this trial, there was a trend toward an actual increase in vascular events in the treated women. Extended follow-up of this cohort did not disclose an accrual of benefit in the treatment group. The Women’s Health Initiative (WHI) study arm, using a similar estrogen plus progesterone regimen, was halted due to a small but significant hazard of cardiovascular events, stroke, and breast cancer. The estrogen without progestin arm of WHI (conducted in women without a uterus) was stopped early due to an increase in strokes, and failed to afford protection from MI or CHD death during observation over 7 years. The excess cardiovascular events in these trials may result from an increase in thromboembolism. Physicians should work with women to provide information and help weigh the small but evident CHD risk of estrogen ± progestin versus the benefits for postmenopausal symptoms and osteoporosis, taking personal preferences into account. Post hoc analyses of observational studies suggest that estrogen therapy in women younger than or closer to menopause than the women enrolled in WHI might confer cardiovascular benefit. Thus, the timing in relation to menopause or the age at which estrogen therapy begins may influence its risk/benefit balance.

The lack of efficacy of estrogen therapy in cardiovascular risk reduction highlights the need for redoubled attention to known modifiable risk factors in women. The recent JUPITER trials randomized over 6000 women over age 65 without known cardiovascular disease with LDL <130 mg/dL and high-sensitivity (hs) CRP >2 mg/L to a statin or placebo. The statin-treated women had a striking reduction in cardiovascular events, as did the men. This trial, which included more women than any prior statin study, provides strong evidence supporting the efficacy of statins in women who meet those entry criteria.

Dysregulated coagulation or fibrinolysis

Thrombosis ultimately causes the gravest complications of atherosclerosis. The propensity to form thrombi and/or lyse clots once they form clearly influences the manifestations of atherosclerosis. Thrombosis provoked by atheroma rupture and subsequent healing may promote plaque growth. Certain individual characteristics can influence thrombosis or fibrinolysis and have received attention as potential coronary risk factors. For example, fibrinogen levels correlate with coronary risk and provide information about coronary risk independent of the lipoprotein profile.

The stability of an arterial thrombus depends on the balance between fibrinolytic factors such as plasmin, and inhibitors of the fibrinolytic system such as plasminogen activator inhibitor 1 (PAI-1). Individuals with diabetes mellitus or the metabolic syndrome have elevated levels of PAI-1 in plasma, and this probably contributes to the increased risk of thrombotic events. Lp(a) (Chap. 31) may modulate fibrinolysis, and individuals with elevated Lp(a) levels have increased CHD risk.

Aspirin reduces CHD events in several contexts. Chapter 33 discusses aspirin therapy in stable ischemic heart disease and Chap. 34 reviews recommendations for aspirin treatment in acute coronary syndromes. In primary prevention, pooled trial data show that low-dose aspirin treatment (81 mg/d to 325 mg on alternate days) can reduce the risk of a first MI in men. Although the recent Women’s Health Study (WHS) showed that aspirin (100 mg on alternate days) reduced strokes by 17%, it did not prevent MI in women. Current American Heart Association (AHA) guidelines recommend the use of low-dose aspirin (75–160 mg/d) for women with high cardiovascular risk (≥20% 10-year risk), for men with a ≥10% 10-year risk of CHD, and for all aspirin-tolerant patients with established cardiovascular disease who lack contraindications.


A large body of literature suggests a relationship between hyperhomocysteinemia and coronary events. Several mutations in the enzymes involved in homocysteine accumulation correlate with thrombosis and, in some studies, with coronary risk. Prospective studies have not shown a robust utility of hyperhomocysteinemia in CHD risk stratification. Clinical trials have not shown that intervention to lower homocysteine levels reduces CHD events. Fortification of the U.S. diet with folic acid to reduce neural tube defects has lowered homocysteine levels in the population at large. Measurement of homocysteine levels should be reserved for individuals with atherosclerosis at a young age or out of proportion to established risk factors. Physicians who advise consumption of supplements containing folic acid should consider that this treatment may mask pernicious anemia.


An accumulation of clinical evidence shows that markers of inflammation correlate with coronary risk. For example, plasma levels of CRP, as measured by a high-sensitivity assay (hsCRP), prospectively predict the risk of MI. CRP levels also correlate with the outcome in patients with acute coronary syndromes. In contrast to several other novel risk factors, CRP adds predictive information to that derived from established risk factors, such as those included in the Framingham score (Fig. 30-4). Recent Mendelian randomization studies do not support a causal role for CRP in cardiovascular disease. Thus, CRP serves as a validated biomarker of risk but probably not as a direct contributor to pathogenesis.



C-reactive protein (CRP) level adds to the predictive value of the Framingham score.
 hsCRP, high-sensitivity measurement of CRP. (Adapted from PM Ridker et al: Circulation 109:2818, 2004.)

Elevations in acute-phase reactants such as fibrinogen and CRP reflect the overall inflammatory burden, not just vascular foci of inflammation. Visceral adipose tissue releases proinflammatory cytokines that drive CRP production and may represent a major extravascular stimulus to elevation of inflammatory markers in obese and overweight individuals. Indeed, CRP levels rise with body mass index (BMI), and weight reduction lowers CRP levels. Infectious agents might also furnish inflammatory stimuli related to cardiovascular risk. To date, randomized clinical trials have not supported the use of antibiotics to reduce CHD risk.

Intriguing evidence suggests that lipid-lowering therapy reduces coronary events in part by muting the inflammatory aspects of the pathogenesis of atherosclerosis. For example, in the JUPITER trial, a prespecified analysis showed that those who achieved lower levels of both LDL and CRP had better clinical outcomes than did those who only reached the lower level of either the inflammatory marker or the atherogenic lipoprotein (Fig. 30-5). Similar analyses of studies of statin treatment in patients after acute coronary syndromes showed the same pattern. The anti-inflammatory effect of statins appears independent of LDL lowering, as these two variables correlated very poorly in individual subjects in multiple clinical trials.



Evidence from the JUPITER study that both LDL-lowering and anti-inflammatory actions contribute to the benefit of statin therapy
 in primary prevention. See text for explanation. hsCRP, high-sensitivity measurement of C-reactive protein (CRP). (Adapted from PM Ridker et al: Lancet 373:1175, 2009.)

Lifestyle modification

The prevention of atherosclerosis presents a long-term challenge to all health care professionals and for public health policy. Both individual practitioners and organizations providing health care should strive to help patients optimize their risk factor profiles long before atherosclerotic disease becomes manifest. The current accumulation of cardiovascular risk in youth and in certain minority populations presents a particularly vexing concern from a public health perspective.

The care plan for all patients seen by internists should include measures to assess and minimize cardiovascular risk. Physicians must counsel patients about the health risks of tobacco use and provide guidance and resources regarding smoking cessation. Similarly, physicians should advise all patients about prudent dietary and physical activity habits for maintaining ideal body weight. Both National Institutes of Health (NIH) and AHA statements recommend at least 30 min of moderate-intensity physical activity per day. Obesity, particularly the male pattern of centripetal or visceral fat accumulation, can contribute to the elements of the metabolic syndrome (Table 30-3). Physicians should encourage their patients to take personal responsibility for behavior related to modifiable risk factors for the development of premature atherosclerotic disease. Conscientious counseling and patient education may forestall the need for pharmacologic measures intended to reduce coronary risk.

Issues in risk assessment

A growing panel of markers of coronary risk presents a perplexing array to the practitioner. Markers measured in peripheral blood include size fractions of LDL particles and concentrations of homocysteine, Lp(a), fibrinogen, CRP, PAI-1, myeloperoxidase, and lipoprotein-associated phospholipase A2, among many others. In general, such specialized tests add little to the information available from a careful history and physical examination combined with measurement of a plasma lipoprotein profile and fasting blood glucose. The high-sensitivity CRP measurement may well prove an exception in view of its robustness in risk prediction, ease of reproducible and standardized measurement, relative stability in individuals over time, and, most important, ability to add to the risk information disclosed by standard measurements such as the components of the Framingham risk score (Fig. 30-4). The addition of information regarding a family history of premature atherosclerosis in parents (a simply obtained indicator of genetic susceptibility), together with the marker of inflammation hsCRP, permits correct reclassification of risk in individuals—especially those whose Framingham scores place them at intermediate risk. Current advisories, however, recommend the use of the hsCRP test only in individuals in this CHD event risk group (10–20%, 10-year risk).

Available data do not support the use of imaging studies to screen for subclinical disease (e.g., measurement of carotid-intima/media thickness, coronary artery calcification, and use of computed tomographic coronary angiograms). Inappropriate use of such imaging modalities may promote excessive alarm in asymptomatic individuals and prompt invasive diagnostic and therapeutic procedures of unproven value. Widespread application of such modalities for screening should await proof that clinical benefit derives from their application.

Progress in human genetics holds considerable promise for risk prediction and for individualization of cardiovascular therapy. Many reports have identified single-nucleotide polymorphisms (SNPs) in candidate genes as predictors of cardiovascular risk. To date, the validation of such genetic markers of risk and drug responsiveness in multiple populations has often proved disappointing. The advent of technology that permits relatively rapid and inexpensive genomewide screens, in contrast to most SNP studies, has led to identification of sites of genetic variation that do reproducibly indicate heightened cardiovascular risk (e.g., chromosome 9p21). The results of genetic studies should identify new potential therapeutic targets (e.g., the enzyme mutated in autosomal dominant hypercholesterolemia, abbreviated PCSK9) and may lead to genetic tests that help refine cardiovascular risk assessment in the future.


Despite declining age-adjusted rates of coronary death, cardiovascular mortality worldwide is rising due to the aging of the population, and the subsiding of communicable diseases and increased prevalence of risk factors in developing countries. Enormous challenges remain regarding translation of the current evidence base into practice. Physicians must learn how to help individuals adopt a healthy lifestyle in a culturally appropriate manner and to deploy their increasingly powerful pharmacologic tools most economically and effectively. The obstacles to implementation of current evidence-based prevention and treatment of atherosclerosis involve economics, education, physician awareness, and patient adherence to recommended regimens. Future goals in the treatment of atherosclerosis should include more widespread implementation of the current evidence-based guidelines regarding risk factor management and, when appropriate, drug therapy.