Atherosclerosis is the accumulation of cholesterol and other fatty substances (lipids) in the walls of arteries, causing the arteries to narrow. Atherosclerosis can affect arteries in any area of the body and is a major cause of stroke, heart attack (see myocardial infarction), and poor circulation in the legs. The arteries become narrowed when fatty substances carried in the blood accumulate on the inside lining of the arteries and form yellow deposits known as atheromatous plaques.
These deposits restrict the blood flow through the arteries. In addition, the muscle layer of the artery wall becomes thickened, which narrows the artery even further. Platelets (tiny blood cells that are responsible for blood clotting) may collect in clumps on the surface of the deposits and initiate the formation of blood clots. A large clot may completely block the artery, resulting in the organ it supplies being deprived of oxygen.
A complete blockage in a coronary artery can cause a sudden, often fatal, heart attack.
The risk of developing atherosclerosis is determined largely by the level of cholesterol in the bloodstream, which depends on dietary and genetic factors. Atherosclerosis is more common in developed countries, where most people eat a diet high in fat. Some disorders such as diabetes mellitus can be associated with a high cholesterol level, regardless of diet.
Atherosclerosis usually produces no symptoms in its early stages. As the condition progresses, symptoms occur as a result of reduced, or total absence of, blood supply to the organs supplied by the affected arteries. Partial blockage of the coronary arteries (which supply the heart muscle) may produce symptoms such as the chest pain of angina pectoris.
Narrowing of the arteries supplying blood to the brain may cause transient ischaemic attacks (symptoms and signs of a stroke that last for less than 24 hours) and episodes of dizziness. Intermittent claudication (a cramplike pain on walking) is often the first symptom of atherosclerosis in the leg arteries. If the condition is associated with an inherited lipid disorder (see hyperlipidaemias), fatty deposits may develop on tendons or as visible lumps under the skin.
Diagnosis and treatment
Blood flow through an artery can be investigated by angiography (X-rays after injection of a radiopaque substance) or Doppler ultrasound scanning
The best treatment for atherosclerosis is to prevent it from progressing by the maintenance of a healthy lifestyle. This includes adoption of a low-fat diet, not smoking, regular exercise, and maintenance of the recommended weight for height. These measures lead to a reduced risk of developing significant atherosclerosis.
Those individuals found to have high blood cholesterol levels but who are otherwise in good health will be advised to adopt a low-fat diet. They may also be given drugs that decrease blood cholesterol levels (see lipid-lowering drugs). For people who have had a heart attack, research has shown that there may be a benefit in lowering blood cholesterol levels, even if the level is within the average range for healthy people.
People with atherosclerosis and those at risk may be prescribed a drug such as aspirin to reduce the risk of blood clots forming on the damaged artery lining. Surgical treatment of atherosclerosis, such as coronary angioplasty (see angioplasty, ballon angioplasty), may be recommended for those people thought to be at high risk of severe complications. If blood flow to the heart is severely obstructed, a coronary artery bypass may be carried out to restore blood flow.
Atherosclerosis is a systemic inflammatory disease. The initial steps of atherogenesis involve cholesterol accumulation in the intima that is thought to mediate recruitment of inflammatory leucocytes, followed by development of a fibro-fatty plaque comprising a lipid core and macrophages that ultimately evolve into lipid-rich foam cells.
Lipoprotein particles accumulate in the arterial intima soon after initiation of hypercholesterolaemia and undergo oxidative and other chemical modifications that can confer proinflammatory properties such as induction of adhesion molecules that mediate leucocyte adherence.
During the initial phases of atherogenesis, endothelial cells express molecules such as vascular cell-adhesion molecule-1 (VCAM-1) in a patchy distribution that reflects the ultimate location of arterial plaques.
Oxidized low-density lipoprotein (LDL) in the arterial intima can mediate other proinflammatory effects, such as (1) stimulating endothelial and smooth muscle cells to produce potent chemokines, which can encourage adherent leucocytes to migrate through the endothelium into the arterial intima to initiate plaque formation; (2) activating leucocytes after their recruitment into the plaque, leading to the production of further inflammatory molecules, such as cytokines, and small molecules, such as biologically active eicosanoids.
Antiatherogenic processes oppose this potent cocktail of proatherogenic events, including reverse cholesterol transport—whereby high-density lipoproteins (HDL) unload cholesterol from lipid-laden plaque macrophages and carry it away from the arterial wall for breakdown and disposal.
Inflammatory monocytes and T cells enter the arterial wall along a chemokine gradient, forming the earliest microscopic lesion of atheroma. The recruited monocytes mature into macrophages, promoting expression of the scavenger receptors that permit the unregulated uptake of cholesterol-laden, modified, lipoprotein particles and leading them to become foam cells, which form a small fatty streak that progresses gradually to become an atheromatous plaque.
As the fatty streak matures, the smooth muscle cells produce extracellular matrix and the fibrous components that produce the characteristic structure of a subendothelial fibrous cap overlying a lipid-rich core and deeper islands of smooth muscle cells and macrophages. Events within the atheromatous plaque are complex: endothelial cells form internal, immature, leaky haemorrhage-prone microvessels that provide a new site for entry into the lesion of inflammatory monocytes that perpetuate the atherosclerotic process; they also present a potential site for the intraplaque bleeding associated with plaque progression. Some plaques show deposition of calcium over time in a process similar to bone mineralization.
Atheromatous plaques are unpredictable—atheroma progresses through very gradual cellular accumulation, as described above, punctuated by crises that promote lesion development. These crises may occur when a plaque erodes or ruptures, exposing its thrombogenic core and causing sudden, partial luminal thrombosis.
Acute coronary syndromes follow sudden thrombotic events related to the exposure of circulating platelets to thrombogenic components of the plaque via either superficial erosions or rupture of the plaque’s fibrous cap. Careful anatomopathological study has given rise to the concept of the ‘vulnerable’ plaque—an intact plaque similar to those present beneath the site of a fatal coronary thrombosis that is characterized by a thin fibrous cap, a relative paucity of smooth muscle cells, and an abundance of inflammatory cells, particularly macrophages. Plaques that rupture are not necessarily those that cause high-grade stenoses: intravascular ultrasound studies and autopsy data show that many individuals have multiple high-risk or vulnerable plaques as well as ruptured plaques, causing symptomatic or fatal acute coronary syndromes.
Cardiovascular disease—already the leading cause of death in Europe (4.35 million/year) and the United States of America (2600/day)—will probably become the leading cause of death worldwide. Atherosclerosis causes about one-half of these deaths from coronary heart disease and one-third from stroke. In the face of this growing threat to the world’s health, researchers are working to develop a greater understanding of the mechanisms of atheromatous vascular disease.
According to the traditional view, atherosclerosis resulted from storage of excessive cholesterol in the arterial intima, forming atheromatous lesions that would eventually lead to stenosis, causing symptoms of angina, or ultimately occlusion, causing myocardial infarction. This concept disregarded the common clinical scenario of myocardial infarction or sudden cardiac death as a first manifestation of coronary atherosclerosis without premonitory ischaemic signs or symptoms. Moreover, evidence accumulated from autopsy and clinical studies showed that only 25 to 33% of lethal coronary thrombi occurred at sites of the most stenotic segments in the infarct-related artery. The discrepancy between the substantial benefits of cholesterol-lowering therapies in altering cardiovascular event rates in the face of minimal changes in severity of coronary stenoses fuelled further doubts about this concept of atherogenesis (Fig. 126.96.36.199).
Today we appreciate a more complex interaction between critical cells of the artery wall and the blood, which helps us better understand the molecular messages they exchange. Our current knowledge supports the theory of inflammation as the driving force behind initiation, progression, and catastrophic thrombotic complications of atherosclerosis. These three phases may occur simultaneously in the arterial tree of an individual, illustrating the nonlinear nature of atherogenesis. Recent studies reveal that patients with acute coronary syndromes may have more than one potentially unstable lesion in addition to the culprit responsible for the acute presentation. These changes in our view of atherogenesis favour the concept of atherosclerosis as a systemic inflammatory disease in which acute revascularization may accomplish important relief of ischaemia due to fixed stenoses and limit damage during ST-segmented elevation myocardial infarction, but does not address the underlying processes governing the condition. Here we review the evolving concepts of pathophysiology of atheroma that help us understand the disease and approach patient diagnosis and management more rationally than in the past.
The normal vessel wall
Diet and lifestyle in the Western world have rendered the normal artery relatively rare outside childhood. Arteries comprise three concentric layers—the tunica intima, tunica media, and adventitia.
The innermost layer—the intima—consists of a thin layer of endothelial cells that form the critical interface with the circulating blood. In healthy vessels, endothelial cells produce nitric oxide (NO) to maintain the arterial bed in a continuous state of relaxation, resist thrombosis and limit inflammation: ‘atheroprotective’ functions often lost in arteries subjected to risk factors for atherosclerosis or disturbed local flow. Endothelial cells also powerfully resist blood clot formation by expressing heparan sulphate proteoglycans on their surface and producing endogenous fibrinolytic agents such as tissue and urokinase plasminogen activators. The endothelium rests on a basement membrane of nonfibrillar collagens such as laminin and type IV collagen, but with age the intima may thicken and incorporate more complex fibrillar collagens (I and III) elaborated by smooth muscle cells.
The tunica media
The media comprises a layer of smooth muscle cells and extracellular matrix, which differs in large and small arteries. The larger vessels have multiple elastin-rich laminae interspersed with smooth muscle cells, while smaller vessels lack these elastic layers, enmeshing the cells directly in the matrix. In both types of arteries, endothelial and smooth muscle cells proliferate very slowly if at all, and, importantly, a balance prevails between extracellular matrix synthesis and breakdown, which preserves the vessel’s structural integrity. The external elastic lamina borders the media and demarcates the outer layer of the artery, the adventitia.
This last layer of the arterial wall contains a loose mesh of collagen fibrils encompassing the vaso vasorum, the nerve supply to the vessel wall, and cells such as fibroblasts and mast cells. Long neglected in comparison to the other layers of the vessel wall, the adventitia has become the focus of more studies, particularly in light of the recognition of the importance of neovascularization in plaque stability.
Initiation of atheroma
Atherogenesis and risk factors for coronary disease
The initial steps to atherogenesis involve cholesterol accumulation in the intima that is thought to mediate recruitment of inflammatory leucocytes followed by development of a fibro-fatty plaque comprising a lipid core and macrophages that will ultimately evolve into lipid-rich foam cells (Fig. 188.8.131.52). Pivotal observational studies in the United Kingdom, Europe, and the United States of America have improved our understanding of risk factors for coronary heart disease such as hypercholesterolaemia, cigarette smoking, hypertension, and diabetes, but the biological links between these risk factors and the pathobiology of atheroma remain incompletely understood.
Hyperlipidaemia links consistently with human and experimental atheroma. Many atherogenesis studies use mice with genetic modification that causes profound dyslipidaemia to stimulate rapid atherogenesis. Studies of such atherosclerosis-prone animals show that lipoprotein particles accumulate in the arterial intima soon after initiation of hypercholesterolemia. The lipids bind to proteoglycans, prolonging their residence in the intima, a site sequestered from certain plasma antioxidants. There, the retained lipoprotein particles can undergo oxidative and other chemical modifications that can confer proinflammatory properties such as induction of adhesion molecules that mediate leukocyte adherence. Endothelial cells express leucocyte adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) during the initial phases of atherogenesis in a patchy distribution, principally at branch points and sites of disturbed flow where there is low shear stress. This nonrandom and discontinuous distribution of VCAM-1 induction reflects the ultimate location of arterial plaques in both animals and humans.
Oxidized low-density lipoprotein (LDL) in the arterial intima can mediate other proinflammatory effects such as stimulating endothelial and smooth muscle cells to produce potent chemokines such as monocyte chemoattractant protein-1 (MCP-1), which can encourage adherent leucocytes to migrate through the endothelium into the arterial intima to initiate plaque formation. Oxidized LDL activates these leucocytes after their recruitment into the plaque and the cells produce further inflammatory molecules such as cytokines and small molecules such as biologically active eicosanoids.
Hypertension may exert some of its deleterious effects on the vasculature via angiotensin II, which can promote production of reactive oxygen species and mediate expression of adhesion molecules on endothelial cells, encouraging leucocyte recruitment. In addition, angiotensin II can advance plaque formation by making smooth muscle cells express chemoattractants such as MCP-1 and proinflammatory cytokines such as interleukin-6 (IL-6).
Diabetes confers substantial cardiovascular risk, and individuals may often have additional risk factors such as hypertension and hyperlipidaemia. Oxidative stress, hyperglycemia, and development of advanced glycation products may enhance inflammation in diabetic vasculopathy. Products of advanced glycation, for example, can promote the release of proinflammatory atherogenic soluble CD40L from megakaryocytes in vitro. Whether good glycaemic control can reduce inflammation and/or reduce vascular events in diabetes remains controversial. Agonists of the peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ nuclear receptors have attracted interest as regulators of key metabolic pathways that may regulate inflammation in diabetes. Human trials have not yet demonstrated that drugs targeting these nuclear receptors reduce cardiovascular disease.
Coronary artery disease affecting transplanted hearts represents an extreme case of atherogenesis accelerated by adaptive immune responses. Recent reviews have highlighted the features of this disease compared to the more common native atherosclerosis.
Recruitment of leucocytes into the developing atherosclerotic plaque provides the building blocks for intense local inflammation. Expression of adhesion molecules such as VCAM-1 on the vascular endothelial cells provides the anchor for leucocytes to attach to the vessel wall via their surface very late antigen 4 (VLA4). Mice deficient in important adhesion molecules such as selectins or expressing dysfunctional truncated VCAM-1 exhibit reduced severity of atheroma. After adhesion, locally produced chemokines such as MCP-1 can attract the leucocyte into the vessel wall. Monocytes participate fundamentally in atherogenesis as they evolve into macrophages that accumulate lipids via their scavenger receptors and become lipid-rich foam cells. These foam cells can produce abundant proinflammatory cytokines and proteases, which potentially promote changes in plaque biology that can precipitate clinical events.
Monocytes accumulate continuously in both early and late plaques in hypercholesterolemic mice, suggesting that leucocyte recruitment reflects an ongoing dynamic process rather than an early trigger of atheroma. Specific monocyte subsets have particular propensity to enter plaques, and certain chemokine receptors (CCR2 and CX3C-chemokine receptor 1) participate in this trafficking. These receptors may form important therapeutic targets, particularly CX3C chemokine receptor 1, which appears more specific to atheroma than general inflammation. The recruitment of monocytes into established plaques in both early and advanced atheroma suggests that modifying the process would require long-term interventions. T cells and mast cells also appear in atherosclerotic plaques, originating not only from the luminal endothelium of the vessel but also from the vasa vasorum that penetrate in to the plaque, probably primarily from the adventitia. Most T cells in the plaque predominantly produce Th1-type cytokines such as interferon-γ (IFN-γ), tumour necrosis factor α (TNFα) and interleukins (IL) 12, 15, and 18. These proatherosclerotic factors promote macrophage activation, production of further Th1 differentiated T cells, protease production and activation, and diminished collagen synthesis and smooth muscle cell proliferation. Long recognized as denizens of the adventitia, and as a small portion of the leucocyte population in plaques, mast cells may also promote atherogenesis, not only by elaborating small-molecule mediators (e.g. histamine), but also proinflammatory cytokines and proteinases.
Advanced senescence of white cells of patients with coronary artery disease correlates with adverse outcomes. Telomere (nucleotide repeats on the ends of chromosomes) length reflects cellular senescence, which in youth may be 10 000 to 20 000 base pairs long but which gradually reduces with cell division and age. Endothelial cells from patients with coronary disease have shorter telomeres. In one nested case-control trial of the West of Scotland Primary Prevention Study, shorter mean telomere length not only predicted future coronary events but also indicated who would benefit most from statin treatment. Telomere length may relate to events associated with inflammation in addition to an inherited component (chromosome 12). Senescent arterial endothelial cells express more ICAM-1 and less NO, while oxidative stress accelerates telomere attrition.
Molecular biology of atheroprotection
Antiatherogenic processes oppose this potent cocktail of proatherogenic events. One of the foremost is reverse cholesterol transport—the ability of high-density lipoproteins (HDL) to unload cholesterol from lipid-laden plaque macrophages and carry it away from the arterial wall for breakdown and disposal. The ABCA1 and ABCG1 lipid transporters mediate this process. HDL particles also oppose atherogenesis by reducing cytokine-induced expression of adhesion molecules in endothelial cells and by providing a source of antioxidants such as paroxonase-1 to oppose the proinflammatory effects of phospholipids. HDL also interacts with NO, increasing production and activation of the enzyme nitric oxide synthase. In turn, NO dilates arteries, opposes leucocyte recruitment into the vessel wall, and combats platelet aggregation. As NO production and stability increase at sites of laminar shear stress, the atheroprotective properties of this gas may in part explain the predilection of regions of disturbed flow to atheroma formation.
The immune system can also defend against atherosclerosis. While adaptive immunity mediated by T cells secreting Th1 type cytokines (e.g. interferon-γ) can aggravate atherosclerosis, Th2 cells (in addition to platelets, macrophages, endothelial cells, and smooth muscle cells) produce antiatherogenic cytokines such as IL-10 and TGFβ. Gain of function or loss of function experiments in atherosclerotic mice have shown a clear atheroprotective role for IL10. In studies of mice with T cells expressing dominant negative TGFβ receptors, two models exhibited marked inflammation and poor matrix formation after prevention of this cytokine’s T-cell-related functions, thus supporting a role for TGFβ in T-cell-mediated suppression of inflammation. TGFβ stimulates collagen production, and these studies also demonstrate its role in enhancing features of plaques linked to resistance to rupture. Humoral immunity can also mitigate atherosclerosis: for example, administration of antibodies raised against oxidized LDL can reduce atherosclerosis, and interference with B cell function can promote lesion formation.
Evolution of atheroma
In the earliest stage of atheroma, LDL particles accumulate in the arterial intima and undergo oxidation as described above. Products of LDL oxidation in turn stimulate endothelial cells to express vital adhesion molecules such as ICAM and VCAM. Inflammatory monocytes and T cells begin to roll along the arterial wall and adhere to the now ‘sticky’ endothelium. These white cells then enter the arterial wall along a chemokine gradient, forming the earliest microscopic lesion of atheroma. Factors such as macrophage colony-stimulating factor (M-CSF) cause recruited monocytes to mature into macrophages and promote subsequent expression of the scavenger receptors that permit the unregulated uptake of cholesterol-laden modified lipoprotein particles and become foam cells (so called due to the microscopic foamy appearance of the pool of intracellular lipid). This process repeats itself, amplifying the atherogenic events within the arterial wall. Foam cells form a small fatty streak that progresses gradually to become an atheromatous plaque.
Smooth muscle cells
The dysfunctional endothelial cell crucially instigates atherogenesis because it recruits cells that mediate inflammation within the wall and has hampered NO production. As the fatty streak matures, the smooth muscle cells and macrophages within the plaque steer much of its subsequent development. While some smooth muscle cells may populate the intima of normal human arteries, intimal inflammation encourages smooth muscle cells from the media to migrate into the intima. The macrophages and foam cells within the plaque secrete chemoattractants such as platelet-derived growth factor (PDGF), which promote smooth muscle cell migration. In contrast to the early response to arterial injury following balloon angioplasty or stenting, proliferation of smooth muscle cells occurs quite slowly in atherosclerosis. Mitoses occur in fewer than 1% of cells in advanced plaques. The combination of smooth muscle cell migration and proliferation during the lengthy development time of atherosclerosis allows smooth muscle cells to contribute to lesion expansion.
The smooth muscle cell produces much of the arterial extracellular matrix, which supplies the fibrous components that add volume to the developing fibro-fatty plaque. The major extracellular matrix macromolecules in plaque include interstitial collagens (types I and III) and proteoglycans such as versican, biglycan, aggrecan, and decorin. Elastin fibres may also accumulate in atherosclerotic plaques and may display more active turnover than previously thought. The matrix components function beyond furnishing a scaffold for the plaque. Some constituents (notably proteoglycans) bind lipoproteins, prolong their residence in the intima, and render them more susceptible to oxidative modification and glycation. The resultant oxidized phospholipids and advanced glycation end-products promote the inflammatory response within the vessel wall, advancing atherogenesis. The matrix can also serve as a storage site for growth factors, and cleaving certain components such as laminin releases sequestered mediators that promote cellular migration. The vascular smooth muscle cell produces these matrix molecules in both diseased and normal arteries. Cytokines such as TGFβ and PDGF derived from T cells, platelets, macrophages, and monocytes stimulate smooth muscle cells to produce excess extracellular matrix. This process not only increases plaque size but also allows the formation of its characteristic structure, with a subendothelial fibrous cap overlying the lipid-rich core and deeper islands of smooth muscle cell macrophages.
Matrix breakdown also participates in plaque progression. Catabolism of extracellular matrix macromolecules at the leading edge of inflammatory monocytes, macrophages, and smooth muscle cells probably facilitates their migration into the intima. In the arterial wall there is a delicate balance between matrix breakdown and synthesis. Four groups of proteases within the vasculature break down the extracellular matrix: metalloproteinases (MMPs), cysteine proteases, serine proteases, and the newest group, distintegrin metalloproteases (or ADAMs). Tight regulation of proteases happens not only at transcriptional level but also through activation, in the case of the metalloproteinases, and endogenous inhibitors. For example, the tissue inhibitors of the metalloproteinases oppose the actions of the MMPs while cystatin C hinders the cysteine proteases such as the cathepsins.
Cell death in the plaque
The importance of programmed cell death within the plaque is increasingly recognized. In more advanced atheromatous plaques, fragmentation of smooth muscle cell DNA occurs, suggesting apoptotic cell death. Proinflammatory T cells may mediate these events because they prompt expression of Fas, which can bind Fas ligand on the smooth muscle cell surface, promoting cell death. The death of lipid-laden macrophages can lead to extracellular deposition of tissue factor (TF), some in particulate form. The extracellular lipid that accumulates in the intima can coalesce and form the classic lipid-rich ‘necrotic’ core of the atherosclerotic plaque.
As plaques develop, smooth muscle cells and macrophages are not the only cell types to proliferate. Oxidized phospholipids within the plaque can stimulate the production of important angiogenic factors such as vascular endothelial growth factor (VEGF) isoforms in both monocytes and endothelial cells. Endothelial cells then form immature, leaky, haemorrhage-prone microvessels within the plaque. These neovessels provide a new site for entry into the lesion of inflammatory monocytes that perpetuate the atherosclerotic process. The microvessels also present a potential site for the intraplaque bleeding associated with plaque progression. Haem-derived iron deposited extracellularly due to haemorrhage in plaques from disrupted microvessels can catalyse reactions that form reactive oxygen species that promote oxidative stress in plaques.
Some plaques show deposition of calcium over time in a process similar to bone mineralization. Some smooth muscle cells elaborate bone morphogenic proteins related to TGFβ. Plaque calcification, even when microscopic, can produce biomechanical changes in plaques that prompt clinical complications. Quantitation of plaque calcification by radiographic techniques may provide a noninvasive assessment of plaque burden. Whether calcium scores provide important prognostic information beyond risk prediction algorithms that do not require imaging remains a matter of debate.
Arterial calcification accelerates in patients with hypercalcaemia related to renal disease in which coronary calcification can affect up to 88% of 20- to 30-year-olds on dialysis, compared to 5% in an age-matched control group. Coronary calcification in renal failure correlates with adverse prognosis. Atherosclerosis of renal failure has features distinct from coronary disease in the general population but still represents the same disease.
Disease progression and positive remodelling
Some of the pathological events associated with atheroma described above suggest a gradual inevitability in progressive arterial stenosis. This model does not fit the pattern seen in experimental or clinical settings. Rather, atheroma progresses through very gradual cellular accumulation punctuated by crises that promote lesion development. These crises may occur when a plaque erodes or ruptures, exposing its thrombogenic core and causing sudden partial luminal thrombosis. These ruptures probably occur frequently and very often remain subclinical. The healing phase that follows may involve further smooth muscle cell proliferation and matrix deposition, which may stabilize but also enlarge the plaque and promote stenosis by constrictive remodelling. In this respect, a plaque is like the cinder cone of an active volcano, which expands with each small eruption but whose size alone does not help predict a catastrophic eruption.
The lack of correlation between pre-existing plaque size and future coronary events also relates to positive remodelling within the arterial wall. Interventional angiographically based therapies for coronary artery disease depend only on the luminal size when assessing lesion severity. This approach allows relevant therapy to treat the often relatively fibrous occlusive lesions that cause stable angina. However, intravascular ultrasound studies have shown that larger areas of plaque burden may exist in regions of the arteries with little or no luminal stenosis. Compensatory outward expansion of the artery’s external elastic lamina can accommodate plaques with large lipid cores that do not appear on angiogram but may nonetheless rupture suddenly, causing thrombus formation and acute coronary syndromes.
Acute coronary syndromes
Acute coronary syndromes form an increasingly large part of the clinical manifestation of coronary artery disease and comprise unstable angina (angina of increasing frequency and severity), non-ST elevation myocardial infarction, and ST elevation myocardial infarction. These definitions have evolved as our ability to detect myocardial necrosis through biomarkers such as troponin I and T has become more sensitive and moves beyond definitions based on the ECG. Acute coronary syndromes follow sudden thrombotic events related to exposure of circulating platelets to thrombogenic components of the plaque via either superficial erosions or rupture of the plaque’s fibrous cap.
Understanding of the mechanisms of plaque erosion has lagged behind that of plaque rupture. Plaque erosion comprises an acute thrombus in direct contact with the intima in an area absent of endothelium. The crucial event appears to be endothelial loss, which follows either apoptosis of endothelial cells or shedding of cells from the basement membrane via the action of proteases such as gelatinases on type IV collagen or other components of the basement membrane upon which endothelial cells rest. Coronary vasospasm may explain the observed lack of endothelium and intact, relatively thick media at erosion sites compared to sites of plaque rupture. Sites of plaque erosion may not exhibit prominent macrophage and lymphocyte accumulation. The underlying plaque in erosions consists of a thickened intima or fibrous cap atheroma, and lesions may be eccentric or calcified. Plaque erosion is found in 20% of all sudden deaths and in 40% of coronary thrombi in patients dying suddenly with coronary artery atherosclerosis. Fatal thrombosis due to plaque erosion associates with smoking, especially in women. Compared to fibrous cap rupture, death due to plaque erosion occurs more often in younger individuals and may affect less severely narrowed arteries at the site of fatal thrombosis. Plaque erosion accounts for more than 80% of thrombi occurring in women less than 50 years of age.
Careful anatomopathological study has given rise to the concept of the ‘vulnerable’ plaque—an intact plaque similar to those present beneath the site of a fatal coronary thrombosis. A thin fibrous cap, a relative paucity of smooth muscle cells, and an abundance of inflammatory cells, particularly macrophages, characterize plaques that have provoked fatal coronary thrombosis. The plaques have a lipid core of variable size formed of foam cells and debris from dead or dying phagocytes that deposited their cholesterol into the plaque. Deposition of cholesterol-rich red cell membranes due to intraplaque haemorrhages from fragile neovessels may also contribute to formation of the plaque’s lipid core. These atheromatous, lipid-rich plaques, distinct from more fibrous and often highly calcified plaques, have shoulder regions where macrophages and T cells accumulate relatively close to the fibrous cap and lumen of the vessel.
The small number of smooth muscle cells likely contributes to the lack of extracellular matrix and the more meager fibrous cap. The interstitial collagens (types I and II) would normally confer mechanical stability on the plaque, but IFN-γ derived from T cells and macrophages reduces production of these structural plaque components in areas of inflammation. IFN-γ also inhibits smooth muscle cell proliferation, contributing further to the lack of smooth muscle cells and matrix in these plaques.
Matrix breakdown within the fibrous cap that reveals the thrombogenic core may trigger rupture, and interstitial collagenase MMP-1, as well as MMP-2, MMP-3, MMP-9, and tissue inhibitors of MMPs (TIMP-1 and TIMP-2), localize in plaques. Shoulder regions of carotid plaques have abundant foam cells, show evidence of collagenolysis in situ, and express MMPs -9, -3, and -1. MMPs colocalize with intraplaque haemorrhages, areas of increased wall stress in human atheroma, and occur in plaques with histological features associated with vulnerability. The interstitial collagenases (MMP-1, -8 and -13) share the unusual ability to initiate collagenolysis by cleaving intact triple helical collagen. MMP collagenases colocalize with cleaved collagen fragments in situ in human lesions.
Breakdown of elastin, a structural component of the arterial wall, may be important in expansive and occlusive remodelling. Human atheromata contain smooth muscle-derived cathepsins S, K, and L, potent elastases that localize at sites of breaks in the elastic laminae. Interestingly, normal vessels contain little or no cathepsins, while fatty streaks—thought to be an early stage of atheroma—have widely distributed cathepsins S and K. More advanced atheroma macrophages express these proteinases in addition to cathepsins B, D, and F, which degrade elastin and collagen. Macrophages in the shoulders of human carotid plaques express the serine proteinase known as neutrophil elastase, and CD40L regulates this enzyme. Serine proteases urokinase-type plasminogen activator (uPA) and tissue plasminogen activator (tPA) occur in intimal smooth muscle cells and macrophage-derived foam cells. Macrophages localized on the necrotic core margin express particularly high levels of uPA while both tPA and uPA abound in the neomicrovessels of plaques, suggesting a role in plaque angiogenesis.
CD40L is an important inflammatory mediator that localizes in plaques and promotes proteolysis. Pathological studies of human atheroma and in mice implicate CD40L in atherogenesis and disease progression. Endothelial cells, smooth muscle cells and macrophages all express the CD40 receptor, and its ligation activates these cell types to produce key molecules in atherogenesis such as cytokines IL-1, IL-6, and IL-8 and adhesion molecules ICAM-1, VCAM-1, and E-selectin. CD40L can prompt production of each MMP listed above. It also enhances thrombogenicity by inducing tissue factor expression within the plaque.
A number of processes foster rapid thrombosis following plaque rupture. Exposure of blood to collagen fibres within the disrupted plaque leads to platelet aggregation. Tissue factor produced by smooth muscle cells and macrophages also potently activates the coagulation cascade. This process promotes thrombin generation, which further activates platelets, endothelial cells, smooth muscle cells, and macrophages. These processes within the plaque interact with the blood. Patients with obesity or diabetes exhibit higher circulating levels of plasminogen activator inhibitor-1 (PAI-1), which disrupts fibrinolytic processes. In addition, disrupted plaques or dying endothelial cells may release tissue factor and microparticles bearing this procoagulant into the blood, causing an additional circulating threat. Accordingly, changes in the fluid phase of blood as well as the solid state of the plaque may enhance susceptibility to acute cardiac events.
Vulnerable plaque and the vulnerable patient
The concept of the vulnerable plaque enhances our understanding of atherogenesis and its crises—the acute coronary syndromes. It may, however, have led to an erroneous expectation regarding the potential to identify threatening plaques and deliver local stabilizing agents—perhaps via interventional techniques—that would alter prognosis. Recent clinical trial data confirm that coronary intervention in stable angina does not reduce death, myocardial infarction, or cardiovascular events compared with optimal medical therapy. These clinical trial results make sense, as plaques that rupture do not necessarily cause the high-grade stenoses that comprise the most appropriate target for revascularization. Both intravascular ultrasound studies and autopsy data also show that many individuals have multiple high-risk or vulnerable plaques as well as ruptured plaques, causing symptomatic or fatal acute coronary syndrome. Attention now focuses on systemic therapies such as statins, which in animal studies alter the character of plaques to a more fibrous, less inflamed type. Quantitative coronary angiographic studies such as the FATs study show that lovastatin and colestipol versus usual therapy correlates with only a –0.3% change in luminal calibre of the fixed stenoses, but a profound 73% reduction in death, myocardial infarction, or repeat intervention for ischaemia.
Interest now focuses on identifying biomarkers that may predict the vulnerable patient who has a modifiable cardiovascular risk. An increased risk of primary or recurrent vascular events is associated with fibrinogen, IL-1, IL-6, IL-8, myeloperoxidase, MMP-9, sCD40L, lipoprotein-associated phospholipase A2, soluble ICAM-1, VCAM-1, P-selectin, leptin, and adiponectin, in addition to the connection with reduced telomere length previously discussed. C-reactive protein, measured with a high-sensitivity assay, currently constitutes the most clinically practical marker of inflammation. Numerous trials of both primary and secondary prevention of cardiovascular risk have found an association between CRP and cardiovascular risk, although CRP probably does not have a direct pathological role. The current most effective treatments for preventing cardiovascular events—the statins—address not only lipid lowering but also other atherogenic processes implicated in reducing systemic inflammation, and appear to stabilize plaques. Thus, these systemic therapies may protect both the vulnerable plaque and the vulnerable patient.