The epidemiology and pathophysiology of coronary artery disease
Epidemiology of coronary heart disease
Advances in the prevention and treatment of coronary heart disease (CHD) have led to significant improvements in prognosis and quality of life, but globally CHD remains a leading cause of premature death and disability. In 2001 CHD was responsible for 11.8% of all deaths in low- and middle-income countries and 17.3% in high-income countries, accounting for over 7 million deaths worldwide(1). By 2020 CHD is projected to be the leading cause of death and disability-adjusted life years(2), reflecting a rapidly increasing prevalence in developing countries and Eastern Europe, and the rising incidence of obesity and diabetes in the Western world.
Mortality
In the United Kingdom around one in five men and one in seven women die from CHD with over 94 000 coronary deaths per annum(3). CHD is the most frequent cause of premature death (before the age of 75) accounting for almost 31 000 such deaths in 2006, including 19% of premature deaths in men and 10% in women. In the United States in 2005, CHD caused nearly 0.5 million deaths and accounted for one in five of all deaths. Although annual CHD mortality declined by 34.3% from 1995 to 2005 the actual number of deaths fell by only 19.4%(4).
There are regional, social, and ethnic variations in coronary disease-associated mortality, and over the last 25 years death rates from CHD have been consistently higher in Scotland than in other regions in the United Kingdom. The highest coronary deaths rates are reported amongst men of South Asian descent and from 1999 to 2003 mortality rates in men of Bangladeshi origin exceeded rates in the general population by 112%. Death rates from CHD increase during the winter months, and in 2004/2005 winter mortality in England and Wales was 19% higher than at other times of the year(3).
Mortality rates from CHD have been declining in industrialized countries over several decades, but there is currently an epidemic of CHD in Eastern Europe (Fig. 1.1). Over the last decade, coronary mortality in the United Kingdom amongst people aged less than 65 years has fallen by 45%. Nevertheless, reductions in coronary mortality have been slower in the United Kingdom than in most other developed countries, and across Western Europe only Ireland and Finland have higher mortality rates (Fig. 1.2)(3,5).
In recent years the decline in coronary mortality in industrialized countries has been slower in younger than in older age groups. For example, in the United Kingdom from 1997 to 2006 there was a 46% fall in CHD mortality amongst men aged 55–64 years but only a 22% fall among men aged 35–44 years(3). In the United States the decline in age-adjusted coronary mortality from 1980 to 2002 slowed markedly in adults aged 35–54 years. Moreover, since 1997 the mortality rate among women aged 35–44 years has been increasing by about 1.3% per year(6).
It has been estimated that 58% of the decline in coronary mortality in the United Kingdom between 1981 and 2000 was attributable to reductions in major risk factors, principally smoking, but the remaining 42% was explained by treatment of individuals, including secondary prevention(7). In the United States it has been estimated that 47% of the reduction in CHD mortality from 1980 to 2000 is attributable to treatments and 44% is attributable to modification of risk factors, but this was partially offset by a rise in mortality attributable to increases in body mass index and diabetes prevalence(8). The WHO-MONICA project examined temporal trends in cardiovascular mortality over the 1980s and 1990s in 21 countries, and demonstrated a strong link between improved care for patients with myocardial infarction and the decline in coronary mortality(9). An investigation into the potential impact of various preventative and interventional strategies on CHD-related mortality in the United States estimated that delivery of ‘perfect care’ (through the modification of risk factors and use of all effective therapies) to a hypothetical population (aged 30–84 years) could prevent or postpone around 75% of cardiac deaths(10).
Whilst the rate of CHD-related mortality in developed countries has been steadily declining over recent decades, the global burden of coronary disease has been increasing, particularly in developing countries(11–13). In Beijing, China, from 1984 to 1999 there was an increase in coronary death rates of approximately 50% in men and 27% in women, primarily attributable to increases in the prevalence of raised total serum cholesterol, smoking, diabetes, and hypertension(11). Cardiovascular mortality in India is projected to increase rapidly and, if current trends continue, by 2020 India will account for more coronary deaths than either China or the established market economies. As with other emerging economies, urbanization of the Indian population has increased exposure to coronary risk factors, including tobacco use, high blood pressure, elevated blood lipid levels, obesity, diabetes, and sedentary lifestyles(13). Increasing rates of CHD have also been observed in sub-Saharan Africa and Latin America(14,15).
Morbidity
Coronary artery disease is a chronic degenerative condition, which can present with a wide range of clinical syndromes, including stable angina, acute coronary syndrome, heart failure, arrhythmia, and death. Estimating the incidence and prevalence of coronary disease-related morbidity is therefore challenging and is confounded by changing definitions and diagnostic criteria over time(16,17).
The reported incidence and prevalence of myocardial infarction is higher in men than in women and increases with age. In 2006 the incidence of myocardial infarction in the United Kingdom was estimated to be between 67 000 and 87 000 per year in men of all ages and between 46 000 and 56 000 per year in women of all ages. The Health Survey for England 2006 reported that 4.1% of all men and 1.7% of all women have had a myocardial infarct. In people aged over 35 years, the prevalence of myocardial infarction has been estimated as 970 000 in males and 439 000 in females. As with CHD mortality there are large regional, socioeconomic, and ethnic variations in the incidence and prevalence of myocardial infarction(3). In the United States in 2006 the prevalence of myocardial infarction in adults aged 20 years or over was estimated at 3.6%, with a prevalence of any coronary disease of 7.6%(4).
Acute coronary syndromes, including unstable angina and myocardial infarction (with and without ST-segment elevation on the electrocardiogram), present a major and growing health burden on industrialized societies. In Scotland in 2000 there were over 9000 admissions to hospital with suspected acute coronary syndrome per million population. These admissions accounted for 19% of all emergency hospitalizations and 12% of medical bed days(18). The annual incidence of hospitalization with suspected acute coronary syndrome without ST-elevation has been estimated at three per 1000 population(17). It has been suggested that the ratio of ST-elevation to non-ST-elevation myocardial infarction is decreasing but whether this is due to a real change in disease prevalence, an effect of treatment, or a change in case recognition is unknown(17).
The incidence and prevalence of stable coronary disease is more difficult to estimate. The incidence of angina in the United Kingdom is approximately 96 000 new cases a year, with a higher rate amongst men than women. In 2006 it was estimated that 14% of men and 8% of women aged 65–74 years had experienced angina at some time in their lives(3). In the United States in 2006 the prevalence of angina in adults aged 20 years or over was estimated at 4.3% in men and 4.5% in women(4). Paradoxically whilst the rate of mortality from CHD in the developed countries has been declining over the last three decades, rates of CHD-related morbidity appear to be increasing, particularly in the elderly(3).
Risk factors
The INTERHEART study investigated various risk factors for myocardial infarction in 15 152 cases in 52 countries, who were matched to 14 820 controls with no history of heart disease. The mean age of first presentation with myocardial infarction was 8 years younger in men than women and 10 years younger in Africa, the Middle East, and South Asia than the rest of the world. Nine easily measured and potentially modifiable risk factors for myocardial infarction were identified, including smoking, hypertension, diabetes, waist-to-hip ratio, low daily fruit and vegetable consumption, physical inactivity, over-consumption of alcohol, abnormal blood lipid levels, and psychosocial factors. The effect of these risk factors was consistent in both genders and across different ethnic groups and geographic regions. Collectively, the nine risk factors accounted for 90% of the population attributable risk for myocardial infarction in men and 94% in women(19).
Tobacco use, perhaps the most important modifiable risk factor, was associated with a nearly threefold increase in the odds of myocardial infarction (odds ratio (OR) for current smokers 2.95; 95% confidence interval (CI) 2.77–3.14, versus never smokers). This increase in risk of myocardial infarction fell after quitting smoking (OR at 3 years 1.87; CI 1.55–2.24) but remained elevated even after 20 or more years of abstinence (OR 1.22; CI 1.09–1.37). These data suggest that the greatest reduction in global CHD risk could be achieved by preventing smoking and by smoking cessation programmes(20).
A meta-analysis of data from 61 prospective observational studies involving almost 900 000 adults, mostly from Western Europe or North America, confirmed a strong positive relationship between total serum cholesterol and coronary mortality, irrespective of age and the level of blood pressure. Of various simple indices involving measurement of low- (LDL) and high-density lipoprotein (HDL) cholesterol levels, the ratio total/HDL cholesterol was the strongest predictor of coronary mortality(21). Randomized trials of just a few years of treatment with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have shown that lowering LDL cholesterol by about 1.5mmol/L reduces the incidence of coronary events by about a third(22).
Global reductions in other modifiable risk factors also have the potential to prevent cardiovascular events, but lowering rates of hypertension, obesity, and diabetes will be challenging. Epidemiological evidence suggests that throughout middle and old age usual blood pressure is strongly and directly related to vascular (and total) mortality without any evidence of a threshold down to at least 115/75mmHg(23). In the United States, however, from 2001 to 2003 state-level age-standardized prevalence of uncontrolled hypertension was estimated to range from 15–21% amongst men and from 21–26% amongst women (Fig. 1.3)(24). Similarly there is robust evidence that an increase in body mass index of 5kg/m2 is associated with about a 40% increase in vascular mortality(25), but from 1999 to 2006 the high prevalence of childhood obesity in the United States remained unchanged(26). Nevertheless, relatively modest downward shifts in the population distribution of modifiable cardiovascular risk factors may have substantial effects on disease prevalence, particularly when compared with prevention strategies directed at high-risk individuals(27).
Pathophysiology
Atherothrombosis
Atherothrombosis, defined as atherosclerosis with superimposed thrombosis, is the principal pathological process underlying the majority of clinical cardiovascular events. Atherosclerosis is a systemic process that involves large and medium-sized elastic and muscular arteries and typically affects the aorta, and coronary, carotid, and peripheral vessels. The epicardial coronary arteries are particularly susceptible, but some arteries including the intra-myocardial arteries are rarely affected.
Atherosclerosis starts in childhood, progresses silently through early adult life, and often manifests in later decades with ischaemia or infarction of the heart, brain, or extremities. The disease is characterized by the development of focal atherosclerotic plaques within the intimal layer of the arterial wall that consist of cells, connective tissue, lipids, and debris. The cellular constituents include endothelial and smooth muscle cells from the vessel wall, and inflammatory and immune cells derived from the circulating blood. As the disease progresses, individual plaque morphology may change abruptly because of plaque rupture and superimposed thrombosis. In addition, secondary changes may develop in the media and adventitia. As a consequence there may be marked heterogeneity in plaque morphology in different vascular territories, even in the same individual. The complex molecular and cellular mechanisms underlying the atherosclerotic disease process are incompletely understood, but it is now recognized that atherosclerosis is an active process involving interplay of cardiovascular risk factors, vascular biology, and chronic inflammation.
Endothelial activation
The vascular endothelium, the innermost cellular layer of blood vessels, has a key role in vascular homeostasis and is critically involved in the development of atherosclerotic disease. In health the endothelium produces a wide range of locally active substances that regulate contractile, secretory, and mitogenic functions of the vessel wall, and influence blood coagulation.
Endothelial physiology
The importance of the endothelium was first demonstrated in studies of vascular tone(28), but it is now recognized that the endothelium releases a range of autocrine and paracrine mediators that control vascular physiology and response to injury. Nitric oxide (NO), the principal endothelium-derived relaxing factor, plays a key role in the maintenance of vascular tone and endothelial reactivity. NO is synthesized from the amino acid L-arginine by the action of endothelial NO synthetase (eNOS). This enzyme requires a critical cofactor, tetrahydrobiopterin, to facilitate endothelial NO production. Following release from endothelial cells NO diffuses into medial smooth muscle cells and activates guanylate cyclase, which results in cyclic guanosine monophosphate (cGMP) mediated vasodilatation. In addition NO maintains the endothelium and medial smooth muscle cells in a non-proliferative state and when released into the blood NO inhibits platelets and leucocytes. An NO-independent pathway also contributes to vasodilator tone but has not yet been fully elucidated(29–31).
The actions of NO are opposed by endothelium-derived vasoconstrictor factors, such as endothelin and vasoactive prostanoids, and by angiotensin-II, which is converted at the endothelial surface from angiotensin-I. These mediators cause vasoconstriction, activate endothelial cells, platelets, and leucocytes, and facilitate thrombosis, directly countering the inhibitory effects of NO(29–31).
Endothelial activation and dysfunction
Exposure to cardiovascular risk factors (including tobacco use, hypertension, hyperlipidaemia, and diabetes) activates mechanisms within endothelial cells that result in expression of chemokines, cytokines, and adhesion molecules programmed to interact with leucocytes and platelets. At a molecular level, risk factor exposure appears to induce a switch from NO-mediated inhibition of endothelial and other cellular processes towards endothelial activation via redox signalling. As part of endothelial activation eNOS, which normally maintains the endothelium in a quiescent state via production of NO, switches to generate reactive oxygen species (ROS). This process is termed eNOS uncoupling and results in superoxide production if there is tetrahydrobiopterin deficiency, and hydrogen peroxide production if levels of L-arginine are inadequate. The resulting oxidative stress within the endothelium leads to increased production of endothelin and other mediators, which promote endothelial activation(30,31). Recently it has been suggested that the effects of cardiovascular risk factors on endothelial function may be mediated by down-regulation of lysyl oxidase (LOX), a copper-dependent amine oxidase that initiates the covalent cross-linking of collagen and elastin, and plays a crucial role in the maintenance of the tensile and elastic features of connective tissues(32).
Collectively, these processes result in endothelial dysfunction, a systemic disorder affecting all arteries that predisposes to vasoconstriction, increased endothelial cell permeability, expression of adhesion molecules, increased chemokine secretion, leucocyte adherence and migration, vascular smooth muscle cell proliferation, and platelet activation and thrombosis (Fig. 1.4A)(31,33).
Clinical indicators of endothelial activation, such as endothelial vasomotor dysfunction, can predict cardiovascular events in patients with and without overt coronary artery disease(34) but correction of cardiovascular risk factors has been shown to improve endothelial function. For example, treatment of hypercholesterolaemia with statins has been shown to improve or normalize endothelial function in patients with mild coronary artery disease(35). Angiotensin-converting enzyme inhibitors (ACE-I) also improve endothelial function through a range of mechanisms (antioxidant effects, favourable effect on fibrinolysis, reduction in angiotensin-II, increase in bradykinin), although a direct relationship between these effects and the risk of adverse cardiovascular events has not yet been clearly established(36).
Early stages of atherosclerosis
The mechanisms that underlie the initial stages of atherosclerosis have not been fully elucidated but endothelial activation appears to be integral to the process. Endothelial activation precedes the onset of the disease, facilitates inflammatory processes that lead to atherosclerosis, and promotes mechanisms of disease progression.
Lipid retention and modification
In the earliest stage of atherosclerosis LDL particles probably enter the subendothelial space from the bloodstream. Apolipoprotein in the LDL particles is thought to bind to extracellular proteoglycans (especially biglycan) and other macromolecules, ensuring retention of lipid within the extracellular matrix(37,38). LDL particles may be modified through oxidation and glycation. The precise pathways of this chemical transformation are uncertain but evidence implicates myeloperoxidase, a haem peroxidase enzyme found predominantly in neutrophils, monocytes, and some macrophages. Myeloperoxidase generates numerous reactive oxidants and diffusible radical species that are capable of initiating and promoting peroxidation and other modifications of the lipid(39).
Inflammation
Modified and oxidized LDL contribute to endothelial activation and initiate an inflammatory response in the vessel wall. Activated endothelium expresses several types of cell adhesion molecules (CAMs), which facilitate adhesion of leucocytes rolling along the endoluminal surface of the vessel wall to the endothelium. Chemokines produced in the endothelial cells then stimulate migration of the adherent monocytes and T-cell lymphocytes into the subendothelial space(40–42).
Macrophage colony stimulating factor, a cytokine produced in the activated endothelial cells, stimulates monocytes within the intima to differentiate into macrophages. This transformation is associated with up-regulation of scavenger receptors and Toll-like receptors on the macrophage cell surface that bind modified LDL and oxidized phospholipid. Activation of macrophage Toll-like receptors also induces intracellular signalling and cell activation, with cytoskeletal rearrangements, stimulation of inflammatory cytokine secretion, and production of proteases and cytotoxic oxygen radicals. These processes facilitate endocytosis and destruction of the oxidized LDL particles, but if the lipid cannot be fully metabolized it accumulates as cytosolic droplets and the macrophage transforms into a foam cell(40,43).
Lymphocytes within the intima also produce inflammatory cytokines, chemokines, proteases, and cytotoxic oxygen and nitrogen radical molecules. Cytokines may induce expression of CD40, a transmembrane protein receptor present on inflammatory cells within the plaque. Activation of CD40 by CD40 ligand, derived from platelets and other cells, signals upregulation of proinflammatory and atherogenic genes(44). This process is known to involve the intracellular nuclear factor kappa B transcription pathway, which controls the transcription of genes for many cytokines, chemokines, adhesion molecules, and regulators of apoptosis(45). These processes augment and perpetuate the inflammatory atherosclerotic process and recruit additional macrophages and medial smooth muscle cells. If the inflammatory response does not remove or neutralize the initiating stimulus it can continue unabated.
The accumulation of lipid-laden monocytes, foam cells and T-cell lymphocytes within the intima leads to the formation of fatty streaks and early atherosclerotic lesions (Fig. 1.5). Fatty streaks are prevalent in young people and are generally considered to be an antecedent of atheroma, but they may also disappear over time(46). Evidence of early atherosclerosis has been demonstrated in post-mortem studies of young soldiers killed during the Vietnam(47) and Korean(48) wars and in intracoronary ultrasound studies of transplanted hearts retrieved from teenage and young adult donors(49).
Disease progression
Plaque growth
As the atherosclerotic process progresses, the plaque increases in size due to accumulation of inflammatory and smooth muscle cells, production of extracellular matrix, and continuing deposition of lipid in the arterial wall. Vascular smooth muscle cells, stimulated by mitogens and cytokines, differentiate into migratory and secretory cells and migrate into the intima (Fig. 1.4B)(50) Smooth muscle cells produce collagen and other matrix proteins, including gylcosaminoglycans, proteoglycans, elastin, fibronectin, laminin, vitronectin, and thrombospondin(51).
Arterial remodelling
During growth of atherosclerotic plaque the entire vessel can vary in size, a process known as remodelling. Enlargement of the vessel may accommodate the plaque volume without compromising the arterial lumen until the plaque enlarges to over 40% of the vessel area, but thereafter further growth in the plaque causes luminal narrowing(51,52). Alternatively, the vessel may constrict and further narrow the arterial lumen. The mechanisms regulating remodelling have not been elucidated but may contribute to heterogeneity in the progression and clinical manifestations of arterial disease(53).
Plaque neovascularization
As atheromatous disease advances, new microvessels may develop from the adventitial vasa vasorum, possibly in response to hypoxia and activation of Toll-like receptors within the expanding atherosclerotic plaque. This process appears to be regulated by vascular endothelial growth factor (VEGF) A, which together with angiotensin II can also induce microvascular permeability. These processes may facilitate extravasation of red blood cells and intraplaque haemorrhage. Release of haemoglobin into the extracellular matrix of the plaque exacerbates oxidative stress, amplifying macrophage activation and pro-inflammatory signals, and accelerating the atherosclerotic process(54).
Apoptosis
Apoptosis of the cellular components of the plaque may be mediated by cytokines including interleukin-1, tumour necrosis factor-alpha, and interferon-gamma(55). Apoptosis has been observed at all stages of atherosclerosis but the consequences for lesion progression may depend on how efficiently the apoptotic cell is cleared by other macrophages. In early lesions phagocytic clearance appears to be efficient, reduces lesion cellularity and atheroma progression. In more advanced lesions phagocytic clearance may be defective, leading to secondary necrosis of the apoptotic cell, further release of inflammatory mediators, and amplification of the inflammatory process. Cumulatively these events may lead to the development of a highly thrombogenic necrotic core within the expanding plaque, which contains cell remnants expressing active tissue factors(56). As the necrotic lipid-rich core expands, a fibrous cap forms over the luminal surface, creating a barrier between the thrombogenic material within the core and the circulating blood (Fig. 1.4B).
Endothelial cells can also progress to senescence and may detach into the circulation. Whole endothelial cells and microparticles derived from activated or apoptotic endothelial cells can be detected in the circulating blood as markers of endothelial injury and are thought to influence blood thrombogenicity(57). Restoration of endothelial integrity involves replication of adjacent mature endothelial cells or recruitment of circulating endothelial progenitor cells. Mobilization of endothelial progenitor cells is influenced by NO and may therefore be impaired in individuals with cardiovascular risk factors(31,58). In animal models restoration of endothelial integrity after balloon injury improves with exercise or statins, which both improve endothelial function(59,60).
Influence of biomechanical forces
Dysfunctional endothelium, fatty streaks, and atheroma all localize preferentially to arterial sites associated with disturbed flow patterns, suggesting an important role for local haemodynamic forces in the development of arterial disease. These sites include branch points on the opposite side of the flow divider, and post-stenotic segments where laminar flow may be disturbed by re-circulation eddies, flow separation, and oscillatory flows. Evidence suggests that exposure of the endothelium to such different biomechanical forces, induces differential expression of specific genes in endothelial cells. Laminar shear stress from the viscous flow of blood against the endothelial cell surface induces eNOS activity, which supports vasoprotective functions in the endothelium. By contrast, reduced or oscillatory shear stress induces endothelial activation, expression of adhesion molecules, and endothelial cell apoptosis(61–65).
Calcification of atheroma
Microscopic areas of calcification may appear within the atherosclerotic plaque, which become denser as the disease advances. The extent of coronary calcification correlates with the severity of luminal narrowing caused by the plaque(66). The predominant chemical constituent of coronary calcification is identical to hydroxyapatite, the main inorganic constituent of bone(67). Osteopontin, a gylcosylated protein involved in the formation and calcification of bone is synthesized by macrophages, smooth muscle, and endothelial cells. Endothelial progenitor cells in patients with coronary disease have also been shown to express osteocalcin, an osteoblastic marker(55,68). The significance of calcification for plaque progression and cardiac events is uncertain, but extensive calcification may impact the outcome of percutaneous coronary intervention. Rarely, eruptive nodular calcification with underlying fibrocalcific plaque is implicated as a cause of coronary thrombosis(69).
Plaque rupture and thrombosis
Most atherosclerotic plaques develop slowly over many years, under the influence of local immune responses and continued exposure to cardiovascular risk factors. Integrity of the fibrous cap overlying the plaque core is maintained by balanced production and degradation of extracellular matrix proteins. If this balance is disturbed, overproduction of matrix may encroach on the arterial lumen, but increased matrix degradation may weaken the plaque cap increasing the risk of plaque rupture.
Matrix metalloproteinases
Matrix protein degradation is mediated by matrix metalloproteinases (MMPs) and other proteases released by inflammatory cells, including macrophages and migrated smooth muscle cells. MMPs are Zinc2+-dependent endopeptidases and include collagenases, gelatinases, stromelysins and metalloelastases. MMP activation is controlled at several levels including induction of MMP gene transcription, post-translational activation of MMP proforms, and interaction with specific tissue inhibitors (TIMPs). MMPs may facilitate smooth muscle cell migration through the internal elastic lamina into the intima, are implicated in vascular remodelling, and appear to have a central role in plaque rupture. Expression of MMP activity is influenced by several drugs including the HMG Co-A reductase inhibitors (statins)(51,70,71). Cysteine proteases, which are induced by certain cytokines and controlled by ‘cystatin’ inhibitors, also have been implicated in matrix metabolism in atherosclerosis(72).
Plaque rupture
Active degradation and remodelling of the extracellular plaque matrix by macrophages, via release of MMPs and other proteases and by subsequent phagocytosis, inhibits the formation of a stable fibrous cap. Further breakdown of collagen and other proteins within the fibrous cap reduces the structural integrity of the plaque and predisposes to plaque rupture(70,71). Interaction between CD40 and CD40 ligand may induce MMP production and may play a role in plaque instability(44). Plaques with a thin fibrous cap, large lipid core, and inflammatory cell infiltrate at the thinnest portion of the cap appear to be particularly vulnerable to rupture (Fig. 1.6)(69). Inflammatory cells are abundant in the shoulder regions of ruptured plaque and many show signs of activation and inflammatory cytokine production(73,74).
Rupture of a coronary artery plaque causes an acute change in plaque morphology, exposure of tissue factor and other thrombogenic plaque contents to the circulating blood, activation of the coagulation cascade, and coronary thrombosis (Fig. 1.4C). The consequences of plaque rupture are determined by the severity of the plaque injury, local rheology, and the balance between thrombotic and lytic activity at the interface between the plaque and the circulating blood. These factors influence the size and stability of the thrombus, and the severity of the resulting coronary syndrome. Partial or complete thrombotic occlusion of the artery, or thrombus embolism into the distal vessel, may cause myocardial ischaemia and an acute coronary syndrome. More frequently, however, it is thought that plaque disruption occurs silently, and subsequent repair of the vascular injury and fibrotic organization of the thrombus may cause accelerated plaque growth, contributing to progression of the atherothrombotic process(55).
Detailed histopathological examination of coronary arteries in sudden cardiac death victims confirms that rupture of a thin collagenous fibrous cap, with discontinuity of the cap at the site of contact between the thrombus and lipid core, is the cause of coronary thrombosis in the majority of cases. In other cases, however, the coronary thrombosis occurs at the site of a superficial plaque erosion, without involvement of a lipid core. The luminal surface is irregular and devoid of endothelial cells, and the plaque in contact with the thrombus is generally cellular and rich in proteoglycan. Endothelial apoptosis with deficient endothelial repair may be the underlying cause of plaque erosion. Plaque erosion is particularly likely in young women, but with advancing age plaque rupture becomes the dominant cause of coronary thrombosis (Figs. 1.4 and 1.5)(66,69).
Angiographic studies of patients before and after myocardial infarction suggest that the culprit stenosis responsible for the acute coronary syndrome is frequently only of moderate severity(75,76). Mild or moderate coronary stenoses may be an important cause of acute coronary syndrome because they are much more prevalent than severe stenoses, which are individually at higher risk of causing coronary thrombosis(77).
Systemic markers of inflammation
There is increasing evidence that atherosclerosis is associated with chronic low-grade inflammation in clinically silent plaques throughout the vascular system(40). Coronary arteriographic studies have demonstrated multiple complex plaques (characterized by thrombus, ulceration, plaque irregularity, and impaired flow) in nearly 40% of patients with recent myocardial infarction, supporting the concept that plaque instability is due to a systemic increase in inflammation(78). The blood levels of several markers of inflammation including C-reactive protein (CRP), interleukins, soluble CD40 ligand, and tissue factor, are all elevated in patients with acute coronary syndromes, and high levels generally predict worse outcome(79,80). Elevated levels of CRP, serum amyloid A, interleukin-6, and soluble intercellular adhesion molecule type 1 are also all associated with cardiovascular risk in apparently healthy populations(81). CRP is an acute phase reactant and is mainly produced in the liver in response to interleukin-6. CRP has therefore been considered an inactive marker of inflammation, but there is increasing evidence that CRP may also play a direct role in atherogenesis(43,79).
Drugs which reduce inflammation may have therapeutic effects in CHD. Aspirin use in otherwise healthy men reduced the risk of first myocardial infarction in those with the highest serum CRP levels(82). Long-term treatment with pravastatin reduces CRP levels and improves clinical outcome(83,84). Recently, 17 802 healthy subjects with low LDL-cholesterol levels and elevated high-sensitivity CRP levels were randomized to treatment with rosuvastatin or placebo, but the trial was stopped prematurely because treatment with rosuvastatin reduced serum LDL and CRP levels and the incidence of major cardiovascular events(85).
Summary
CHD remains a leading cause of death and disability across industrialized countries, is prevalent in Eastern Europe, and is a major threat to health in developing countries. Increases in the prevalence of coronary artery disease, both in the developed and developing countries can be largely explained by coronary risk factors, including tobacco use, high blood lipid levels, hypertension, obesity, and diabetes.
Atherothrombosis, the pathological process underlying most cases of CHD, is defined as atherosclerosis with superimposed thrombosis. The molecular and cellular mechanisms of atherothrombosis are incompletely understood, but there is compelling evidence that the disease is due to a chronic inflammatory process in the arterial intima. Exposure to risk factors and deposition of lipoprotein in the intima cause up-regulation of atherogenic and pro-thrombotic processes. Monocytes are recruited into the intima from the circulating blood and a series of inflammatory mechanisms lead to the development of an atherosclerotic plaque. Endothelial apoptosis and inadequate endothelial repair over the plaque may lead to endothelial erosion and arterial thrombosis. Development of a necrotic lipid core within the plaque and degradation of the overlying fibrous cap by proteases, render the plaque vulnerable to disruption. Plaque rupture exposes the core contents to the circulating blood and potent thrombogenic stimuli activate the coagulation cascade, causing arterial thrombosis. In many cases coronary plaque erosion or rupture occur silently, but if the thrombosis impedes coronary blood flow the myocardium may become ischaemic, and the patient may present with an acute coronary syndrome, myocardial infarction, or death. The development of treatment strategies to combat these complex molecular, cellular, and physiological disturbances presents interventional cardiology with the greatest challenge.
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