Atherosclerotic plaque rupture and resulting intracoronary thrombosis are thought to account for most acute coronary syndromes. These syndromes include unstable angina, non-Q-wave myocardial infarction (MI) and Q-wave MI. In addition, many cases of sudden cardiac death may be attributable to atherosclerotic plaque disruption and its immediate complications. Our understanding of the atherosclerotic process and the pathophysiology of plaque disruption has advanced remarkably. Despite these advances, event rates after acute coronary syndromes remain unacceptably high. This review will focus on the pathophysiology underlying atherosclerotic plaque development, the sequellae of coronary plaque rupture, and current therapies designed to treat the acute coronary syndromes. It is hoped that as our understanding of the atherosclerotic plaque improves, treatment strategies for the acute coronary syndromes will advance.
Time for primary review 41 days.
Atherosclerotic plaque rupture in the coronary arteries represents a main focal point for clinical cardiologists and cardiovascular researchers. The process of plaque rupture is thought to underlie most acute coronary syndromes, including unstable angina, non-Q wave and Q-wave myocardial infarctions (MI), as well as many cases of sudden cardiac death and thus is a major cause of overall morbidity and mortality [1, 2]. In addition, syndromes resulting from atherosclerotic plaque rupture account for a significant proportion of total health care expenditures .
Intracoronary thrombosis, the immediate result of plaque rupture, was hypothesized to be the cause of acute MI as early as 1912 by Herrick . Plaque rupture and resulting intracoronary thrombosis, however, were not universally accepted as major mechanisms underlying the acute coronary syndromes until the modern medical era [5–10]. Large scale randomized, controlled trials confirming the efficacy of thrombolytic therapy were not performed until over 70 years after Herrick's report suggested that intracoronary thrombosis resulted in acute MI [11, 12].
Mortality from the acute coronary syndromes began declining before thrombolysis became routine therapy for acute MI [13–18]. Much of the decline stems from treatments which ameliorate the effects of atherosclerotic plaque rupture. These treatments include antithrombotics, antianginal therapies and revascularization techniques, in addition to thrombolysis . Only very recently has an appreciation developed of the importance of stabilizing the atherosclerotic plaque and preventing its progression and rupture . Novel approaches in the treatment of acute coronary syndromes remain necessary despite declining overall cardiac mortality. Standard therapy in the most recent large-scale randomized, controlled trials still yields 10–25% 1-month recurrent cardiac event rates [21–25].
This review is intended to explore the pathophysiology underlying atherosclerotic plaque development and the clinical sequellae of plaque rupture in the coronary arteries. With a more detailed understanding of the biology of the atherosclerotic plaque, it is hoped that treatment strategies for the acute coronary syndromes will continue to develop.
2 Pathophysiology of coronary atherosclerotic plaque rupture
2.1 Lesion morphology in atherosclerotic plaque rupture
Types of atheromatous plaques (Table 1) vary widely in morphology even when found in varying locations in the coronary arteries of the same patient . Early lesions, marked by foam cell infiltration (type I lesions), mature into lesions with smooth muscle infiltration and lipid (type II, “fatty streak”) and connective tissue deposition (type III) . The early lesions develop within the first three decades of life in areas of localized turbulent flow within the coronary arteries. Their development is accelerated by conditions such as hypertension, diabetes mellitus, hypercholesterolemia and smoking. As these early lesions grow into softer plaques with a high extracellular lipid and cholesteryl ester content and progressively thinner fibrous cap (types IV–Va, “atheroma”), they become more vulnerable to disruption (Fig. 1) [26, 27].
Ruptured plaques with overlying thrombus (type VI) are described as complicated lesions. When they achieve a significant degree of stenosis without sufficient collateralization, these lesions result in acute coronary syndromes (Fig. 2). In the period after the acute syndrome, thrombus over the complicated disrupted lesion organizes and the lesion calcifies (type Vb) or fibroses (type Vc) into a chronic stenotic lesion, as seen in Fig. 3. The complicated lesion may contain organizing thrombus from prior episodes of plaque rupture, cap ulceration or intra-plaque hemorrhage, followed by spontaneous clot lysis and organization. Like the earlier lesions, the complicated plaque contains a number of cell types, including inflammatory cells and smooth muscle cells (SMCs) [28, 29].
Accumulation of intracellular lipid in infiltrating macrophages and smooth muscle cells
As above, plus incipient extracellular lipid and connective tissue deposition
Large extracellular intimal lipid core; inflammatory cell infiltration, including macrophages, foam cells and T-cells
Usually asymptomatic; can also be associated with stable angina
Atheroma with fibrous layer or layers
Same as type IV
Atheroma with extensive calcification in the lipid core or elsewhere in the lesion
Stable angina pectoris; can also be asymptomatic
Fibrosed atheroma or organized mural thrombus with minimal or absent lipid component
Same as type Vb
VI, “Complicated lesion”
Disrupted type IV or V lesion with intramural hemorrhage and/or overlying thrombosis
Acute coronary syndrome or asymptomatic lesion progression
The advanced, stenotic plaques, however, are not the only types of plaques prone to disruption. In fact, plaque disruption occurs independently of lesion size and degree of stenosis, a relationship complicated by vascular remodeling [8, 30]. Most acute coronary syndromes actually result from disruption of lesions which are initially not flow-limiting, with rapid progression to severe stenoses [31, 32]. Culprit lesions in acute coronary syndromes tend to have less calcification, which implies a certain softness of the plaque and vulnerability to shear forces . Often, the complicated lesion has a central lipid core [8, 31, 34]. The lipid composition of complicated disrupted plaques can vary, however. Disrupted and thrombosed plaques with little lipid content are described in a recent autopsy report of plaque morphology in sudden cardiac death .
2.2 Phases of atherosclerotic plaque growth
The coronary atherosclerotic lesion appears to grow in fits and starts [8, 20, 35]. The gradual process by which material accumulates within the lesion is occasionally punctuated by sudden spurts of plaque growth which occur with plaque rupture and the resulting intracoronary thrombosis. It is by these abrupt episodes of plaque rupture that even mildly or moderately stenotic plaques can acutely progress to totally occlusive lesions . Thus, abrupt episodes of plaque disruption and growth account for many acute coronary syndromes. However, these episodes occur against a backdrop of gradual atheromatous plaque growth which progresses over decades.
The development and growth of the coronary atherosclerotic plaque can be subdivided into five phases based on lesion morphology and associated clinical sequellae (Fig. 4) [34, 36]. Phase 1, the asymptomatic development of lesion types I-III, occurs in most individuals in the first few decades of life. Phase 2, in which the atheroma (lesion types IV and Va) develops, is usually asymptomatic but may be accompanied by stable angina pectoris. Plaque disruption occurs in phase 3, resulting in a nonocclusive overlying mural thrombus and in the sudden growth of a complicated lesion (type VI). Phase 3 plaque disruption may lead to the development of angina, but is often asymptomatic.
Histopathologic section of a human coronary atheroma. At low magnification (right panel), a large lipid core and thin fibrous cap are clearly evident. Higher power (left panel) reveals foam cell infiltration into the fibrous cap. Erythrocytes are noted in the lipid core just below the fibrous cap, the result of incipient cap disruption or intra-plaque hemorrhage. Reproduced with permission .
The acute coronary syndromes, on the other hand, are associated with phase 4 plaque disruption (also type VI lesions), which is complicated by a large, often occlusive thrombus. The phase 4 acute syndromes include myocardial infarction, unstable angina and ischemic sudden death. The key distinction between phases 3 and 4 lies in the associated clinical syndrome, since total vessel occlusion is not necessary in the development of an acute coronary syndrome. Phases 3 and 4 are followed by the development of chronic phase 5 calcified (type Vb), or fibrotic (type Vc) lesions, which are often marked by stable angina pectoris. Severely stenotic phase 5 plaques can occlude without plaque rupture in a myeloproliferative process or from stasis in the vessel leading to thrombus. Occlusion of a phase 5 lesion is often clinically silent, as distal myocardium is frequently supplied by collateral flow around the chronically diseased vessel.
2.3 Factors in plaque instability and disruption
2.3.1 External physical forces
Blood flow impacting on the plaque and vessel wall stress are key external factors affecting plaque stability . These external forces may be influenced by systemic factors, such as environmental or pharmacologic stressors. Factors intrinsic to the plaque which make it particularly sensitive to external physical forces include the size, location and content of the lipid core, as well as the integrity of the fibrous cap. A weak point in the cap which is vulnerable to shear forces appears to be at its insertion into the vessel wall [9, 31]. Here, the fibrous cap thins and is often replete with lipid-packed macrophages (foam cells) [29, 31].
Photomicrograph demonstrating plaque rupture in a human coronary atherosclerotic lesion with overlying occlusive thrombus (T). The arrow indicates the site of disruption of the fibrous cap (FC) of the lesion. The lipid core (LC) is noted underneath the fibrous cap. Courtesy of Dr. John T. Fallon.
Chronic stenotic atheromatous lesions in the human coronary artery. The lesion on the upper left-hand portion of the section is typical of a calcified type Vb lesion, in which fibrous connective tissue (F) surrounds an area of calcium deposition (Ca2+), which has replaced the lipid core. A fibrotic type Vc lesion is noted on the lower right-hand portion of the section, containing dense fibrotic tissue (F) overlying the lipid core (LC). Courtesy of Dr. John T. Fallon.
Schematic representation of the phases of atherosclerotic lesion progression, and the associated pathologic lesion types and clinical syndromes. Adapted with permission .
2.3.2 Internal forces
Inflammatory cell activity in the atherosclerotic plaque appears to have an important impact on plaque stability [28, 29]. For instance, macrophages secrete metalloproteinases which have activity against the collagen component of the plaque and may act to weaken the fibrous cap [8, 37–39]. Macrophage-derived foam cells have also been shown to activate matrix metalloproteinases by elaborating reactive oxygen species .
Macrophages in the atherosclerotic plaque derive from circulating monocytes, which adhere to the vessel wall in areas of turbulent flow. Monocytes are drawn into the vessel wall by chemotactic factors such as MCP-1, which also acts to induce tissue factor expression in monocytic and smooth muscle cell lines (see below) . In addition to macrophages, T-lymphocytes are found in abundance in atheromatous plaques . Systemic infections (e.g. C. pneumoniae, cytomegalovirus and H. pylori) have been linked to atherosclerotic disease, although a causal relationship is far from clear [43–47]. Infectious agents may affect endothelial function [48, 49], and activate monocytes and macrophages to secrete inflammatory cytokines . These cytokines, in turn, stimulate the production of reactive oxygen species and proteolytic enzymes which may influence plaque stability. Oxidative stress and the antioxidant capacity of the arterial wall appear to play important roles in the progression of atherosclerotic disease, in addition to plaque rupture [51, 52].
Both T-lymphocytes and macrophages have been shown to undergo apoptosis in the advanced atherosclerotic plaque [42, 53]. SMCs express Bax, a proapoptotic protein, in carotid plaques  and can be induced to undergo apoptosis in the presence of cytokines secreted by macrophages and T-lymphocytes . Apoptotic cell death, particularly involving SMCs in the fibrous cap, may contribute to the destabilization of advanced atherosclerotic plaques [42, 56].
2.4 Thrombosis and vasospasm following plaque disruption
Fracture of the fibrous cap exposes intensely thrombogenic material to the blood elements within the vessel lumen [57, 58]. Platelets accumulate over a layer of fibrin, forming the initial “white clot” which directly overlies the disrupted plaque. Subsequently, a fibrin and erythrocyte-rich “red clot” forms over the “white” platelet clot, in a process dependent on stasis [59, 60]. Fibrinolytic therapy can lyse the “red” clot, but concomitant antiplatelet therapy is needed to prevent growth of the platelet thrombus. Fibrinolysis can have prothrombotic effects in the absence of antiplatelet agents and systemic anticoagulation by releasing thrombin which had been bound in the fibrin clot. Unopposed thrombin acts to convert fibrinogen to fibrin and to stimulate platelet aggregation. Platelets also elaborate plasminogen activator inhibitor-1 (PAI-1) a potent inhibitor of fibrinolysis .
Of the components of the plaque, the lipid core appears to have the highest thrombogenicity . This increased thrombogenicity largely results from factors, such as tissue factor, apparently elaborated by cells infiltrating the plaque and possibly by vascular SMCs, as well [9, 41, 58]. Tissue factor contributes to thrombin generation by activating factors IX and X through its complex with factor VIIa . Tissue factor staining is stronger in the lipid core of the atheromatous plaque than in other areas of the arterial wall . The tissue factor staining tends to co-localize with areas of macrophage infiltration in atherectomy specimens .
Thrombus accumulates over the disrupted plaque, leading to a spectrum of clinical possibilities. The clinical manifestation of the event may range from asymptomatic progression of the lesion to significant impairment of coronary blood flow resulting in ischemia with unstable angina or infarction. Often, many systemic and local factors coexist which increase the thrombogenicity around the ruptured plaque. Acute plaque rupture may change the geometry of the atherosclerotic lesion thereby increasing turbulence in the overlying vessel lumen. The resulting alteration in blood flow leads to stasis around the ruptured plaque and expansion of thrombus . Frequently, in addition to other risk factors, patients with coronary disease have atherothrombotic risk factors, such as smoking, elevated lipoprotein(a), or elevated fibrinogen [64–66].
Vasoconstriction at the site of the ruptured plaque often exacerbates the acute syndrome . Systemic catecholamine release, prompted or enhanced by the stress of the event, contributes to vasoconstriction. Platelet-derived factors as well as thrombin may stimulate vasoconstriction in the presence of a damaged coronary vessel wall [67, 68]. In addition, vessel spasm may derive from abnormal endothelial responses and hypercontractile vascular smooth muscle associated with atherosclerotic plaques [7, 9, 68].
2.5 Clinical sequellae of plaque rupture
From a clinical standpoint, a spectrum of acute coronary events may follow atherosclerotic plaque rupture. These events range from the asymptomatic to those resulting in critical illness or sudden death. The pathophysiology underlying these clinical events involves a reduction in blood flow supporting myocardium distal to the site of acute plaque rupture. As reviewed above, blood flow is reduced by accumulated thrombus, as well as vasospasm over the ruptured plaque. The severity of the resulting coronary event appears to be related to the change in blood flow around the site of plaque disruption. In those cases where blood flow is essentially unaffected, plaque rupture may result only in asymptomatic progression of the atherosclerotic lesion. If blood flow is reduced, a change in the pattern of angina may result, producing unstable angina. If complete vessel occlusion follows plaque rupture acutely in the absence of sufficient collateral blood flow, acute MI results [36, 69].
The risk of adverse outcomes after acute coronary syndromes appears to be related to the type of event. Cumulative 6-month mortality is highest in acute MI when compared with unstable and stable angina . Clinical outcome data, including cumulative death or MI and cardiac event rates, are similar for non-Q and Q-wave MI [70, 71]. The risk of adverse outcome with unstable angina is highest in the post-MI setting, or with recent (<48 h) onset of rest angina. The process of plaque rupture may play a major role in the pathogenesis of these entities. On the other hand, if external factors which trigger worsened angina (e.g., anemia, environmental stresses) can be identified and corrected, prognosis may be improved .
Of course, factors other than plaque rupture must always be considered in the differential diagnoses of chest pain and unstable angina. A number of thoracic and intra-abdominal structures can produce a chest pain syndrome which resembles cardiac angina. If a diagnosis of unstable angina or non-Q wave MI is made, usually by a combination of history, electrocardiographic changes (i.e., ST-segment and T-wave changes) and cardiac enzyme elevations (e.g., elevated CK-MB, troponin I and/or troponin T), exacerbating factors must be ruled out or corrected [69, 73, 74]. Factors that may exacerbate chronic angina in the presence or absence of plaque rupture include those that increase myocardial oxygen demand (e.g., catecholamine surges, tachyarrhythmias) or decreased oxygen delivery to the heart (e.g., anemia, pulmonary disorders) .
An important cause of mortality in the setting of intracoronary thrombosis is sudden death . Up to one half of all cardiovascular deaths in the US result from sudden arrhythmic death. Most sudden death, in turn, occurs in the setting of coronary artery disease . Acute ischemia has been shown in experimental models to predispose to malignant arrhythmias [77, 78]. Several pathologic studies of patients that died suddenly implicate acute coronary thrombosis as a possible cause of sudden death, in addition to primary arrhythmias from a pre-existing ventricular scar [75, 79–82].
Acute coronary syndromes also play an important role in the progression of heart failure. It is estimated that the majority of cases of cardiomyopathy in the US is ischemic in origin . Furthermore, interventions which slow the progression of coronary artery disease (i.e., lipid lowering therapy) also appear to reduce the incidence of congestive heart failure .
2.6 Treatment of plaque rupture and its complications
As atherosclerotic plaque rupture represents an important aspect of the pathophysiology of the acute coronary syndromes, the clinical approach to these syndromes (Table 2) must address the potential complications of plaque rupture. Thus, antithrombotic therapy, designed to halt or reverse the accumulation of thrombus over the disrupted plaque, has become a mainstay of therapy in acute coronary syndromes. Antianginal therapy helps treat the coronary vasospasm associated with the ruptured plaque. In addition, antianginals reduce the metabolic needs of the heart and the propensity towards arrhythmia associated with the acute coronary syndromes . Most importantly, prevention in coronary disease is geared towards increasing the stability of the atherosclerotic plaque, preventing its progression, and reducing systemic thrombogenic factors which may complicate plaque rupture.
Thrombolytic therapy represents a substantial advance in the reduction of mortality after acute MI [11, 12]. However, thrombolysis has not proven effective in the treatment of unstable angina . Unstable angina is felt to depend mainly on platelet-mediated mechanisms of thrombosis . As a result, unstable angina is less responsive to fibrinolytic therapies than to antiplatelet strategies such as aspirin and the glycoprotein IIb/IIIa antagonists. In fact, aspirin has been shown to improve survival and reduce recurrent vascular events in unstable angina . Newer antiplatelet agents, such as the glycoprotein IIb/IIIa antagonists, have also shown impressive results in the treatment of unstable angina and non-Q wave MI [21, 25]. Like aspirin, abciximab, a glycoprotein IIb/IIIa antagonist, has proven effective at reducing cardiac events after coronary interventions in the setting of acute coronary syndromes [86, 87]. Therapy with antiplatelet agents has been associated with an increased risk of bleeding . However, bleeding risk with abciximab as an adjunct to percutaneous intervention has improved substantially with dose modification and other improvements [86, 87].
Vascular mortality data in the first 35 days after acute myocardial infarction in the Second International Study of Infarct Survival (ISIS-2). Reproduced with permission .
The glycoprotein IIb/IIIa antagonists, in addition to the other more established antithrombotics, may play an important role in the treatment of transmural MI. Aspirin has proven as effective at reducing mortality in acute MI as thrombolysis . Furthermore, the survival benefit with aspirin in acute MI is additive to that of thrombolysis with streptokinase (Fig. 5) . More recent trials have shown that glycoprotein IIb/IIIa antagonists, when added to aspirin, improve the reperfusion rates of thrombolytic reperfusion and reduce the incidence of recurrent cardiac events [88, 89]. Experimental data suggest that the addition of glycoprotein IIb/IIIa antagonists prevents thrombotic reocclusion of the coronary arteries after treatment with thrombolytics . Glycoprotein IIb/IIIa antagonists reduce the dose of fibrinolytic needed to achieve thrombolysis [91, 92]. In addition to the antiplatelet agents, the direct thrombin inhibitors hirudin and hirulog, as well as low-molecular-weight heparins have shown promise in the treatment of acute coronary syndromes when compared with unfractionated heparin [22, 93–95]. These clinical observations underscore the central role of platelet- and fibrin-dependent mechanisms in the pathogenesis of the acute coronary syndromes .
2.8 Antianginal therapy
Antianginal therapy in acute coronary syndromes involves approaches not directly related to the ruptured atheromatous plaque. Nitrates are routinely employed in the setting of ischemia to help reverse the vasospasm associated with atherosclerotic plaque rupture and intracoronary thrombosis. Beta-blockers, as well as nitrates, help to reduce myocardial oxygen demand and increase coronary blood flow in the setting of an acute coronary event. Beta-blockers also decrease the propensity towards arrhythmia and myocardial rupture in acute MI. In addition, supplemental oxygen is used to improve oxygen delivery to ischemic myocardium .
3 Prevention of acute coronary syndromes
The primary and secondary prevention of acute coronary syndromes includes aggressive cholesterol lowering therapy. Lipid lowering has been demonstrated to significantly improve prognosis following acute coronary syndromes and in hypercholesterolemic patients without a history of coronary disease [96–98]. Interestingly, studies have failed to show angiographic regression of coronary disease with lipid lowering therapy to a level similar to the reduction in cardiac events [99, 100]. It appears, however, that cholesterol lowering stabilizes the atheromatous plaque by increasing the net efflux of lipid from the plaque. This effect may make the plaque more resistant to disruption [20, 101].
Systemic lipid lowering stabilizes the atheromatous plaque through several mechanisms. Firstly, reduced lipid intake results in a less lipid-rich plaque with reduced macrophage foam cell infiltration. Reduced macrophage infiltration likely plays an important role in the observed decrease in metalloproteinase activity in plaques from animals fed regression diets. The decreased enzymatic activity, in turn, allows for a higher collagen content in the atherosclerotic plaque [102–104]. Reduced inflammatory cell infiltration with dietary cholesterol withdrawal also appears to correlate with a reduction in apoptotic cell death in the plaque. In addition, expression of the proapoptotic protein Bax is significantly reduced in the cells remaining in the plaque after cholesterol lowering .
Lipid lowering agents have also been shown to decrease systemic thrombogenicity. The antithrombotic effect of the statins may derive, at least partially, from an inhibitory effect on tissue factor . Lipid lowering agents have been shown to improve endothelium-mediated vasodilator responses when used alone  and in combination with antioxidants [20, 107]. Prevention of acute coronary syndromes must also include steps to reduce systemic thrombogenicity with antiplatelet agents (e.g., aspirin, clopidogrel, ticlopidine) [85, 108], smoking cessation and correction of thrombogenic risk factors (e.g., elevated fibrinogen and lipoprotein(a) levels) [65, 66], or causes of endothelial dysfunction (e.g., diabetes mellitus and elevated homocysteine) [109, 110].
Plaque disruption and its resulting coronary thrombosis are thought to be the pathophysiological basis of most acute coronary syndromes. Despite our advanced understanding of the biology of the atherosclerotic process, and the many approaches available for treatment, event rates in coronary disease remain high. In the most recent trials involving acute coronary syndromes, the control group incidences of recurrent cardiac events ranged from 10–25% in the first month after randomization [21–25]. Thus, there remains a need for more effective treatment strategies to improve outcome after acute coronary syndromes. As a result, basic research and clinical investigation continue to refine our understanding and treatment approaches to plaque disruption, coronary thrombosis, and the resulting clinical events.
The authors would like to thank Dr. John T. Fallon for his help in preparing the figures and for his thoughtful review of the manuscript.
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