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Vulnerable Plaque: Pathobiology and Clinical Implications
- Iftikhar J. Kullo, MD;
- William D. Edwards, MD; and
- Robert S. Schwartz, MD
- From the Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Grant Support: In part by the Mayo Foundation Clinician-Investigator Training Program (Dr. Kullo) and by the Minnesota affiliate of the American Heart Association (Dr. Kullo). Requests for Reprints: Iftikhar J. Kullo, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Current Author Addresses: Drs. Kullo, Edwards, and Schwartz: Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
Abstract
Purpose: To review the pathobiology and clinical implications of vulnerable coronary atherosclerotic plaques and to discuss the identification of vulnerable plaques and mechanisms of plaque stabilization.
Data Sources: English-language articles in the MEDLINE database that were published from 1966 to the present, identified by using the terms atherosclerotic plaque, myocardial revascularization, and plaque stabilization. Selected references cited in identified articles were reviewed.
Study Selection: Experimental, clinical, and basic research studies related to coronary atherosclerotic plaques.
Data Synthesis: Rupture at the site of a vulnerable atherosclerotic plaque is the most frequent cause of acute coronary syndromes. Typically, such plaque does not cause high-grade stenosis and has a large lipid core and a thin fibrous cap that is often infiltrated by inflammatory cells. Mechanical stresses contribute to plaque vulnerability, and certain triggers may cause plaque disruption directly. The most important consequence of plaque rupture is thrombosis. No method reliably identifies plaques prone to rupture. The reduction of coronary events by lipid-lowering agents despite only modest luminal changes suggests that these agents have a plaque-stabilizing effect. Surgical or percutaneous revascularization does not address the basic biology of coronary atherosclerosis and therefore may have little effect on plaque vulnerability.
Conclusions: Improved understanding of the biology of atheromatous plaques has led to the concept of plaque vulnerability. Identification and stabilization of vulnerable plaques are important new directions in the treatment of coronary atherosclerosis. The relative benefits of aggressive medical therapy aimed at plaque stabilization should be compared with those of revascularization in the management of chronic coronary artery disease.
As early as 1926, Benson [1] postulated that coronary thrombi result from disruption of the intima that exposes lipid to flowing blood. In 1966, Constantinides [2] was the first to establish conclusively that plaque rupture was the immediate cause of coronary thrombosis. He examined 17 consecutive cases of coronary thrombosis seen on autopsy and concluded that fracture of the fibrous lining of the atherosclerotic plaques led to thrombus formation. Subsequently, in a series of studies [3-7], Davies and colleagues established the importance of plaque fissuring and subsequent thrombosis in myocardial infarction, unstable angina, and sudden death due to ischemia.
In 1980, angiographic studies by DeWood and coworkers [8] revealed that occlusive thrombus was responsible for most cases of acute myocardial infarction. Thrombus formation was subsequently implicated in the pathogenesis of unstable angina [9]. At that time, the prevailing concept was that myocardial infarction resulted from occlusion at a site of high-grade stenosis. The establishment of coronary thrombosis as the most common cause of myocardial infarction led to the development and use of thrombolytic agents. In 1986, Brown and colleagues [10] used quantitative angiography to show that after thrombolysis, residual stenosis at the site of thrombus formation averaged only 56%. In 1988, Little and colleagues [11] studied 42 consecutive patients who underwent coronary angiography before and up to a month after having an acute myocardial infarction. They concluded that most of the infarctions resulted from a coronary occlusion that had previously shown stenosis of less than 50% on angiography. The severity of coronary stenosis on angiography did not accurately predict the location of a subsequent coronary occlusion. Ambrose and associates [12], in the same year, confirmed that myocardial infarction often developed in territories supplied by coronary arteries with noncritical stenoses.
With these studies emerged the concept of the vulnerable atherosclerotic plaque. Such plaque does not cause high-grade stenosis, yet it may result in an acute coronary syndrome, such as unstable angina, myocardial infarction, or sudden death. Identifying and stabilizing the vulnerable plaque will be important challenges in cardiology in the coming years. In this review, we focus on the pathobiology of vulnerable coronary atherosclerotic plaque and the clinical implications of studies of plaque biology.
Methods
English-language articles were identified through a search of the MEDLINE database from 1966 to the present by using the terms atherosclerotic plaque, myocardial revascularization, and plaque stabilization. Of 3462 articles, 202 reports of experimental, clinical, and basic research studies related to coronary atherosclerotic plaques. Both human and animal studies related to pathobiology and therapy were considered. Selected references cited in identified articles were also reviewed. The incidence of nonfatal myocardial infarction was studied in randomized trials comparing medical treatment with mechanical revascularization (coronary angioplasty or coronary artery bypass grafting). The same end point was also studied in multicenter randomized trials comparing routine angiography and revascularization with a more “conservative” strategy in the management of acute coronary syndromes.
Plaque Vulnerability and Disruption
Rupture of a fibrous cap overlaying a vulnerable plaque is the most common cause of coronary thrombosis. In up to 25% of cases, however, thrombosis may result from superficial erosion over a plaque [13]. Plaques prone to rupture are characterized by a large lipid core and a thin fibrous cap, but plaques with erosion vary in size and composition [14]. Inflammatory activity has been associated with plaque erosion and may have a role in the pathogenesis of endothelial damage [15]. However, Farb and colleagues [16] have shown that erosions and subsequent thrombosis can develop in plaques that are relatively rich in proteoglycan matrix and smooth-muscle cells and that lack a superficial lipid core. In the discussion below, we focus predominantly on plaque rupture, which results from intrinsic plaque vulnerability, mechanical stresses, and extrinsic triggers.
Bases of Plaque Vulnerability
Atherosclerotic plaques prone to rupture have certain characteristic structural, cellular, and molecular features (Figure 1, Table 1). A plaque with a thin fibrous cap overlaying a large lipid core is at high risk for rupture [17, 18]. Gertz and Roberts [19] examined the lipid composition of plaques from 17 infarction-related arteries at autopsy and noted that lipid cores were much larger in the 39 segments with plaque disruption than in the 229 segments with intact surfaces. The nature of the lipid present in a plaque may also be a factor. Lipid in the form of cholesteryl ester softens the plaque, whereas crystalline cholesterol may have the opposite effect [17].
An inflammatory-cell infiltrate is a marker of plaque vulnerability. In one study [15], the site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques was characterized by an inflammatory infiltrate regardless of plaque structure. Several factors, including lipoproteins (principally oxidized lipoproteins); infectious agents; or autoantigens, such as heat-shock proteins, may incite a chronic inflammatory reaction in an atherosclerotic plaque [20]. Influx of activated macrophages and T lymphocytes into the plaque follows, with subsequent elaboration of cytokines and matrix-degrading proteins, leading to a weakening of the connective-tissue framework of the plaque. Smooth-muscle cells may counteract some of these effects by producing matrix, collagen, and inhibitors of the matrix-degrading enzymes called metalloproteinases [20].
At the molecular level, matrix metalloproteinases and certain cytokines are important factors in the pathogenesis of plaque vulnerability. Matrix metalloproteinases are a family of proteolytic enzymes that degrade various components of the extracellular matrix. In the atherosclerotic plaque, foam-cell macrophages, activated T cells, and smooth-muscle cells secrete these enzymes after stimulation by various cytokines, such as interferon-γ, tumor necrosis factor, interleukin-1, and macrophage colony-stimulating factor [20]. Hansson and colleagues [21] demonstrated the presence of chronically activated, interferon-γ-producing T cells in human atheroma. Interferon-γ inhibits proliferation of smooth-muscle cells and collagen synthesis and thus may contribute to plaque vulnerability.
Mechanical Stresses
Mechanical stresses may play an important role in plaque rupture [22, 23]. Irregularity of plaque shapes and the presence of a lipid core result in uneven distribution of wall tension along the arterial wall, with critical elevations at certain points [24]. The thinner the fibrous cap, the less able it is to withstand chronic or progressive wall stress. Richardson and colleagues [24] used computer modeling in simulated plaques to show that circumferential stress in a plaque with an eccentric lipid pool is concentrated near the shoulder of the plaque, the most frequent site of rupture noted at autopsy. Cheng and colleagues [25] computed stress distribution in plaques that had ruptured and confirmed that most fibrous caps (58%) ruptured where the estimated circumferential stress was highest.
Sudden accentuation of wall stress may directly trigger plaque rupture. In addition, repetitive stretching, bending, and flexion due to cardiac motion may impose chronic stresses on the coronary arteries [26]. These, in turn, may lead to plaque fatigue, weakening of the fibrous cap, and spontaneous rupture [23].
Trigger Events
Although plaque rupture may occur spontaneously, it may be triggered by certain events. Half of patients with myocardial infarction report a trigger event, most often emotional stress or physical activity [27]. A sudden surge in sympathetic activity with an increase in blood pressure, heart rate, force of cardiac contraction, and coronary blood flow may lead to plaque disruption [28]. It has been proposed that coronary vasospasm triggers plaque rupture by compressing the atheromatous core and causing eruption of lipid into the lumen [29]. In certain settings, a hypercoagulable-hypofibrinolytic state may directly promote occlusive thrombus formation and a clinical event [30, 31].
Consequences of Plaque Rupture
Plaque rupture usually leads to various degrees of thrombus formation. The factors that determine the extent of thrombus formation and clinical outcome are outlined in Figure 1. Thrombosis may result in unstable angina, myocardial infarction, or sudden death, particularly if collateral flow is inadequate. However, if the plaque disruption is minor, local flow is high, and the fibrinolytic system is active, thrombus formation may be minimal. In such a scenario, plaque rupture may remain clinically silent. Indeed, in up to 8% of patients with coronary atherosclerosis who died of noncardiovascular causes, such as accidents, a small, recent plaque disruption was found at autopsy [32]. In patients with diabetes or hypertension, the frequency of disrupted plaques at autopsy was as high as 22% [32]. In some patients who died of ischemic heart disease, more than one plaque disruption was noted, although one of the thrombi in each case was larger and was considered to be the lesion that had caused death [6]. Plaque disruption may be more frequent than initially thought, with a high proportion of these events remaining clinically silent. Asymptomatic thrombus formation on a disrupted plaque may be an important mechanism of plaque growth and may eventually lead to such symptoms as chronic stable angina [33].
Identification of Vulnerable Plaques
Coronary angiography is only luminography and gives little information about arterial wall pathology [34]. The phenomenon of remodeling makes angiography a poor technique with which to assess the true atherosclerotic burden. Arteries accommodate plaque growth through outward displacement of the vessel wall, thereby preserving the lumen cross-sectional area [35]. The angiogram may be normal even if a significant atherosclerotic plaque is present in the arterial wall. If the plaque is unstable and ruptures, a clinical event may result from a site that showed minimal or no stenosis. Development of clinically useful imaging techniques for identifying vulnerable plaques is an active area of research. Imaging methods in clinical use that attempt to identify vulnerable plaques are discussed below, and some of the experimental methods are summarized in Table 2.
Intravascular Ultrasonography
Intravascular ultrasonography has advanced our understanding of atherosclerosis by demonstrating extensive atheromatous burden in coronary arteries that appear normal on angiography. Luminal geometry and the cross-sectional area of the plaque can be assessed, and certain characteristics of the plaque, such as amount of fibrosis and presence of calcification, can be identified [40]. Large amounts of lipid or necrotic material can be imaged. In a 1995 study, de Feyter and colleagues [41] used angiography, intravascular ultrasonography, and angioscopy to assess ischemia-related coronary lesions in patients with unstable and stable angina. Ultrasonic imaging with a 30-MHz probe was unable to discriminate between stable and unstable plaques in their study. Improved technology may permit better delineation of the size of the lipid core and thickness of the fibrous cap, two features that distinguish stable from unstable plaques.
Electron-Beam Computed Tomography
The amount of coronary artery calcification determined by electron-beam computed tomography correlates well with the total area of coronary artery plaque, especially in patients older than 50 years of age [42]. Patients with greater amounts of coronary calcification are more likely to have a clinical event than are patients without calcification or with less calcification [43]. However, the relation of calcification to the process or likelihood of plaque rupture and the role of calcification in the biology of the unstable plaque remain unclear. Some authors suggest that the presence of calcium may stabilize a plaque [25]; others postulate that calcification in small to moderate-sized plaques may increase shear stress (because of the presence of a tissue interface of different physical properties) and predispose to rupture [44]. Regardless of which hypothesis is correct, coronary calcification as detected by electron-beam computed tomography seems to be an indicator of atherosclerotic burden and indirectly suggests the presence of lipid-rich unstable plaques.
Angioscopy
Percutaneous coronary angioscopy permits direct visualization of the luminal surface of coronary arteries and can elucidate the surface characteristics of atherosclerotic plaques. The major role of angioscopy has been in the assessment of lumen structure before and after interventions [45]. In the study by de Feyter and colleagues [41], angioscopy showed that plaque rupture and thrombus occurred in 17% of patients with stable angina and 68% of those with unstable angina. Yellow plaques were defined as homogeneous yellow areas clearly distinguishable from the normal white wall. The investigators found no difference in the frequency of yellow plaques in the two groups; the plaques were detected in approximately two thirds of patients in each group. Angioscopy does not reliably identify the lipid-rich plaque with a thin cap.
Magnetic Resonance Imaging
Magnetic resonance imaging has been used to visualize atherosclerotic lesions (including advanced lesions, such as the fibrous cap, the lipid core, and even plaque fissuring) in rabbits [46]. Serial imaging over time has allowed assessment of lesion progression and regression. Toussaint and colleagues [47] imaged carotid lesions in six patients who required carotid endarterectomy. They then repeated these measurements in vitro on the resected fragments and compared magnetic resonance images with histologic findings. They showed that noninvasive imaging of lipid cores, fibrous caps, calcification, normal media, and adventitia, as well as intraplaque hemorrhage and acute thrombosis, may be possible with this technique. It is also possible that magnetic resonance imaging could be used to study plaque progression, stabilization, and rupture in human atherosclerosis. Imaging the coronary arteries, however, is technically challenging because of cardiac motion.
Stabilization of Vulnerable Plaques
Several drugs may have a stabilizing effect on atherosclerotic plaques (Table 3). β-adrenergic receptor blockers reduce recurrence of myocardial infarction [55], and angiotensin-converting enzyme inhibitors have been shown to reduce the incidence of myocardial infarction when given to patients with left ventricular dysfunction [52, 53]. It has also been postulated that antioxidants [50] and antibiotics [57, 58] have beneficial effects on plaque biology. Table 3 does not include antithrombotic agents because, strictly speaking, these agents do not stabilize the vulnerable plaque. Instead, they exert their effects by limiting thrombosis, an important consequence of plaque rupture.
Among drugs with possible plaque-stabilizing effects, the lipid-lowering agents are probably the most important. The recent lipid-lowering trials that have used 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have shown that lowering plasma low-density lipoprotein (LDL) cholesterol levels in several clinical settings leads to a decrease in risks for acute ischemic events and death [59-61]. The modest change in luminal narrowing that accompanies lipid lowering is unlikely to be the principal mechanism of reduction in clinical events and revascularization rates [62]. Several other mechanisms have been postulated, including plaque stabilization, improvement in endothelial function, and a favorable effect on thrombosis and fibrinolysis. Initially, beneficial effects may be due to enhanced endothelial function and a favorable effect on blood coagulation and fibrinolysis. Later, effects on plaque composition and size may be operative [63]. These mechanisms are discussed below. Most, but not all, of the beneficial effects of statins are probably due to lipid lowering [64].
Plaque Stability
The precise mechanisms by which lipid lowering may stabilize vulnerable atherosclerotic plaques have yet to be clearly defined. Alterations at the physical, cellular, and biochemical levels are probably operative. In primates with diet-induced atherosclerosis, the lipid content of atheromatous plaques begins to decrease 6 months after the normalization of increased plasma cholesterol values and at 2 years, 60% of plaque cholesterol is depleted [65, 66]. The reduced lipid content is accompanied by an increase in collagen concentration that may increase the mechanical strength of the plaque [67, 68]. Lipid depletion occurs mainly as a result of the removal of plaque-softening cholesteryl ester, with a resulting increase in the concentration of crystalline cholesterol [68]. Loree and colleagues [17] showed that the stiffness of model atherosclerotic plaque lipid pools is related to the concentration of cholesterol monohydrate crystals. The increase in the relative concentration of cholesterol monohydrate due to lipid lowering may result in stiffening of the plaque and increased plaque stability.
Inflammation is associated with increased expression of tissue factor and matrix metalloproteinases within the plaque; this predisposes to rupture as well as increased thrombogenicity [20]. At the cellular level, an important mechanism by which cholesterol lowering may prevent plaque disruption is through a decrease in inflammatory cells and macrophage activation in the plaque. Lowering of serum cholesterol levels in experimental animals leads to a decrease in inflammatory cells within atherosclerotic plaques [65, 69-71]. In primates with diet-induced atherosclerosis, normalization of plasma cholesterol levels led to the disappearance of lipid-laden macrophages (foam cells) within 6 months. In Watanabe rabbits, lowering of plasma lipid values decreases the macrophage content of the arterial lesions [69]. At the molecular level, lipid lowering has been shown to decrease matrix metalloproteinase activity in atheromatous plaques of hypercholesterolemic rabbits [71], providing yet another possible mechanism for plaque stabilization.
Endothelial Function
Hypercholesterolemia causes endothelial dysfunction and abnormal vasoreactivity in epicardial coronary arteries [72, 73]. The microvasculature is also affected, as was demonstrated in a study in which coronary flow reserve was reduced in hypercholesterolemic patients without overt coronary stenosis [74].
Several studies have shown that cholesterol lowering with a statin improves endothelial function in the epicardial coronary arteries of patients with coronary artery disease [75, 76] or hypercholesterolemia [77]. A beneficial effect on the coronary microvasculature has been shown in several studies in which cholesterol lowering led to an improvement in myocardial perfusion defects measured by thallium-201 scintigraphy or positron emission tomography [78-81].
Three recent studies have shown that the beneficial effect of the statins on the endothelial function of epicardial arteries and the coronary microvasculature translates into an anti-ischemic effect. Andrews and colleagues [82] objectively demonstrated a decrease in myocardial ischemia during daily life as a result of cholesterol lowering with a statin. Forty patients with coronary artery disease, total serum cholesterol values between 4.94 and 8.46 mmol/L (190 and 330 mg/dL), and at least one episode of ST-segment depression on ambulatory electrocardiographic monitoring were randomly assigned to an American Heart Association Step I diet plus placebo or to the same diet plus lovastatin therapy. The diet-plus-lovastatin group had lower mean total and LDL cholesterol levels after 4 to 6 months of therapy and a significant reduction in the number of episodes of ST-segment depression compared with the diet-plus-placebo group. ST-segment depression completely resolved in 13 of 20 patients (65%) in the diet-plus-lovastatin group but in only 2 of 20 patients (10%) in the diet-plus-placebo group. In another randomized, placebo-controlled study, men with coronary artery disease and serum cholesterol levels between 4 and 8 mmol/L (155 and 310 mg/dL) were treated with pravastatin for 2 years. Patients treated with pravastatin had a decreased incidence of myocardial ischemia, as documented by ambulatory electrocardiographic monitoring [83]. Finally, de Divitiis and colleagues [84] showed a significant improvement in myocardial effort ischemia after 12 weeks of treatment with simvastatin compared with placebo in patients who had stable angina and mild to moderate hypercholesterolemia.
These studies show that amelioration of endothelial dysfunction by statins may improve local regulation of coronary arterial tone and may thereby relieve ischemic symptoms. The divergence of survival curves in the large statin trials at 2 years or earlier may be a result of these early beneficial effects on endothelial function in epicardial arteries and the microcirculation, preceding macroscopic changes in the vasculature [64].
Thrombogenicity and Fibrinolysis
Hypercholesterolemia is associated with enhanced platelet reactivity as a result of several mechanisms, including lipid peroxidation, enhanced thromboxane production, and alterations of platelet cell membrane and cytosolic calcium [85]. In an ex vivo system, baseline platelet thrombus formation was significantly higher in hypercholesterolemic patients with coronary artery disease than in normocholesterolemic patients; after 2 to 3 months of pravastatin therapy, however, platelet aggregation decreased at both low and high shear stress rates [86]. The statins have been shown to decrease adenosine diphosphate-induced platelet aggregation [87], thromboxane B2 production [88], and cytosolic calcium in platelets [89].
Apart from affecting platelets, statins may favorably modulate tissue factor expression in the plaque, blood viscosity, and fibrinolytic capacity. Fluvastatin and simvastatin decrease tissue factor expression by cultured human macrophages [90]. A decrease in blood viscosity was seen in hypercholesterolemic patients receiving pravastatin [91]. Pravastatin may enhance plasma fibrinolytic action by decreasing plasminogen activator inhibitor type 1 production by the endothelium [92].
Future Therapies
With a better understanding of the molecular bases of vulnerable plaque and continuing progress in the field of gene therapy, an exciting possibility is the use of gene therapy to stabilize the vulnerable plaque. Possible strategies include overexpression of tissue inhibitors of matrix metalloproteinases; antisense strategies to block proinflammatory molecules, such as nuclear factor κ B; and overexpression of nitric oxide synthase [93, 94] or prostacyclin synthase [95] to ameliorate endothelial dysfunction and the associated procoagulant state. Tissue factor contributes substantially to the thrombogenic potential of ruptured plaques, and overexpression of the tissue factor pathway inhibitor may limit thrombosis and the likelihood of a clinical event after plaque rupture. Currently, the lack of an adequate animal model with which to test such strategies is a considerable obstacle.
Coronary Artery Disease: Should Plaque Stabilization Be the Primary Goal?
For many years, the management of coronary artery disease has been guided by the severity of stenosis, as assessed by coronary angiography. Progressive narrowing of coronary arteries is assumed to lead to complete occlusion and myocardial infarction. In many patients with severe stenosis on coronary angiography, revascularization eventually occurs with balloon angioplasty or bypass surgery. However, previous and emerging evidence suggests that although revascularization relieves symptoms, it does not prevent myocardial infarction.
In the 1970s and early 1980s, three large randomized trials of early bypass surgery and initial medical therapy were done [96-98]. These trials primarily included men younger than 65 years of age who had stable angina. Despite the infrequent use of lipid-lowering agents, aspirin, and β-adrenergic receptor blockers in the participants, none of the studies showed an advantage of surgical over medical therapy in decreasing the risk for subsequent myocardial infarction [99]. Yusuf and colleagues [100] performed a meta-analysis of seven randomized trials (including the three major trials cited above) comparing coronary artery bypass grafting with medical therapy and including a total of 2649 patients. In this analysis, no significant difference was found in the incidence of nonfatal myocardial infarction in the two groups at 5 years.
Percutaneous revascularization does not seem to decrease the incidence of myocardial infarction in patients with stable coronary artery disease. In the Angioplasty Compared to Medicine study, patients with angina and single-vessel coronary artery disease were randomly assigned to medical therapy or angioplasty [101]. At 6 months, mortality and the incidence of myocardial infarction did not differ in the two groups. In the Medicine, Angioplasty or Surgery Study [102], 214 patients with proximal left anterior descending artery disease were randomly assigned to bypass grafting, angioplasty, or medical therapy. No difference was seen in mortality or myocardial infarction in the three groups after an average follow-up of 3 years. The second Randomized Intervention Treatment of Angina trial [103] randomly assigned 1018 patients with chronic stable angina, one- or two-vessel disease, and preserved left ventricular function to balloon angioplasty or medical treatment. At a median follow-up of 2.7 years, the combined end point of death or definite myocardial infarction was significantly higher in the angioplasty group than in the medically managed group (6.3% compared with 3.3%; P < 0.02), largely as a result of procedure-related events. At 1 year, 14.9% of the angioplasty group and 15.4% of the medically treated group required revascularization. Although angioplasty was more effective at relieving angina and improving exercise duration, the risk for procedure-related death or myocardial infarction offsets this advantage.
Medical management may be as effective as a routine invasive strategy in the setting of acute coronary syndromes, including unstable angina, non-Q-wave myocardial infarction, and Q-wave myocardial infarction treated with thrombolytic therapy. In five large prospective trials, patients with these acute coronary syndromes were randomly assigned to routine invasive management or to a more conservative strategy in which angiography and revascularization were done only if spontaneous or provoked myocardial ischemia was demonstrated [104-108]. All but one [107] of the studies showed that routine angiography and revascularization did not reduce the incidence of nonfatal myocardial infarction or death. Indeed, in the Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital study [108], all-cause mortality was significantly higher at hospital discharge, 1 month after discharge, and 1 year after discharge in the invasive group.
An improved understanding of the biology of atherosclerotic plaques provides an explanation for the results of the studies discussed above. Most acute coronary events result from plaque rupture at sites of less-than-severe coronary artery narrowing. The resulting thrombotic occlusion leads to a clinical event because of the absence of protective collateral flow. Although severe stenosis may progress to complete occlusion, the presence of collateral flow associated with severe stenosis may protect against the development of myocardial infarction. Because arterial revascularization is directed at treating severe coronary stenosis and does not alter the biology of the atherosclerotic disease process, the problem of plaque instability remains. It is therefore not surprising that infarctions that develop after coronary artery bypass grafting or balloon angioplasty generally occur at untreated sites [109, 110].
The new, still evolving paradigm of management of coronary artery disease may have begun with studies that showed the possibility of slowing the progression or even causing regression of coronary lesions by lipid lowering [62]. Major primary prevention trials, such as the Lipid Research Clinics Coronary Primary Prevention Trial [111] and the Helsinki Heart Study [112], demonstrated that cholesterol lowering reduced mortality rates for coronary disease but did not answer questions about overall mortality rates and the possibility of harmful drug effects. These were followed by landmark studies of the statin drugs in primary and secondary prevention, which showed a dramatic decrease in overall and cardiovascular mortality [59-61]. These studies suggested that lipid-lowering agents may be more effective than revascularization in preventing myocardial infarction in patients with coronary artery disease. However, no studies have compared the long-term outcome of aggressive lipid-lowering therapies with the outcome of mechanical revascularization in the management of chronic coronary artery disease [113].
In an era of evidence-based medicine and cost containment, it is time to re-evaluate the relative benefits of intensive medical therapy that includes lipid-lowering agents and revascularization in the management of chronic coronary artery disease [114]. An example of a step in this direction is a trial comparing aggressive lipid lowering using atorvastatin with percutaneous revascularization procedures in patients with significant coronary artery disease [115]. In this open-label, randomized study, 341 patients with serum LDL cholesterol levels greater than 3 mmol/L (115 mg/dL), class I or II angina, and significant narrowing (>50%) in one or more coronary arteries have been randomly assigned to receive atorvastatin or to undergo a catheter-based revascularization procedure. The primary end point of the study is the incidence of ischemic events in 18 months, and data collection was completed in June 1998.
Summary and Conclusions
Our understanding of plaque biology and the triggering of plaque rupture has increased dramatically in the past decade. Progress has been made in identifying some of the molecular and cellular mechanisms that lead to plaque instability. It is time to translate the newer insights and knowledge related to plaque vulnerability into clinical practice. Management of the stable anginal syndrome needs to be viewed separately from the prevention of thrombus-based events. Aggressive medical management may lessen the need for invasive procedures in many patients, as the recent statin trials show. The preoccupation with coronary luminology needs to give way to a better understanding of the biology of atherosclerosis. We need to re-evaluate the relative benefits of aggressive medical therapy aimed at plaque stabilization and revascularization in the management of angina pectoris and other forms of chronic myocardial ischemia. Future research in vascular biology will probably be directed at developing new strategies to stabilize vulnerable lesions and reducing the size of a thrombus occurring in the presence of a ruptured plaque. This could decrease the frequency and magnitude of myocardial infarction, unstable angina, and stroke. The promise of molecular and genetic therapies in this area is considerable [116]. However, a pre-eminent need exists for methods with which to easily and reliably identify vulnerable plaques. Once these plaques are identified, pharmacologic and molecular therapies may allow their stabilization.
- Copyright ©2004 by the American College of Physicians
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