The Vulnerable Coronary Plaque

Vulnerable coronary plaques are asymptomatic atherosclerotic lesions with the tendency to rupture. Plaque rupture is the initiating event in most acute coronary syndromes including sudden cardiac death, acute myocardial infarction, and unstable angina. Vulnerable plaques are commonly found in coronary arteries at autopsy but are virtually undetectable by standard diagnostic techniques such as stress testing and coronary angiography. Using new imaging techniques, in particular intravas-cular ultrasound and magnetic resonance imaging (MRI), scientists are now able to identify these plaques in vivo. A better understanding of the pathophysiology of plaque vulnerability and rupture will eventually lead to the therapeutic goal of plaque stabilization in the prevention of acute coronary syndromes. This article reviews the role of plaque vulnerability in coronary artery disease. The anatomy and pathophysiology of vulnerable plaques as well as diagnostic and therapeutic implication will be described.

INTRODUCTION

Vulnerable coronary plaques are asymptomatic atherosclerotic lesions with the tendency to rupture. Plaque rupture is the initiating event in most acute coronary syndromes including sudden cardiac death, acute myocardial infarction, and unstable angina. Vulnerable plaques are commonly found in coronary arteries at autopsy but are virtually undetectable by standard diagnostic techniques such as stress testing and coronary angiography. Using new imaging techniques, in particular intravascular ultrasound and magnetic resonance imaging (MRI), scientists are now able to identify these plaques in vivo. A better understanding of the pathophysiology of plaque vulnerability and rupture will eventually lead to the therapeutic goal of plaque stabilization in the prevention of acute coronary syndromes.

This article reviews the role of plaque vulnerability in coronary artery disease. The anatomy and pathophysiology of vulnerable plaques as well as diagnostic and therapeutic implication will be described.

STABLE AND UNSTABLE CORONARY SYNDROMES

The clinical spectrum of coronary artery disease includes unstable coronary syndromes, stable coronary syndromes, and silent disease (Fig 1). Acute coronary syndromes represent a continuum of presentations including sudden cardiac death, acute myocardial infarction, and unstable angina. Together, they are the major cause of morbidity and mortality in western societies. It is now well established that most acute coronary syndromes are initiated by the rupture of vulnerable plaques and subsequent intraluminal thrombus formation. ^1-5 Conversely, stable coronary syndromes, particularly stable angina pectoris, are caused by highly stenotic, but stable lesions, that limit blood flow under conditions of increased demand, ie, during exertion.

Fig 1

Importantly, most patients with atherosclerotic coronary disease are not symptomatic, although atherosclerotic plaques, including vulnerable lesions, are already present in their coronary arteries. The first manifestation of this silent stage of coronary artery disease can be mild angina pectoris or a catastrophic acute myocardial infarction caused by the sudden rupture of a vulnerable plaque. ⁵ Because of the central role of vulnerable plaques in coronary syndromes, diagnostic and therapeutic strategies directed at these lesions have a tremendous potential to prevent the manifestation of coronary artery disease. ⁶

ANATOMY OF THE VULNERABLE (UNSTABLE) PLAQUE

Most of the initial knowledge about vulnerable plaques evolved from histologic studies. ^7-11 These studies describe vulnerable plaques as lesions located in the vessel wall with a large, often eccentric lipid core separated from the lumen by a thin fibrous cap (Fig 2). An important characteristic of vulnerable plaques is "positive arterial remodeling," which describes the expansion of vessel size at the site of the atherosclerotic lesion. Positive arterial remodeling of human coronary arteries was first described by Glagov et al. as a compensatory vessel enlargement in response to plaque growth in early coronary atherosclerosis. ¹² Because of the outward directed growth of the plaque, lumen size is initially unaffected despite increasing plaque burden. ^13,14 Recent intravascular ultrasound data demonstrate that positive remodeling is strongly associated with plaque vulnerability. Specifically, positively remodeled plaques are found more frequently in patients with acute coronary syndromes (Fig 3). ^15,16

Fig 2

Fig 3

Vulnerable plaques exhibit specific patterns of cell accumulation. In early atherosclerotic lesions macrophages accumulate at the plaque site and, by incorporating cholesterol, become so-called foam cells. ¹⁷ This cell accumulation is the precursor of the lipid core. Macrophages are also found in the fibrous cap of more advanced lesions. ^18-20 Vascular smooth muscle cells migrate from the media into the plaque site and can be found in the fibrous cap (Fig 2). ¹⁹

The anatomical and ultrastructural characteristics of vulnerable plaques cause their increased tendency to rupture. The size of the lipid core and the thickness of the fibrous cap influence stress distribution across the lesion. The border between the fibrous cap and normal vessel wall over a large lipid core (the so-called shoulder area) is subjected to particular high stress and therefore is prone to rupture. ^21,22 The accumulation and activation of macrophages and other inflammatory cells induce the secretion of enzymes that weaken the connective tissue framework (extracellular matrix) of the fibrous cap, thereby initiating plaque rupture. In particular, the group of matrix-metalloproteinases (MMPs) plays a central role in the degradation of the extracellular matrix. ^23-25

The recent finding that increased MMP3 is found more frequently in positively remodeled lesions ²⁶ underscores the described association between positive remodeling and unstable coronary syndromes. It has been postulated that the same pathophysiologic mechanisms responsible for expansion of the vessel wall can also cause plaque vulnerability and rupture. ²⁷

Plaque rupture initiates a cascade of events eventually leading to thrombus formation. Initially subendothelial structures are exposed to the blood stream. ^1-5 Platelets accumulate on the exposed plaque and become activated. Activated platelets increase the expression of the glycoprotein IIb/IIIa membrane receptor complex on the cell surface, initiating further platelet aggregation and fibrin deposition, eventually forming a luminal thrombus. The size of the thrombus is determined by the balance between this prothrombotic milieu and local, intrinsic thrombolytic activity. Clinical presentation is related to the size and stability of the thrombus. A completely occlusive thrombus causes acute q-wave myocardial infarctions; a non-occlusive thrombus results in manifestations of non-q-wave myocardial infarction or unstable angina, but can be clinically silent.

VULNERABLE (UNSTABLE) AND STABLE CORONARY LESIONS

In contrast to vulnerable plaques as described above, stable plaques have a decreased tendency to rupture. Stable plaques are characterized by fibrosis, ^28,29 leading to a thick fibrous cap and a small lipid core (Fig 2). Intravascular ultrasound studies found that lesions of patients with stable coronary syndromes are associated with negative remodeling (vessel shrinkage) at the lesion site. ¹⁵ It has been suggested that the fibrotic changes and vessel shrinkage, while causing more severe luminal stenosis, render lesions more resistant to rupture.

Despite their differences, stable and unstable plaques are likely a continuum of the same disease rather than two different entities. Current theories of atherosclerosis ¹⁷ describe the formation of atherosclerotic plaques as "response to injury." Repeated injury to the vessel wall caused by smoking, hypertension, and hypercholesterolemia leads to endothelial activation and development of early lesions called "fatty streaks." These lesions have been demonstrated in young patients at autopsy and recently in vivo with intravascular ultrasound. ^30,31 Lesions progress through repeated cycles of vulnerability and rupture. Some of these episodes are clinically symptomatic (acute coronary syndromes), but most episodes are silent and may lead to plaque fibrosis and healing. Silent episodes of plaque rupture with subsequent lesion stabilization are the most common form of disease progression. Eventually fibrosis and shrinkage can lead to a transition of vulnerable to stable plaques. This unifying hypothesis has major diagnostic and therapeutic implications.

Diagnostic implications

Because of its anatomic character, the vulnerable plaque is virtually undetectable by standard diagnostic methods. The basic principle of exercise testing is that oxygen and substrate delivery through flow-limiting lesions cannot match increased demand during exertion. Therefore, exertion-related angina and ischemia develop. Because most vulnerable plaques are only mildly stenotic and not flow limiting, they are usually not detected by stress testing. Angiography evaluates lesions by the extent of stenosis based on the size and shape of the vessel lumen. The vessel wall, which is the site of atherosclerotic plaque growth, cannot be seen by angiography. ³²

The inability of angiography to recognize plaque growth is influenced to a great extent by positive remodeling. The outward growth of the developing plaque conceals plaque growth particularly in early coronary artery disease (Fig 4). This insensitivity is exemplified by a critical review of the observed differences between histologic and angiographic studies regarding the size of vulnerable plaques. Postmortem studies have shown that vulnerable lesions harbor large atherosclerotic plaques. ^7-10 However, patients with myocardial infarction in whom an angiogram is performed within 1 year before the coronary event most frequently demonstrate a stenosis of <50% at the culprit lesion site responsible for subsequent acute occlusion. ^33-36 These differences can be explained by the outward expansion of the vessel, which attenuates the encroachment of the plaque into the lumen and thereby maintains the lumen area. Plaque growth and positive arterial remodeling, characteristics of vulnerable plaques, are therefore not reliably identified by coronary angiography. ¹⁴

Fig 4

In summary, stress testing and angiography are very effective in identifying fixed, flow-limiting lesions in stable coronary syndromes and vessel occlusion by acute coronary syndromes. However, these techniques are generally not capable of identifying vulnerable plaques before rupture. Vulnerable plaques can be identified only by imaging techniques that visualize the vessel wall, such as intravascular ultrasound and MRI.

Intravascular ultrasound provides tomographic images of the vessel wall including vessel size, plaque size, and plaque morphology (Fig 5). ³⁷ During cardiac catheterization, a miniature ultrasound catheter interfaced with a scanner is placed beyond the target lesion site. The ultrasound catheter is then withdrawn during continuous imaging, resulting in a stack of cross sections (Fig 6). The lumen and vessel wall of each crosssection can be measured and described by its signal character on a continuum from echodense (bright echo signal) to echolucent (faint echo signal). Using intravascular ultrasound, several groups have examined differences between stable and vulnerable coronary plaques. In comparative histologic studies, echolucent appearance by intravascular ultrasound was correlated with the lipid content of plaques. ³⁸ In other studies, plaque echolucency has been associated with the clinical presentation of unstable angina. ³⁹ Recent studies describe an association between acute coronary syndromes and positive remodeling. ^15,16 Our group has studied 85 patients with unstable and 46 patients with stable coronary syndromes using intravascular ultrasound. Positive remodeling was significantly more frequent in unstable than in stable lesions (51.8% vs. 19.6%), whereas negative remodeling was more frequent in stable lesions (56.5% vs. 31.8%) [p = 0.001]. ¹⁵ (Fig 7).

Fig 5

Fig 6

Fig 7

Magnetic resonance tomography can provide anatomic images of atherosclerotic lesions noninvasively. The extent of atherosclerotic plaque has been defined with high resolution MRI in human popliteal arteries. ⁴⁰ Significant plaque burden was observed in angiographically "normal" vessel segments, providing indirect evidence of positive remodeling. In human carotid arteries, MRI has been shown to discriminate various components of atherosclerotic plaques in vivo. ⁴¹ Therefore, morphologic characteristics of vulnerable plaques like increased lipid content can potentially be identified. A recent article by Shinnar et al ⁴² describes the diagnostic accuracy of MRI for plaque characterization but also the technical improvements that will be necessary before this technique can be applied to the examination of coronary arteries in clinical settings.

Evidence that inflammation has a prominent role in unstable coronary syndromes has led to interest in the evaluation of serum markers of plaque vulnerability and rupture. Higher levels of C-reactive protein (CRP) have been documented in patients with unstable coronary syndromes compared with patients with stable angina. ⁴³ In studies of initially healthy subjects, CRP has been found to predict the risk of future myocardial infarction and stroke. ^44,45 Other potential markers include interleukins and MMPs. Elevated blood levels of these inflammatory mediators have been observed in patients with acute coronary syndromes. ^46,47 The increase of these markers represents the inflammatory response associated with plaque vulnerability and rupture. Unfortunately, these markers are unspecific and can be elevated in other inflammatory or immunologic diseases.

IMPLICATION FOR PREVENTION AND TREATMENT

Because of the central role of vulnerable plaques in coronary artery disease, treatment strategies directed at the stabilization of these lesions have tremendous potential. While established treatments of coronary syndromes such as percutaneous transluminal coronary angioplasty, thrombolysis, and IIB/IIIA inhibitors intervene upon lesion after rupture, "plaque stabilization" would intervene at an earlier stage in the development of coronary lesions and could therefore potentially prevent acute coronary events.

It is likely that many preventive measures (diet, smoking cessation, exercise) and pharmacological interventions (statins, beta-blocker, ASA) reduce acute coronary syndromes by "stabilizing" vulnerable plaques. This hypothesis explains why large lipid-lowering trials with clinical and angiographic endpoints show a significant reduction in clinical events out of proportion to angiography changes. ^48-50 Mechanisms other than reduction of luminal stenosis (of highly stenotic lesions) are obviously responsible for the clinical effect. These mechanisms are summarized in the concept of plaque stabilization (see Table 1). ⁵¹ The above described imaging technologies allow the identification of plaque characteristics associated with vulnerability. Longitudinal observation of plaques before and after pharmacologic therapy could potentially visualize mechanisms of plaque stabilization and predict the effectiveness of therapy.

Table 1

Based on observations in highly stenotic lesions, it has been hypothesized that interventional techniques such as angioplasty could be used to "stabilize" vulnerable plaques by inducing fibrosis. ^52,53 No clinical experience, however, supports this concept of "plaque sealing."

CONCLUSIONS

The vulnerable plaque is the central pathophysiologic event in coronary artery disease (Fig 8). Our knowledge about vulnerable plaques, based on basic research, is farther advanced than our clinical ability to diagnose or treat these lesions. New imaging techniques, in particular intravascular ultrasound, can identify morphologic characteristics of vulnerable plaques. The potential for prevention of lesion formation and stabilization of existing plaques is tremendous and needs to be tested in controlled studies.

Fig 8