Is the Concept of Vulnerable Plaque Relevant to Practitioners?
Is the Concept of Vulnerable Plaque Relevant to Practitioners?
There has been great interest in identifying plaques that might be the site of future acute coronary events. The majority of these "vulnerable plaques" are lipid-rich with an abundance of inflammatory cells and a thin fibrous cap. Several techniques are in various stages of development to potentially identify and therapeutically modify such lesions to avoid future acute events. However, Staniloae and Ambrose have noted significant potential limitations to this approach. First of all, it is not known with certainty what a vulnerable plaque looks like. Furthermore, the natural history of a presumed vulnerable plaque is unknown and clinical trials utilizing this strategy of identification and therapeutic intervention are presently lacking. Finally, in any given high risk patient, multiple "vulnerable" plaques are likely to be present. Consequently, while the idea of identifying a local vulnerable plaque seems promising, is it relevant to practitioners?
The clinical/pathological spectrum of atherosclerotic disease is comprised of: 1) stable plaque, with a low likelihood of progression to an acute coronary syndrome (ACS) or sudden cardiac death (SCD) in the absence of PCI; 2) vulnerable or high-risk plaque, with a higher likelihood of ACS/SCD; and 3) a thrombosed or unstable plaque, which is already disrupted and/or thrombotic, and the immediate cause of ACS/SCD in a majority of cases.
The question of just what is a vulnerable plaque became less clear in 1996 when Farb et al. noted that coronary plaque erosion without any rupture of a lipid core is a frequent cause of coronary thrombosis and sudden coronary death. They showed that superficial erosion of nonlipid-rich plaque probably accounts for about one-third of ACS/SCD events, with an even higher incidence of such erosions among women and in non-exercise related events.
With the concept of "vulnerable" plaque not nearly as straightforward as once thought, there are challenges to creating a local interventional approach for asymptomatic vulnerable plaques. First, there must be an ability to identify vulnerable plaque with non-invasive (preferably) or invasive techniques. Coronary plaque composition can be predicted via intravascular ultrasound (IVUS), allowing real-time analysis and in vivo plaque characterization (Slide 1).
(Enlarge Image)
Figure 1.
Left Anterior Descending Artery Depicted by Intravascular Ultrasound-Virtual Histology, Where Calcified, Fibrous, Fibrolipidic, and Necrotic Core Regions are Labelled White, Green, Greenish-Yellow, Red, Respectively
Source: Clinical image provided by the American College of Cardiology Foundation
A second challenge: a lesion-specific local intervention requires that the number of vulnerable plaques in each patient needs to be known and the number of such lesions need to be limited. That's not the case, however. Autopsy studies by Falk, Davies, and others indicate the presence of multiple "lipid-rich" vulnerable plaques in patients dying after ACS or with SCD. Moreover, multiple complex plaques have been widely reported, in both culprit and nonculprit arteries, including up to 79% of patients referred for PCI after ACS. Further complicating the issue: coronary occlusion and myocardial infarction usually evolve from mild to moderate stenoses --- 68% of the time, according to an analysis of data from four separate studies --- as initially reported by Ambrose et al and Little et al, with subsequent confirmation by others.
The third and fourth prerequisites to a lesion-specific, local interventional approach to vulnerable plaques: The natural history of vulnerable plaque (with respect to incidence of acute events) has to be documented in patients treated with patient-specific systemic therapy; and the approach has to be proven to significantly reduce the incidence of future events relative to its natural history. At this time, neither is documented/proved.
According to Dr. Ambrose, "The problem with the whole concept of vulnerable plaque is it's very difficult at the present time to know what exactly is a vulnerable plaque." Certainly there are vulnerable plaque characteristics that can be determined pathologically and perhaps angiographically. "But the definition of a plaque leading to an acute event is a difficult concept because we don't, as of yet, have natural history studies to know before an event occurs, which plaque is definitely vulnerable. We only have what we think are presumed vulnerable plaques, mostly based on what the pathology of the disrupted plaque looks like."
Dr. Ambrose agrees with another approach urged by Naghavi et al.: targeting the vulnerable patient, as defined by the possible presence of vulnerable plaque, but also vulnerable blood (prone to thrombosis) and/or vulnerable myocardium (prone to life-threatening arrhythmia). In short, Dr. Ambrose said, while vulnerable plaque is "a vital concept for all practitioners, it's probably more important that we consider the concept of the vulnerable patient."
Based on available knowledge, Dr. Ambrose asked, "How many vulnerable plaques will never rupture?" The answer is unknown, "but I suspect conservatively it is the vast majority of them. Perhaps, vulnerable plaque as described is not the appropriate target for local therapy. Asymptomatic ruptured plaques might be more appropriate as these are the immediate precursors to AMI."
Recently, Dr. Ambrose proposed a classification of systemic therapies for potential stabilization of vulnerable plaque based on both biologic plausibility (a potential mechanism to explain the effect) and clinical evidence (i.e., whether the agent reduced acute myocardial infarction in well-designed clinical trials). He and colleague David J. D'Agate selected therapies possessing biologic plausibility and classified them into four groups based on clinical data (Slide 2).
(Enlarge Image)
Figure 2.
Proposed Classification of Systemic Therapies for Stabilization of Vulnerable Plaque
Source: Clinical image provided by the American College of Cardiology Foundation
"We asked: Did they have anti-inflammatory effects? Did they have effects that reduce thrombosis risk? Did they improve endothelial function? Did they reduce wall stress? Did they modify the lipid content of the plaque?" Group 1 consisted of therapies with positive clinical evidence that they reduce myocardial infarction. Potentially, he said, these are plaque stabilizing. The second group includes agents with mostly negative data; so, there is biologic plausibility, but nothing that has been confirmed in clinical trials. The third group has inconsistent data; not all negative but not all positive either. Finally, the fourth group consists of agents that Dr. Ambrose calls the most interesting: they have biologic plausibility, but as of yet not enough clinical evidence.
"All of these therapies," he added, "should be with the backdrop of lifestyle changes. We cannot forget that smoking cessation, proper diet, and exercise all help reduce risk in vulnerable patients."
Alfred A. Bove, MD, FACC: Because we now recognize atherosclerosis as a diffuse, multisystem disease, it is essential to assess total patient vulnerability and not just search for a single, unstable coronary plaque. Future efforts may identify plaques that are on a trajectory of evolution toward a vulnerable state, and help us target interventions to those plaques most likely to develop thrombosis. Similarly, we look forward to a time when factors that protect plaques from becoming vulnerable will be identified. Until then, we go in search of the vulnerable patients in our practice who, with optimal care, may end up with far fewer vulnerable plaques to worry about.
Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. For either the full report or Executive Summary, click here.
Grundy SM, Cleeman JI, Merz CN; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44:720-32. NCEP ATP III
Taylor AJ, Merz CN, Udelson JE. 34th Bethesda Conference: Executive summary --- can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease?. J Am Coll Cardiol 2003;41:1860-917.
The Challenge
There has been great interest in identifying plaques that might be the site of future acute coronary events. The majority of these "vulnerable plaques" are lipid-rich with an abundance of inflammatory cells and a thin fibrous cap. Several techniques are in various stages of development to potentially identify and therapeutically modify such lesions to avoid future acute events. However, Staniloae and Ambrose have noted significant potential limitations to this approach. First of all, it is not known with certainty what a vulnerable plaque looks like. Furthermore, the natural history of a presumed vulnerable plaque is unknown and clinical trials utilizing this strategy of identification and therapeutic intervention are presently lacking. Finally, in any given high risk patient, multiple "vulnerable" plaques are likely to be present. Consequently, while the idea of identifying a local vulnerable plaque seems promising, is it relevant to practitioners?
The Data
The clinical/pathological spectrum of atherosclerotic disease is comprised of: 1) stable plaque, with a low likelihood of progression to an acute coronary syndrome (ACS) or sudden cardiac death (SCD) in the absence of PCI; 2) vulnerable or high-risk plaque, with a higher likelihood of ACS/SCD; and 3) a thrombosed or unstable plaque, which is already disrupted and/or thrombotic, and the immediate cause of ACS/SCD in a majority of cases.
The question of just what is a vulnerable plaque became less clear in 1996 when Farb et al. noted that coronary plaque erosion without any rupture of a lipid core is a frequent cause of coronary thrombosis and sudden coronary death. They showed that superficial erosion of nonlipid-rich plaque probably accounts for about one-third of ACS/SCD events, with an even higher incidence of such erosions among women and in non-exercise related events.
With the concept of "vulnerable" plaque not nearly as straightforward as once thought, there are challenges to creating a local interventional approach for asymptomatic vulnerable plaques. First, there must be an ability to identify vulnerable plaque with non-invasive (preferably) or invasive techniques. Coronary plaque composition can be predicted via intravascular ultrasound (IVUS), allowing real-time analysis and in vivo plaque characterization (Slide 1).
(Enlarge Image)
Figure 1.
Left Anterior Descending Artery Depicted by Intravascular Ultrasound-Virtual Histology, Where Calcified, Fibrous, Fibrolipidic, and Necrotic Core Regions are Labelled White, Green, Greenish-Yellow, Red, Respectively
Source: Clinical image provided by the American College of Cardiology Foundation
A second challenge: a lesion-specific local intervention requires that the number of vulnerable plaques in each patient needs to be known and the number of such lesions need to be limited. That's not the case, however. Autopsy studies by Falk, Davies, and others indicate the presence of multiple "lipid-rich" vulnerable plaques in patients dying after ACS or with SCD. Moreover, multiple complex plaques have been widely reported, in both culprit and nonculprit arteries, including up to 79% of patients referred for PCI after ACS. Further complicating the issue: coronary occlusion and myocardial infarction usually evolve from mild to moderate stenoses --- 68% of the time, according to an analysis of data from four separate studies --- as initially reported by Ambrose et al and Little et al, with subsequent confirmation by others.
The third and fourth prerequisites to a lesion-specific, local interventional approach to vulnerable plaques: The natural history of vulnerable plaque (with respect to incidence of acute events) has to be documented in patients treated with patient-specific systemic therapy; and the approach has to be proven to significantly reduce the incidence of future events relative to its natural history. At this time, neither is documented/proved.
Interpretation
According to Dr. Ambrose, "The problem with the whole concept of vulnerable plaque is it's very difficult at the present time to know what exactly is a vulnerable plaque." Certainly there are vulnerable plaque characteristics that can be determined pathologically and perhaps angiographically. "But the definition of a plaque leading to an acute event is a difficult concept because we don't, as of yet, have natural history studies to know before an event occurs, which plaque is definitely vulnerable. We only have what we think are presumed vulnerable plaques, mostly based on what the pathology of the disrupted plaque looks like."
Dr. Ambrose agrees with another approach urged by Naghavi et al.: targeting the vulnerable patient, as defined by the possible presence of vulnerable plaque, but also vulnerable blood (prone to thrombosis) and/or vulnerable myocardium (prone to life-threatening arrhythmia). In short, Dr. Ambrose said, while vulnerable plaque is "a vital concept for all practitioners, it's probably more important that we consider the concept of the vulnerable patient."
Based on available knowledge, Dr. Ambrose asked, "How many vulnerable plaques will never rupture?" The answer is unknown, "but I suspect conservatively it is the vast majority of them. Perhaps, vulnerable plaque as described is not the appropriate target for local therapy. Asymptomatic ruptured plaques might be more appropriate as these are the immediate precursors to AMI."
Recently, Dr. Ambrose proposed a classification of systemic therapies for potential stabilization of vulnerable plaque based on both biologic plausibility (a potential mechanism to explain the effect) and clinical evidence (i.e., whether the agent reduced acute myocardial infarction in well-designed clinical trials). He and colleague David J. D'Agate selected therapies possessing biologic plausibility and classified them into four groups based on clinical data (Slide 2).
(Enlarge Image)
Figure 2.
Proposed Classification of Systemic Therapies for Stabilization of Vulnerable Plaque
Source: Clinical image provided by the American College of Cardiology Foundation
"We asked: Did they have anti-inflammatory effects? Did they have effects that reduce thrombosis risk? Did they improve endothelial function? Did they reduce wall stress? Did they modify the lipid content of the plaque?" Group 1 consisted of therapies with positive clinical evidence that they reduce myocardial infarction. Potentially, he said, these are plaque stabilizing. The second group includes agents with mostly negative data; so, there is biologic plausibility, but nothing that has been confirmed in clinical trials. The third group has inconsistent data; not all negative but not all positive either. Finally, the fourth group consists of agents that Dr. Ambrose calls the most interesting: they have biologic plausibility, but as of yet not enough clinical evidence.
"All of these therapies," he added, "should be with the backdrop of lifestyle changes. We cannot forget that smoking cessation, proper diet, and exercise all help reduce risk in vulnerable patients."
Second Opinion
Alfred A. Bove, MD, FACC: Because we now recognize atherosclerosis as a diffuse, multisystem disease, it is essential to assess total patient vulnerability and not just search for a single, unstable coronary plaque. Future efforts may identify plaques that are on a trajectory of evolution toward a vulnerable state, and help us target interventions to those plaques most likely to develop thrombosis. Similarly, we look forward to a time when factors that protect plaques from becoming vulnerable will be identified. Until then, we go in search of the vulnerable patients in our practice who, with optimal care, may end up with far fewer vulnerable plaques to worry about.
Guidelines:
Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97. For either the full report or Executive Summary, click here.
Grundy SM, Cleeman JI, Merz CN; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol. 2004;44:720-32. NCEP ATP III
Taylor AJ, Merz CN, Udelson JE. 34th Bethesda Conference: Executive summary --- can atherosclerosis imaging techniques improve the detection of patients at risk for ischemic heart disease?. J Am Coll Cardiol 2003;41:1860-917.
