New Opportunities for Identification and Reduction of Coronary Risk
Treatment of Vulnerable Patients, Arteries, and Plaques
James E. Muller, MD*,a,*,
Ahmed Tawakol, MD*, ,b,
Sekar Kathiresan, MD*,,c and
Jagat Narula, MD, PhD, FACC ,d
* Harvard Medical School, Boston, Massachusetts
Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts
University of California–Irvine School of Medicine, Irvine, California
Manuscript received September 29, 2005;
revised manuscript received November 28, 2005,
accepted December 1, 2005.
* Reprint requests and correspondence: Dr. James E. Muller, InfraReDx, Inc., 34 Third Avenue, Burlington, Massachusetts 01803. (Email: jmuller{at}infraredx.com).
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Abstract
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Advances in the understanding of the role of vulnerable plaque in the causation of coronary events, coupled with novel diagnostic and therapeutic approaches, create a new opportunity for progress against cardiovascular disease. The recognition that non–flow-limiting plaques often produce cardiac events has led to the development of invasive and non-invasive methods to identify such plaques prospectively. Treatments such as stenting, photodynamic therapy, and novel pharmaceutical agents are under consideration as methods to stabilize the vulnerable plaques and patients that might be detected, thereby enhancing both primary and secondary prevention. Despite the promise of the field, many issues remain to be resolved, including the focality versus systemic nature of the atherosclerotic process, the ability of detectors to identify the target for which they were developed and prove that such a target is linked to clinical events, and the efficacy of specific therapy. If vulnerable plaques and patients can be successfully identified and treated, there will be immense clinical benefits, accompanied by cost savings.
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Abbreviations and Acronyms
| | CT = computed tomography | | DES = drug-eluting stents | | IVUS = intravascular ultrasound | | MI = myocardial infarction | | MR = magnetic resonance | | MSCT = multislice computed tomography | | PCI = percutaneous coronary intervention | | PROVE IT–TIMI 22 = Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 | | TCFA = thin-cap fibroatheroma |
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Advances in three areas related to vulnerable plaque have created a new opportunity for progress against acute coronary events. The role of vulnerable plaque in the pathophysiology of myocardial infarction (MI) and sudden death is better understood, novel diagnostic methods for the assessment of plaque are becoming available, and new therapeutic approaches are emerging. Rapid translation of new knowledge from these three areas into cardiovascular care has the potential to greatly decrease cardiovascular death and disability.
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Advances creating the opportunity to improve prevention
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With regard to pathophysiology, it is now well-documented that the majority of infarctions result from the rupture of high-risk/vulnerable plaques that in most cases did not cause flow limitations before the acute event (1). Inflammation has also been recognized as playing a central role in plaque disruption (2). These insights have created a strong interest in moving beyond the stress test and the coronary angiogram to attempt to diagnose and treat vulnerable/high-risk plaques that are not flow-limiting (3–5).
Advances in diagnostic capabilities to identify vulnerable patients and vulnerable plaques, the focus of this Supplement, have occurred in the areas of blood sampling, non-invasive imaging, and intracoronary diagnostic devices. C-reactive protein has been proven to be a particularly useful predictor of coronary events (6). Multiple additional risk predictors, including genetic biomarkers, may prove to be effective markers of atherosclerosis and risk. Rapid increases in accuracy of multislice computed tomography (MSCT) permit the detection of coronary calcification and imaging of coronary artery wall after only a peripheral injection of a contrast agent (7). In the future, both magnetic resonance (MR) and MSCT have the potential to provide a non-invasive method to detect vulnerable patients and vulnerable coronary artery plaque. For patients already undergoing cardiac catheterization for treatment of coronary artery stenosis, numerous intracoronary devices are being developed to provide improved plaque characterization from the excellent vantage point provided by the coronary artery lumen. As described elsewhere in this supplement, research is being conducted on multiple invasive coronary artery diagnostic devices to improve plaque characterization. The methods include intravascular magnetic resonance imaging, modifications of intravascular ultrasound, near-infrared spectroscopy, nuclear methods, optical coherence tomography, palpography, and thermography.
These advances in the understanding of pathophysiology and diagnostics are accompanied by new therapeutic approaches. In patients who have recently suffered an acute coronary syndrome, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT–TIMI 22) trial demonstrated that lowering of low-density lipoprotein to approximately 62 mg/dl (below the prior guideline of 100 mg/dl) produced additional clinical benefits, presumably related to plaque stabilization (8). New agents, which can raise high-density lipoprotein or reduce inflammation, offer additional promise for improved systemic treatment of vulnerable plaques, even if they are not directly identified.
Novel approaches are also possible for regional and local treatment of vulnerable plaques and vulnerable segments of arteries. Promising studies in animals with photodynamic therapy indicate that inflammation can be safely eradicated in a region of an artery. The new drug-eluting stents have reduced the restenosis rate to a level at which stents may be considered for treatment of non-stenotic vulnerable plaques, although the propensity of stents to cause thrombosis, which may be fatal, must be included in the risk/benefit analysis.
As might be expected, many issues remain unresolved in this rapidly developing field. While the causation of disease by rupture of less occlusive vulnerable plaques is universally accepted, there are varying opinions about the likelihood that either local diagnosis or treatment will be of value. In the following text, we will examine methods to test what might be called the vulnerable plaque hypothesis—that a cost-effective manner to greatly reduce the risk of coronary artery disease is to precisely identify levels and areas of vulnerability, administer systemic therapy to match the level of risk, and add supplemental regional and/or local therapy when indicated.
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The current management of coronary risk
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New approaches are required, because despite the great progress against coronary artery disease achieved over the past three decades, extensive morbidity and mortality still occur. Each year in the U.S. alone, approximately 500,000 die of cardiac disease, and an additional 600,000 suffer a non-fatal MI (9). Many of these events occur suddenly in patients previously free of coronary artery disease, but almost as many events occur in those with known coronary disease who have already had the benefit of optimal current therapy, including percutaneous coronary interventions (PCIs) and aggressive medical therapy with statins and antiplatelet agents. The path to prevention is quite different for the primary events, which occur in the general population, and the secondary events, which occur in an identifiable group of patients with coronary artery disease known to be at markedly increased risk.
Secondary prevention in cardiac patients.
For patients with known coronary artery disease, definitive diagnosis is usually based on coronary angiography. If significant stenosis is detected, treatment consists of PCI or coronary artery bypass grafting followed by medical management. The stenosis-oriented approach in the catheterization laboratory or the operating room generally succeeds in relieving angina, but, in most cases, prevention of subsequent cardiac events results only from ongoing medical therapy (10).
Although it is widely acknowledged that the benefits of systemic medical therapy are substantial, much room for improvement remains after even the best currently available medical treatment, as exemplified by the PROVE-IT study. By the end of two years in that study, 22% had experienced death, MI, unstable angina requiring hospitalization, revascularization, or stroke (8).
The number of events due to new lesions (those not due to restenosis) occurring on standard medical therapy after PCI has recently been clarified (11). In the year following PCI, 5.8% of a cohort of 3,747 patients underwent a repeat PCI for a clinical event unrelated to the original culprit lesion. When additional non-fatal infarctions (which did not lead to a repeat PCI) and deaths are added to this total, the event rate from new lesions in the year following PCI was approximately 10%.
Advances in understanding of vulnerable plaque, plus new methods that might enhance its diagnosis and treatment, make it possible to establish the goal of the complete eradication of subsequent coronary events in patients undergoing PCI. The catheterization laboratory could become the place where stenoses are repaired, vulnerable plaques, vulnerable arteries and vulnerable patients are identified, and intensive preventive measures are initiated.
Primary prevention.
The prevention of primary coronary events in the general population, which generates most cardiac events, requires a different strategy than that used for secondary prevention. At present, a group of high-risk patients can be identified, but many of the events occur in the far more numerous individuals deemed (incorrectly) to be at moderate or low risk by standard screening methods. Powerful preventive regimens are available, but their side effects, while minimal, and cost, which can be considerable, increase the need for improved risk stratification.
Fortunately, advances are available that can provide such improved stratification. It is possible to envision a screening system based on three components—the standard risk factors such as those developed by the Framingham Heart Study, novel blood biomarkers including genetic measures, and newer methods of non-invasive imaging, such as MR of the coronary arteries; multislice computed tomography (CT), including calcium scoring; and nuclear methods, including positron emission tomography (in combination with CT or MR) (12).
Such a screening system is likely to identify some asymptomatic individuals at very high risk—a >10% chance of a cardiac event in the ensuing year. This produces the following clinical dilemma: should cardiac catheterization be performed in such a high-risk individual who has no cardiac symptoms? Would catheterization provide additional risk stratification that would alter therapy, or is there a local therapy that is needed? Definitive answers to these questions must await completion of research studies designed to resolve multiple questions about the possible detection and treatment of vulnerable plaque in the catheterization laboratory.
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Areas of uncertainty concerning invasive measures to detect and treat vulnerable plaque
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At present, there is little supporting evidence for invasive cardiac catheterization as a clinical technique to prevent acute coronary syndromes—most studies have shown that even the use of drug-eluting stents does not reduce the rate of subsequent MI and death. There is, however, a great opportunity to conduct research in patients already undergoing catheterization for clinical indications to resolve important unanswered questions about vulnerable plaque and the possible use of cardiac catheterization for prevention.
The major issues surrounding the vulnerable plaque hypothesis can be divided into: 1) questions about the pathophysiology of atherosclerotic coronary artery disease; and 2) questions related to the evidence required to validate the novel diagnostic and therapeutic approaches to vulnerable plaque that are being proposed. The pathophysiologic issues can be addressed by study of data already presented by Falk (13) and Virmani et al. (14) in autopsy specimens, and with research already performed utilizing conventional angiography and intracoronary diagnostic devices in patients undergoing catheterization. The diagnostic and therapeutic questions will require new clinical investigations.
The pathophysiology of atherosclerosis.
In the vulnerable plaque discussion, the major question regarding pathophysiology is that of the systemic as opposed to focal nature of atherosclerosis. On the one hand, autopsy studies have firmly established that atherosclerosis is a systemic disease that in almost all cases affects many arterial vessels, and many sections of a vessel in an afflicted individual. These autopsy findings have been supported by MR and CT findings in peripheral arteries in patients, and intravascular ultrasound (IVUS) findings in the coronary arteries of patients undergoing catheterization. There is no doubt that in afflicted individuals, atherosclerosis, of some degree of activity, is widely distributed throughout the vasculature. This observation leads logically to the view that neither focal diagnosis nor therapy is likely to be of value.
However, autopsy and clinical studies have also demonstrated that most cases of MI or sudden cardiac death result from a single thrombus caused by a single disrupted (previously vulnerable) plaque. In a smaller fraction of cases, the disease is active in a multifocal pattern (15), but in such cases, the number of plaques that are disrupted is rarely greater than five. Clinical experience supports the concept of the relatively low frequency of truly vulnerable plaques, because events in patients often occur only once in decades despite the presence of widespread atherosclerosis.
It has also been shown that disease activity has a geographic concentration—the proximal and mid-portions of the major coronary arteries have been shown to be the most frequent sites of plaque ruptures that result in acute coronary syndromes (16).
The aforementioned considerations support the conclusion that atherosclerosis is a systemic disease with focal manifestations. It is probable that identification of individual plaques likely to cause a focal manifestation will require approaches beyond angiography and conventional IVUS since these tools, which are of great value for detection and characterization of stenosis, do not appear to provide sufficient information about plaque composition to predict disruption.
A second controversy results from varying usage of the term "vulnerable plaque." If "vulnerable plaque" is equated with an inflamed thin-cap fibroatheroma (TCFA), it then follows that not all clinical events are caused by vulnerable plaque, since in 20% to 40% of cases, particularly in women, the event is caused by a thrombus overlying an erosion site. However, the preferred usage of the terms vulnerable, high-risk, or thrombosis-prone plaque, as suggested by the Santorini meeting on the topic (17), is as synonyms to designate any plaque that is at increased risk of disruption leading to thrombus formation (Fig. 1). A TCFA is recognized to be one type of plaque that is suspected, but not yet proven prospectively to be a vulnerable plaque. Erosion sites, which are rich in proteoglycans, are a second type of suspected vulnerable plaque. There are likely to be others. The usage of the term "vulnerable plaque" proposed by the Santorini participants would encompass virtually all plaques causing thrombus-related clinical events.
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Figure 1 A two-day meeting of more than 30 investigators active in the vulnerable plaque field was held on the island of Santorini in Greece, 2003. The investigators came to a consensus on the proposed terminology for the vulnerable plaque field shown in the figure. Modified from Schaar et al. (15).
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While all coronary events due to atherothrombosis are caused by vulnerable plaques (when the Santorini definition is used), the converse—that all vulnerable plaques cause events—is not true for several reasons. Because vulnerability is a statistical concept (likelihood of rupture), not all vulnerable plaques rupture, and even those that rupture do not always cause an event. Events occur when a flow-limiting thrombus forms over a ruptured vulnerable plaque in an artery serving a critical area of myocardium not adequately supplied by collateral vessels. Fibrillation may occur if the myocardium is vulnerable to arrhythmia. Hence, vulnerable blood, coronary anatomy, and myocardium may all play a role in the steps leading from plaque rupture to a clinical event. Together these factors lead to a vulnerable patient. Although the vulnerable plaque is only one link in this causal chain, it remains a promising target for prevention because of its proximal location.
Aspects of vulnerable plaque detection and treatment requiring validation in clinical studies.
As described in this supplement of the Journal, there are many new diagnostic approaches, both invasive and non-invasive, that are designed to improve the characterization of atherosclerotic plaques for the purpose of assessing vulnerability. Most of these techniques have already been validated in autopsy specimens or carotid endarterectomy material for their ability to identify features of inflamed TCFAs, the structures suspected to be responsible for most events, and the easiest form of presumed vulnerable plaque to identify. Some aspects of detection capability have been validated in animal models, although it has been difficult to identify an animal model that develops plaques similar to those in humans.
The immediate clinical research task is to determine if these techniques can be used as tools to measure the parameter of interest (inflammation, lipid pool, increased temperature, thin cap, and so on) in patients. For both non-invasive and invasive approaches, the validation task is complicated in the coronary arteries by the absence of a gold standard, because tissue from patients for histologic examination is not routinely available. The clinical validation must therefore rely on comparisons between culprit lesion sites (once vulnerable sites) and other parts of the artery, comparisons between findings in patients with acute coronary syndromes (who presumably have more vulnerable plaques) and patients with stable angina, and similarities of clinical diagnostic findings to autopsy findings for which a histologic gold standard is available. In this Supplement, various levels of evidence will be found for each of the diagnostic approaches.
While confirmation that a specific plaque feature such as increased temperature, deformability, inflammation, or lipid-rich content is being measured will be an advance over current approaches, definitive proof that a vulnerable plaque has been identified requires a prospective demonstration of a linkage between the given finding (or combination of findings) and the clinical events of unstable angina, MI, or sudden death caused by the plaque at that site. Such information will be difficult to obtain because of the relatively low event rate, even in PCI patients (approximately 10% in the first year); the low rate of autopsies performed; the causation of events by plaques other than TCFAs; the fact that not all TCFAs cause events; and the possibility that identification of multiple characteristics of plaques (inflammation plus lipid-rich content, for instance) might be required to identify vulnerability with optimal sensitivity and specificity. Although these obstacles are considerable, they are not insurmountable, given the issues at stake. Several natural history studies are in progress, but it appears likely that they will lack the needed statistical power to provide a full test of the hypothesis. They are likely to be valuable as a basis for larger studies.
The conduct of clinical trials of detection of a specific plaque feature, or of vulnerability itself, will be required to answer the question of the time course of vulnerability. Because in vivo detection has not been possible, knowledge of the time course of development of TCFA and plaque inflammation has been limited to autopsy studies, which provide only a photograph of a moment in time. Non-invasive measures will be particularly useful for this purpose.
Outcome studies will also be required to evaluate the effectiveness of various proposed treatments of vulnerable plaque. A treatment that has engendered considerable discussion is the placement of drug-eluting stents (DES) at a site or region of artery suspected to be vulnerable. The discussion is particularly pertinent for sites producing an intermediate degree of stenosis (40% to 60%) in which the decision to stent or not to stent is often difficult. The rationale for such treatment is that restenosis, the most common complication of DES placement, is now less frequent (<5% of cases), and not likely to produce an event. However, the DESs in current use result in potentially fatal thrombosis in 0.5% to 1.0% of cases in the year after placement. Evidence-based use of DES placement for the treatment of non-flowing limiting stenoses for presumed vulnerability requires a randomized trial demonstrating that the risk generated by the types of sites being stented is greater than the risk created by stenting.
Finally, the new diagnostic methods described in this Supplement, both non-invasive and invasive, may be useful for the assessment of pharmaceutical agents designed to stabilize plaques. It may become possible to accurately stage the disease for an individual patient (as is already done for cancer patients) and thereby assist drug development. With the success of current regimens, event rates in many patients are so low that studies to determine the optimal dose or clinical efficacy of a new drug require many thousands of patients studied for multiple years.
A new method to characterize plaque might aid drug development by identifying a very high-risk subgroup in which most events would be expected to occur. This subgroup could then be selected for a randomized evaluation of the new agent in a relatively small number of patients. The primary end point would, of course, be clinical events, but a secondary end point of improvement in the appearance of the artery as judged by the diagnostic approach could also be evaluated.
Since a novel pharmaceutical agent is expected to be safe and would be tested in clinical trials regardless of the imaging technique, it would be possible to conduct such a study before the availability of data proving that the promising diagnostic device is indeed capable of finding a vulnerable plaque. In the randomized design, the placebo group would provide information to test the ability of the diagnostic method to identify individual plaques, patients, or groups of patients at increased risk.
Consequences of improved prevention by optimal treatment of vulnerable plaques, arteries, and patients.
The opportunity created by the convergence of developments in these multiple fields is impressive, but its pursuit will not be simple, as indicated by the questions that remain unanswered. The extensive effort and expense that are required by these studies are justified by the consequences of success. If vulnerable plaque could be detected, and treated, many gains would occur. Sudden cardiac death would be greatly diminished, as would non-fatal MI. Preservation of myocardium would be enhanced, while the debilitating and costly development of congestive heart failure would be diminished. Prevention of myocardial scarring would reduce the tendency to arrhythmia and decrease the need for costly defibrillators. The immense gain in the quality of life of patients would even be accompanied by cost savings generated when the downstream effects of acute coronary syndromes were reduced (18). The benefits resulting from an enhanced preventive regimen argue in support of the effort to evaluate these new approaches.
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Footnotes
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Dr. William A. Zoghbi acted as guest editor.
a Dr. Muller is co-founder and President of InfraReDx, Inc., a company developing a near-infrared catheter to detect vulnerable plaques, and Professor of Medicine on leave of absence from the Harvard Medical School. 
b Dr. Tawakol is an instructor in medicine at the Harvard Medical School and a member of the Cardiology Division, Massachusetts General Hospital.
c Dr. Kathiresan is an instructor in medicine at the Harvard Medical School and Director, Cardiovascular Disease Prevention Center, Cardiology Division, Massachusetts General Hospital.
d Dr. Narula is a professor of medicine and a member of the University of California–Irvine Medical Center.
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Abstract
Advances creating the...