| | Identifying the Vulnerable Patient with Rupture-Prone PlaqueAtherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the United States, and the obesity epidemic combined with aging of the population seems destined to increase the burden of this disease. Traditional cardiovascular risk assessment accounts for <50% of the variability in risk in the United States. Therefore, better and more effective identification of persons at high cardiovascular risk is needed. Our understanding of atherosclerosis has shifted from a focal disease whose hallmark is symptoms caused by a severe stenosis to a systemic disease characterized by endothelial dysfunction (ED) and plaque inflammation, with the potential for rupture and thrombosis mainly in those with subcritical stenosis. Under the new paradigm, clinicians require updated strategies to better assess the quality of arterial plaque. Effective tools for primary and secondary prevention of heart attack and stroke include intensive lifestyle modification, blood pressure reduction, and lipid-modifying therapies. These interventions are now understood to decrease plaque inflammation and thereby promote plaque stability. Lipoprotein-associated phospholipase A2 (Lp-PLA2) appears to be a specific marker of plaque inflammation that may play a direct role in the formation of rupture-prone plaque. In contrast, traditional risk factors, lipid measurement, and most vascular imaging modalities do not directly assess the acute ischemic potential in the arterial wall. Measuring Lp-PLA2 levels in human serum or plasma is noninvasive and relatively inexpensive. Lp-PLA2 may provide additional clinically relevant information that shows which patients have a high level of atherosclerotic disease activity as manifested by vascular inflammation, ED, and increased risk for progression toward rupture-prone plaque. Cardiovascular disease (CVD), consisting of cardiac death and stroke, continues to be the leading cause of death in the United States, surpassing all cancers, stroke, accidents, and diabetes mellitus (Figure 1),1 despite significant advances in treating CVD over the past 20 years. Cardiovascular health complications, subsequent disease manifestations, and decreases in functionality and quality of life as a result of cardiovascular events continue to place immense economic and emotional burdens on much of the population. An estimated 80 million US adults (1 in 3) have ≥1 types of CVD.1 Of these, 15.8 million individuals in the United States were diagnosed with coronary artery disease (CAD), resulting in >400,000 deaths annually.1 As the US population ages, the prevalence of CVD will place an intolerable burden on the quality of life and the nation's economy without significantly more intensive application of already-proven primary and secondary prevention therapies. It is widely understood by healthcare providers and the general public that the incidence of heart disease is extremely high for men. Indeed, the lifetime risk for myocardial infarction (MI) in men is 42%. Far less recognized, however, is the toll of CVD on women. Heart disease is the number 1 killer of women, far surpassing breast cancer, lung cancer, stroke, and other cancers (Figure 2).2 Data show that 1 in 4 women will die of heart disease, regardless of race or ethnicity. Heart disease strikes women at younger ages than men, and the risk increases in middle age. Additionally, approximately 66% of women who have heart attacks never fully recover.2 Overall, the American Heart Association estimates that 50 million individuals in the United States are diagnosed with cardiometabolic syndrome, and an additional 8 million are undiagnosed.1 Khot et al3 report that there are 4 established conventional risk factors in CAD: hypertension, smoking, hypercholesterolemia, and diabetes. Yet, approximately 62.4% of individuals already diagnosed with CAD present with only 0 to 1 of these major modifiable risk factors. Fully 19% present with absolutely no risk factors (Figure 3) and another 43% have only 1 risk factor.3 Therefore, Framingham risk scoring may incorrectly identify many persons who develop CAD as being at low risk for developing CAD. The Adult Treatment Panel III national cholesterol guidelines acknowledge this by explaining that the major cardiovascular risk factors “account for only about half of the variability in coronary heart disease risk in the US population.”4 Coronary atherosclerosis is almost ubiquitous in US adults, and 1 in 6 adolescents have significant coronary intimal thickening.5 By 50 years of age, 85% have significant coronary atherosclerosis. So atherosclerosis typically remains silent for decades until it finally presents with plaque rupture and thrombosis. In fact, the initial presentation of CAD is MI or sudden cardiac death syndrome in 62% of men and 42% of women.6 Primary prevention of heart attack and stroke, beginning with lifestyle intervention, should therefore be initiated in young adulthood, if not in adolescence. Thus, it is apparent that risk prediction models relying on traditional risk factors, although adequate on the population level, have relatively low sensitivity and specificity for individual CAD.7 Although age is the most robust predictor of cardiovascular event risk of the traditional risk factors, it does not help clinicians discriminate which of 2 elderly patients are at highest risk. Current guidelines for risk prediction based on the Framingham Heart Study are strongly age biased and predominately geared toward white men. Medical strategies appropriate for primary prevention require a more detailed analysis for risk factors. Better and more effective identification of persons at high cardiovascular risk is needed. To put this into perspective, it is useful to refer to other disease states, such as breast and colorectal cancers. Although the death rates for these are significant and accounted for >40,000 and 52,000 deaths, respectively, in 2005,8 they pale in comparison to mortality from CVD. Yet, although noninvasive testing (mammography, prostate-specific antigen levels, etc.) for various subclinical cancers is commonplace, noninvasive testing for subclinical atherosclerosis in at-risk individuals to prevent MI and stroke is still not widely recommended. This is despite the fact that costs of treating MI and stroke, both acutely and chronically, have significantly escalated.9 Limitations of Cholesterol Screening in Risk Stratification  Today, the cornerstone of primary prevention of CAD in the United States is cholesterol management. The National Cholesterol Education Program (NCEP) was established to educate professionals and the public on the importance of cholesterol abnormalities and CAD.4 Guidelines published by the NCEP for the treatment of primary and secondary prevention of CAD were originally derived from evidence-based practice to demonstrate how treatment of high cholesterol after acute MI improves outcomes. Similarly, large trials have shown the benefits of prophylactic treatment for primary prevention in certain high-risk individuals. Although cholesterol levels are widely used as surrogate markers for coronary health, this offers limited clinical value in prediction of cardiovascular events. As little as a quarter of premature CAD diagnoses are solely attributed to elevated low-density lipoprotein (LDL) cholesterol levels.10 An analysis of the 26-year Framingham Heart Study follow-up data showed that only 50% of individuals who develop CAD are identified using total cholesterol levels alone.10, 11 Consequently, 80% of individuals who have an MI have similar cholesterol levels to those who did not have an MI, and the median LDL level in CAD is near the median LDL level in the United States (150 mg/dL; 1 mg/dL = 0.0259 mmol/L).11 In a retrospective analysis of 222 young adults presenting with premature MI, Akosah et al12 found their mean LDL and high-density lipoprotein (HDL) levels to be relatively good (126 mg/dL and 43 mg/dL, respectively). The 10-year CAD risk in these patients was stratified according to the number of major risk factors present and LDL cholesterol level. According to NCEP guidelines, only 12% of these patients with premature MI would have been correctly identified as high-risk patients, and only half would have qualified for pharmacotherapy. Remarkably, most (70%) of these adults with premature CAD were stratified into the 2 lowest risk categories (n = 156). Overall, 166 individuals (74.7%) did not meet criteria to be identified as at sufficient risk to qualify for pharmacotherapy. In the current retrospective analysis of the same 222 patients, the goal was to determine each individual's level of risk and whether they would have met criteria for medical management if they had presented to their physicians before their initial MI. Ideally, all 222 patients would have been candidates for primary prevention, yet, as many as 75% did not qualify for medical management. The investigator concludes that we need to improve on traditional risk factors if we are to properly identify who is at risk for premature CAD. However, most young people did not have multiple risk factors, and few (16%) had moderately elevated LDL cholesterol levels. By contrast, the rates of categorical risk factors including overweight/obesity, smoking, and hypertension were high. Increased age along with elevated cholesterol levels have long been the standard for identifying patients at high risk for CAD, yet recent studies have shown that there is measurable atherosclerosis in undiagnosed healthy individuals. Necropsy studies have demonstrated that atherosclerosis begins at a very early stage in life. As mentioned above, Tuzcu et al5 demonstrated unequivocal in vivo evidence of atherosclerosis in young asymptomatic individuals with no evidence of clinical CAD using coronary intravascular ultrasound (IVUS). This study is unique because it provides detailed, clinically relevant, quantitative, in vivo information on early atherosclerosis from an asymptomatic young population. Of the patients studied, 92% had completely normal angiographic findings, yet 33% of those aged 20 years and 60% of those aged 30 years had significant coronary intimal thickening >0.5 mm with IVUS. No angiogram result was abnormal in any patient aged <30 years, yet 28% of these subjects had significant intimal thickening with IVUS. A limitation of angiography is that it can only reveal intraluminal plaque and not plaque “hidden” in the artery wall. Because coronary and carotid arteries remodel outwardly as plaques form, the arterial lumen may remain patent and appear normal.13 This compensatory, outward remodeling is evident in many atherosclerotic plaques that have become inflamed and rupture prone. The greater sensitivity of coronary and carotid ultrasound is a result of its ability to identify this “occult” plaque hidden in the vessel walls. Tuzcu et al5 also detected a high prevalence of atherosclerosis in young people consistent with earlier necropsy studies. There was unequivocal evidence of atherosclerosis in 28% of subjects aged <30 years and in 17% of individuals aged <20 years.3 Importantly, the coronary atherosclerosis described in the aforementioned study represents early phases of what, for most in the United States, is a decades-long process of plaque maturation, culminating in plaque inflammation, thinning of the fibrous cap, and ultimately, in the plaque rupture and thrombosis that causes most cardiovascular events. These findings represent a clear indication that age is not an adequate identifier of individuals who would be at low risk for CAD and who could be treated preventatively with pharmacotherapy. Viewing CVD as a systemic disease where many rupture-prone plaques are distributed in different arteries in the same individual, and only modest stenosis is present reminds us that interventions aimed at alleviating stenosis may be a mere “thumb in the dike.” Whereas numerous studies have shown that percutaneous transluminal coronary angioplasty and stent implantation are lifesaving procedures in acute coronary syndromes, the utility of percutaneous coronary intervention (PCI) over optimal medical therapy (OMT) in patients with stable CAD has been called into question, as in the Randomized Interventional Treatment of Angina (RITA) study. In a meta-analysis of 11 randomized clinical trials (N = 2,950) of patients with stable CAD, when analyzing heart outcomes (such as cardiac death and MI, nonfatal MI, and revascularization with surgery), conservative medical management was favored and considered not inferior to catheter-based intervention.14 Intensive application of lifestyle changes, anti-lipid therapy, and antihypertensive medications are required to reduce global risk, and PCI alone should be regarded as predominantly palliative, perhaps akin to removing a cancerous breast lump but then not offering chemotherapy and hormonal therapy. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) study was funded by the US Department of Veterans Affairs to determine whether OMT along with PCI would be superior to OMT alone in patients with stable CAD in the primary outcome of all-cause mortality or nonfatal MI.15 Patients were selected on the basis of having an 80% blockage in a coronary artery and classic angina, or a 70% stenosis with electrocardiographic evidence of prior MI or a positive stress test result. Lifestyle modification attempts were encouraged, such as smoking cessation; ≥150 minutes of exercise per week; nutritional counseling to control dietary cholesterol and sodium intake; and ideally, a body mass index <25. Lipid goals included LDL <85 mg/dL (preferably closer to 60 mg/dL), HDL >40 mg/dL, blood pressure <130/85 mm Hg, and glycosylated hemoglobin in accordance with the endocrinology guidelines. A majority of this population had multivessel disease, <33% had single-vessel disease, and an equal number had proximal occlusions in the left anterior descending coronary artery but with left ventricular function preserved. In a further analysis, nuclear imaging identified single-vessel defects in approximately 20% of the patients, whereas approximately two thirds of the patients had multiple significant reversible defects. Standard treatment with some kind of interventional strategy on the basis of proximal disease that was severe in ≥1 artery with multiple perfusion defects should have been implemented, but in actuality, only several entities responded to the therapy.15 Results of the study showed that systolic blood pressure that began at 130 mm Hg was lowered to 124–126 mm Hg after 1 year and was slightly lower after 5 years. Similarly, LDL cholesterol levels that started at approximately 100 mg/dL decreased to approximately 80 mg/dL at the 1-year evaluation and decreased to approximately 70–74 mg/dL at 5 years. However, similar effects were not evident with HDL levels. There was a 10% reduction in triglycerides that remained at an intermediate level, which is consistent with the fact that the body mass index was not reduced. There was a similar effect on glycosylated hemoglobin, which showed an nonsignificant reduction, despite the fact that approximately 50% of patients participated in moderate exercise ≥5 days a week.15 Analysis of the 5-year data demonstrated that the incidence of fatal MI and nonfatal MI were identical whether the patients were randomized to OMT or OMT with PCI (hazard ratio, 1.05; 95% confidence interval, 0.87–1.27; p = 0.62).15 This raises the question of the necessity to perform these invasive procedures in patients with stable CAD. The treatment effect on secondary outcomes trended with similar results; hospitalization for acute coronary syndromes and the inclusion of stroke or MI trended better for medical therapy, although these results were not statistically significant. These findings are consistent with the concept that plaque stabilization with lifestyle modification and intensive lipid modification with combination anti-lipid therapy should be the goal of secondary prevention strategies. The COURAGE data prompt discussion as to whether there are other (non–stenosis-related) indicators within the blood that can predict the success of the patient's therapy. Recently, the proinflammatory enzyme lipoprotein-associated phospholipase A2 (Lp-PLA2) has been proposed as a novel biomarker for the presence of, or impending formation of, rupture-prone plaque. This hypothesis is now supported by 25 prospective epidemiologic studies, histopathologic staining that shows intense Lp-PLA2 staining in late stage, rupture-prone plaques but not early stable plaques,16 as well as evidence using a novel inhibitor of the Lp-PLA2 enzyme that reduces cytokine formation in carotid plaques in vivo.17 It is now established that lifestyle modification, including exercise, can lower Lp-PLA2, a novel biomarker for the presence of rupture-prone plaque.18 Also, combination anti-lipid therapy may be a very effective means of lowering Lp-PLA2 relative to statins alone.19, 20 Significantly, >50% of the patients in the OMT-alone arm of the COURAGE trial were on combination anti-lipid therapy at year 5 of the study. Identifying Rupture-Prone Lesions As discussed above, coronary atherosclerosis is present in nearly all middle-aged US adults. A purpose of preventative cardiology is to determine whether atherosclerosis has evolved to the point where it is more inflamed and prone to rupture. Lesions that are more stenotic with luminal encroachment, small lipid-rich cores, and very thick fibrous caps typically occur in patients with angina on exertion and can be identified by positive stress testing with or without perfusion imaging or wall motion studies.21 Very stenotic lesions producing angina such as these respond positively to local therapy/revascularization methods. Unfortunately, it is often the case that asymptomatic and modestly stenotic lesions are the potentially fatal lesions. These latter lesions typically present with thinned fibrous caps, large lipid cores, and inflammation. A method used to identify which patients with minimal-to-modest stenosis have more advanced plaque is to measure endothelial dysfunction (ED). Assessing ED with flow-mediated dilatation has the advantage of being a noninvasive, office-based procedure. Flow-mediated dilatation uses ultrasound of the brachial artery to assess its reflexive dilatation after 10 minutes of ischemia produced by compression with a sphygmomanometer. This technique has some problems with reproducibility, likely related to technical skill, and is an independent predictor of cardiovascular events in some but not all studies.22 A more precise means of identifying microvascular ED in coronary arteries is based on introducing acetylcholine, a vasoconstrictive agent, into the left anterior descending coronary artery and measuring for reflexive dilatation in the coronary artery diameter and rebounding coronary blood flow. This approach to measurement of ED is strongly and independently associated with coronary events and stroke in multiple studies.23, 24 Relying on stress tests alone is not a good clinical predictor of risk because severe stenosis is not a prerequisite for rupture-prone plaque formation. In other words, many persons with low-grade stenosis may have relatively advanced “atherosclerosis disease activity.” In fact, most MIs and sudden death occur from atherosclerotic lesions in modestly stenotic arteries. Falk et al25 found that most acute MIs present from atheroma showing <50% occlusion (Figure 4). Only 16% of MIs occur where there is >70% stenosis.25 Furthermore, a study from Kolodgie et al16 found that 76% of sudden deaths were attributable to plaque rupture, and only 24% of MIs were associated with severe luminal narrowing. Patients may have stress treadmill testing and coronary angiography results that may appear normal or reveal minimal stenosis, but most of these patients may still be at high risk from plaque rupture. Thus, it is imperative to shift from our concept of MI and stroke as a “plumbing problem” that is necessarily focal to the concept of atherosclerosis as a systemic disease that produces cardiovascular events by plaque rupture and occlusion from thrombosis mainly at sites of mild-to-modest stenosis. A key characteristic of rupture-prone plaques is that the fibrous cap over the lipid core has thinned to <65 μm.26 Current imaging modalities, including coronary IVUS or carotid ultrasound do not have the resolution to identify lesions with thin fibrous caps or thin cap fibroatheroma. A novel technology, optical coherence tomography, does have sufficient resolution to identify plaques whose caps have thinned under the influence of inflammation to the 65-μm threshold for plaque rupture.27 However, this technology is invasive and not available commercially at the present time. Thus, a noninvasive, reproducible, and affordable means of identifying individuals with a thin fibrous cap or rupture-prone plaques could fill an important unmet clinical need. Plaques harvested at autopsy or carotid tissue obtained via endarterectomy, provide the opportunity to measure the thickness of the fibrous cap, to stain for macrophage infiltration, and also to assess the size of the lipid core. Recently, Kolodgie et al16 reported a study of progressively more advanced atherosclerotic lesions, which they individually stained using antibodies for the novel inflammatory biomarker Lp-PLA2.16 The investigators reported that Lp-PLA2 is strongly expressed within the necrotic core and surrounding macrophages of vulnerable and ruptured plaques, with relatively weak staining in less advanced lesions. These findings together with the association of Lp-PLA2 in apoptotic macrophages suggest that Lp-PLA2 has a potential role in promoting plaque instability (Figure 5). These findings seem to suggest that Lp-PLA2 may be more a marker of rupture-prone plaque than of early, stable plaque. In contrast to Lp-PLA2, a high level of LDL cholesterol does not provide information about endothelial health or how advanced and inflamed the atherosclerotic plaque has become. Although elevated levels of LDL contribute to and undoubtedly accelerate atherosclerosis, hyperlipidemia drives atherosclerosis over decades and provides little information about the state of the artery wall today. LDL cholesterol is not the sole contributing factor for CAD. This may be best exemplified in insulin-resistant patients, who do not have high levels of LDL cholesterol. Yet as these patients transition to type 2 diabetes, their coronary event risk equals that of someone who has already had an MI. The patient with metabolic syndrome or prediabetes has several risk factors, including low levels of HDL cholesterol, small LDL particles, and often, elevated remnant lipoproteins, as well as systemic inflammation. In addition to this atherogenic dyslipidemia, patients with metabolic syndrome also have a greater degree of oxidant stress and inflammation. We know that the adipose cells present in visceral fat tend to generate inflammatory cytokines, which in turn, transit downstream to the liver and trigger hepatic production of C-reactive protein.28 Interestingly, macrophages resident within adipose cells tend not to exhibit high inflammatory responses, but under excessive weight gain or in the presence of a high-fat diet, increased expression of cytokines and chemokines, such as tumor necrosis factor–α, interleukin-B, and interleukin-6, as well as nuclear factor–κB, has been documented. As a result of the increased inflammatory response, there is also a resultant milieu that is more resistant to insulin along with an increased release of free fatty acids. Consequently, there is also evidence of an increased stimulation for angiotensinogen and angiotensin, which also drives the prooxidant state and increased blood pressure. This process of increasing obesity levels and the consequent development of significant atherosclerotic risk has begun to significantly outweigh other genetic factors as significant causalities of risk. The metabolic syndrome paradigm serves to illustrate that there are many processes, in addition to high levels of LDL cholesterol, which affect atherosclerosis disease activity. Interestingly, although many patients with abdominal obesity and insulin resistance have elevated C-reactive protein, Lp-PLA2 has been shown to be independent from obesity and insulin resistance.29 Thus, the metabolic syndrome and Lp-PLA2 would be expected to be additive risk markers, a fact that has been recently reported in both the Intermountain Heart Study and the Malmo Diet and Cancer Study.30, 31 Clinically stable plaque tends to have a thick fibrous cap with a high degree of collagen in addition to a small, contracted lipid pool as its core. Stable plaques also contain few inflammatory cells and a low amount of Lp-PLA2. By contrast, unstable plaque tends to have a similar lumen but is identifiable by a thin fibrous cap, low collagen content, and a large lipid pool. The differentiating factor between stable plaque and unstable plaque can also be established by the presence of activated inflammatory cells and elevated levels of Lp-PLA2 in unstable plaque.16, 26 Lp-PLA2 is produced by macrophages and foam cells in atherosclerotic plaques and may be tested relatively inexpensively and noninvasively in the clinical laboratory. In addition, Lp-PLA2 is associated primarily with LDL particles in the blood and is the sole enzyme responsible for the hydrolysis of oxidized phospholipids on LDL particles. The products of this reaction—oxidized fatty acids and lysophosphatidylcholine—are well-established triggers of the inflammation cascade. Lp-PLA2 may represent a noninvasive tool to assess plaque stability. Conclusion Prevention strategies are shifting from identification of stenosis, which is often a focal disease, to identification of patients whose plaque has become inflamed and rupture prone. Rupture-prone plaques are characterized by high levels of atherosclerotic disease activity with thinned fibrous caps, macrophage infiltration, and large lipid cores, with or without luminal stenosis. Lipids and lipoproteins are well-established agents of the decades-long process of atherosclerosis, but they provide little information about the level of atherosclerosis disease activity within the artery wall at any given point in time. Similarly, although nonlipid risk factors, such as age, smoking status, and blood pressure, are associated with ED, they only provide crude estimates of plaque stability. In contrast, elevation of the Lp-PLA2 biomarker appears to be specific for high levels of atherosclerotic disease activity, independently and additively to traditional risk factors and the metabolic syndrome. As such, Lp-PLA2 could alert the clinician to initiate proven strategies for coronary event and stroke risk reduction. Author Disclosures The author who contributed to this article has disclosed the following industry relationships. Howard S. Weintraub, MD, is a member of the Speakers' Bureau for Pfizer, Inc, CVT Inc., diaDexus, Novartis, Merck & Co., and Takeda Pharmaceuticals. References 1. 1Rosamond R, Flegal K, Friday G, Furie K, Go A, Greenlund K, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115:e69–e171.
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Division of Cardiology, Department of Medicine, New York University Medical Center, New York, New York, USA.  Address for reprints: Howard S. Weintraub, MD, Division of Cardiology, Department of Medicine, New York University Medical Center, 530 First Avenue, Suite 9U, New York, New York 10016.
Statement of author disclosure: Please see the Author Disclosures section at the end of this article. PII: S0002-9149(08)00684-X doi:10.1016/j.amjcard.2008.04.013 © 2008 Elsevier Inc. All rights reserved. | |
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