Until recently, most clinicians and

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1 NEW INSIGHTS INTO THE PATHOLOGY OF CORONARY ARTERY DISEASE * Keith C. Ferdinand, MD, FACC ABSTRACT Atherosclerosis leading to myocardial infarction (MI) is no longer considered a problem of simple mechanical obstruction. The atheroma is a complex structure created by and perpetuating an inflammatory response, which creates a prothrombotic state. It is the thrombus from a ruptured plaque that causes occlusion and ultimately MI, not simply growth of the fatty plaque. As we understand the key components of this complex atheroma, we appreciate emerging risk factors that can provide additional information to the major risk factors identified by the National Cholesterol Education Program, particularly on an individual level. This article reviews the pathophysiology of a developing atherosclerotic plaque and outlines the emerging risk factors (lipid and nonlipid) under investigation. In particular, small, dense low-density lipoprotein and C-reactive protein are reviewed, and recommendations for their incorporation into clinical practice are discussed. Although recommended therapies and their targets are not yet changed, *Based on a presentation given by Dr Ferdinand at a symposium held in conjunction with the American Academy of Physician Assistants 31st Annual Physician Assistant Conference. Clinical Cardiologist and Medical Director, Heartbeats Life Center, and Professor, Clinical Pharmacology, Xavier University College of Pharmacy, New Orleans, Louisiana. Address correspondence to: Keith C. Ferdinand, MD, FACC, Director, Heartbeats Life Center, 1201 Poland Ave, New Orleans, LA kcferdmd@aol.com. testing for certain emerging cardiovascular risk factors can help to identify at-risk individuals who may otherwise be overlooked by populationbased guidelines. (Adv Stud Med. 2003;3(9A):S857-S863) Until recently, most clinicians and researchers considered a myocardial infarction (MI) to be the result of artery blockage by an atherosclerotic plaque. This concept has evolved, however, from a concept of simple mechanical obstruction to a more in-depth understanding of the complex inflammatory processes that lead to MI. Most MIs are not associated with tight stenoses from atherosclerotic plaques. Although these lesions may cause exertional angina (chest pain with exertion), most MIs are the result of a moderate lesion with a superimposed thrombus, typically from a ruptured plaque. To understand this, it is useful to review the pathophysiology of a developing atherosclerotic plaque. UNDERSTANDING THE ATHEROSCLEROTIC PROCESS Atherosclerosis typically begins as a fatty streak along the inside of the artery in which excess cholesterol, in the form of low-density lipoprotein (LDL) cholesterol, accumulates. LDL cholesterol usually functions as a delivery mechanism of cholesterol from the liver and intestines to various tissues, which use Advanced Studies in Medicine S857

2 cholesterol in a wide range of metabolic processes, including membrane repair and steroid production. Excess dietary cholesterol results in excess LDL ( bad ) cholesterol, which then accumulates inside the arterial wall when the tissues are not in need of cholesterol. LDL cholesterol becomes enmeshed in the matrix of the intima (the arterial layer closest to the inside of the artery, containing endothelium, the extracellular matrix, and smooth muscle cells, which produce the connective tissue of the matrix). LDL cholesterol attached to artery walls undergoes oxidation and glycation. This modified form of LDL emits proinflammatory signals to the immune system. 1 The first response by the immune system is the attachment of monocytes (circulating white blood cells) to adhesion molecules on arterial endothelial cells. Once attached, monocytes can squeeze through the epithelial cells to the inner intima. Once inside, they form macrophages and begin to ingest the modified (oxidized) LDL. They ultimately consume so much LDL cholesterol that the fatty droplets inside the macrophage look like foam under a microscope. Thus, these cells are referred to as foam cells. During this time, T-cells are also recruited to the site. 1 As in other inflammatory responses, a braking mechanism for the inflammatory response is in place to begin healing the wound. In this case, the smooth muscle cells from below the intima resurface to the plaque and secrete matrix components to build a fibrous cap over the plaque. As this occurs, some foam cells die, releasing their fatty contents (including the oxidized LDL) into the center of the plaque. This region is often referred to as the lipid or necrotic core. Inside the lipid core, macrophages and T-cells release cytokines to recruit more monocytes to the complex atheroma. Thus, a vicious cycle continues: monocytes are continuously recruited to the complex atheroma, ingesting further oxidized LDL and forming foam cells, which rupture and release more oxidized LDL, as well as cytokines to recruit monocytes. 2,3 High-density lipoprotein (HDL) cholesterol is an important component of the braking mechanism because it inhibits LDL oxidation and effluxes the cholesterol back out into the bloodstream from the lipid core. 4 Of particular import, however, is that the plaque and its cap do not initially narrow the lumen of the artery. Rather, the plaque is formed within the structure of the arterial wall. This process, known as remodeling, allows near-normal blood flow to be maintained. Thus, angiography does not always reveal stenosis when cholesterol levels are abnormally high. 5 MI occurs when a plaque ruptures, causing a blood clot to form over the break. The blood clot is spurred on by procoagulation proteins within the lipid core of the plaque. Many clots may be cleared naturally; some may cause an even larger atheroma as the ruptured plaque is repaired, but those that do block blood flow cause an MI or unstable angina. 5 Clearly, atherosclerosis is insidious. Results from the Bogalusa Heart study, a long-term epidemiologic investigation of the early natural history of atherosclerosis, confirm this. The study began in 1973 to 1974, with height, weight, and lipid-level data from children ranging in age from birth through 14 years in a biracial (black and white) population in Bogalusa, Louisiana. From the wealth of information gleaned from this large dataset, a stark trend emerges showing that atherosclerosis begins early in life even before age 20 years in most patients. 6,7 In middle age, especially in those with type 2 diabetes (another emerging epidemic), the risk for platelet aggregation, vasoconstriction, and blood clotting increases dramatically. In these cases, 40% to 60% stenosis is common, and patients who have moderate coronary artery disease are at a greatly increased risk for an MI. Given what is now known about the perils of atherosclerosis, it behooves clinicians to identify risk factors for atherosclerosis and ways to reduce them. The major risk factors are well known: high LDL cholesterol levels, low HDL cholesterol levels, hypertension, increasing age, male sex, diabetes, and cigarette smoking. The Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP III) has identified diabetes as a coronary heart disease (CHD) risk equivalent 8 ; ie, having type 2 diabetes puts one at as much risk for a future CHD event as having had a previous MI. Young women are at less risk for CHD, perhaps because of estrogen. However, premenopausal women with type 2 diabetes lose this cardiovascular benefit. A prominent focus of public health initiatives is to reduce these major risk factors, in particular, reducing cholesterol levels. However, total cholesterol does not provide a complete picture of CHD risk. Data from the Framingham Heart Study (with 26-year followup) show that fully half of CHD occurs in those with total cholesterol levels below the average level (220 mg/dl); 35% of CHD occurs in those with total cho- S858 Vol. 3 (9A) October 2003

3 lesterol levels below 200 mg/dl. 9,10 As a result, the NCEP ATP III acknowledges that CHD risk is influenced by other factors not included in the major independent risk factors outlined above. Although the Framingham score provides estimates of CHD risk in populations, emerging risk factors under investigation could enhance the predictive power of CHD risk in individuals. 8 EMERGING CHD RISK FACTORS The emerging CHD risk factors can be divided into 2 groups: lipid and nonlipid (Table). Lipid risk factors define cholesterol levels in further detail from the standard lipid profile (ie, LDL cholesterol, HDL cholesterol, triglycerides, and total cholesterol). For example, the size of the LDL particle affects risk the smaller the LDL particle, the greater the risk. Similarly, larger HDL particles, particularly HDL cholesterol, 2 are somewhat more protective. However, NCEP ATP III at this time does not recommend regular testing of these subfractions; the tests for measuring them are not readily available, and their use as independent risk factors is not established. They can be used, however, to support the implementation of therapeutic lifestyle changes. 8 Nonlipid risk factors include markers of inflammation (eg, C-reactive protein [CRP]), thrombogenic/ hemostatic factors, impaired fasting glucose (often a precursor to frank diabetes), and homocysteine. This article will focus on CRP. LIPID FACTORS: SMALL DENSE LDL LDL cholesterol can be further fractionated based on its density. Researchers are examining the possible differences in heart disease risk based on density of LDL, theorizing that smaller, denser LDL particles are more easily able to penetrate the arterial endothelium and therefore are more atherogenic. As a result, small dense LDL particles may better predict cardiovascular events. Several small studies have shown that patients with small dense LDL are at greater risk for ischemic heart disease. A study of 2034 men in the Quebec Cardiovascular Study showed that small dense LDL particles (<255 Å width) are strongly associated with the risk of ischemic heart disease (Figure 1), regardless of LDL cholesterol levels above 146 mg/dl. 11 Clearly, more work needs to be done to clarify these results and provide insight into the relationship of lipoprotein density and CHD. LIPID FACTORS: TRIGLYCERIDES AND NON-HDL CHOLESTEROL It is difficult to determine whether triglyceride level is an independent risk factor. Triglyceride levels appear to be related to CHD risk, but a better way of assessing their impact is via non-hdl cholesterol. Non- HDL cholesterol is measured by subtracting HDL cholesterol values from total cholesterol levels (Figure 2). If serum triglyceride levels are moderately high Table. Emerging Risk Factors LIPID Lipoprotein(a) Small dense LDL HDL Triglycerides and lipoprotein remnants NONLIPID Inflammatory markers (CRP) Thrombogenic/hemostatic factors Impaired fasting glucose Homocysteine LDL = low-density lipoprotein; HDL = high-density lipoprotein; CRP = C-reactive protein. Figure 1. Small Dense LDL and Cardiovascular Risk: Results from the Quebec Cardiovascular Study LDL = low-density lipoprotein. Reproduced with permission from St-Pierre et al. Circulation. 2001; 104: Advanced Studies in Medicine S859

4 ( 200 mg/dl), calculating non-hdl cholesterol offers some assessment of risk. Non-HDL cholesterol includes all atherogenic lipoprotein particles, including LDL, lipoprotein(a), intermediate-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol, which is a measure of atherogenic remnant lipoproteins. 8 Results from the Lipid Research Clinics Program Follow-up Study show that levels of HDL and non-hdl cholesterol at baseline were significant and strong predictors of death from cardiovascular disease in both sexes (mean follow-up, 19 years; N = 2462). 12 The NCEP ATP III guidelines recommend cutoff points for triglyceride levels as follows: normal, below 150 mg/dl; borderline high, 150 to 199 mg/dl; high, 200 to 499 mg/dl; very high, 500 mg/dl or above. Very high levels confer risk of acute pancreatitis, and drug treatment is therefore recommended. Lifestyle modification, weight loss, and decreased alcohol consumption may have an impact in patients with marginally elevated triglycerides. CRP is linked to atherothrombosis through several mechanisms. Cytokines released from the atheroma include interleukin-6, tumor necrosis factor-alpha, and interleukin- 1B. They are not measured directly, so hscrp is considered a surrogate marker for those cytokines in an atheroma. CRP is easier to measure because it is more stable (ie, can be kept in samples for long periods of time), and a cost-effective assay is available in most clinical laboratories. Measuring hscrp can help to Figure 2. Non-HDL Cholesterol Non-HDL cholesterol = total cholesterol HDL cholesterol = LDL cholesterol + VLDL cholesterol Total cholesterol = LDL cholesterol + HDL cholesterol + (Triglycerides/5)* NONLIPID RISK FACTORS: CRP CRP is gaining great interest, in part because it is more clearly associated with acute coronary artery disease than triglycerides, HDL, or homocysteine. CRP is an acute-phase protein produced by the liver in response to cytokines released in the complex atheroma. A form of CRP assessment, called high-sensitivity CRP (hscrp), provides an accurate measure of CRP when it is present in very low levels. In large population studies, hscrp has been associated with an increase in coronary events. However, some factors may confound the results of hscrp testing. Cigarette smokers may have elevated hscrp levels without complex atheromas; hscrp may also be an innocent bystander during a nonatheroma-related inflammatory response, thus showing misleadingly high levels. Prior infection with chlamydia, Helicobacter pylorus, or cytomegalovirus will confound hscrp results. Assessing risk by simply obtaining blood levels of hscrp can therefore be difficult. *Valid only for persons with triglyceride levels below 400 mg/dl. HDL = high-density lipoprotein; LDL = low-density lipoprotein; VLDL = very-low-density lipoprotein. Data from 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) final report. 8 Figure 3. Risk Markers for Future Cardiovascular Events: Results from the Women s Health Study hscrp = high-sensitivity C-reactive protein; TC = total cholesterol; HDL = high-density lipoprotein; LDL = low-density lipoprotein. Data from Ridker et al. 13 S860 Vol. 3 (9A) October 2003

5 assess risk in people with subclinical atherosclerosis who require other means of measuring plaque buildup (eg, electron beam computed tomography, anklebrachial index), as well as help to identify those prone to an acute coronary event. Patients with insulin resistance, obesity, or the metabolic syndrome may underestimate their risk based on major risk factors alone; hscrp may provide greater insight into their risk. Finally, hscrp can also assist in determining plaque vulnerability (ie, the likelihood that an atherosclerotic plaque will rupture). The Women s Health Study provides clear evidence that hscrp may provide additional predictive value for future cardiovascular events. 13 In this study, premenopausal women were followed up for a mean of 3 years to assess risk of cardiovascular events, after measuring baseline levels of markers of inflammation. Cardiovascular events were defined as death from CHD, nonfatal MI or stroke, or the need for coronary revascularization procedures. Of all the markers analyzed, hscrp showed a high predictive value in determining risk of future events (Figure 3), followed by the ratio of total cholesterol to HDL cholesterol. A higher ratio indicates that the level of HDL is low compared with the level of total cholesterol. The goal is therefore to lower the ratio. The relationship among hscrp, total cholesterol, and risk of coronary events is shown in Figure 4. Based on these results, we infer that unstable plaques have an increase in leukocytes (monocytes and macrophages) and T-cells. They rupture, releasing cytokines, which are indirectly measured by hscrp. The corollary suggests that lipid lowering may reduce plaque formation, stabilize existing plaques, and reduce the numbers of macrophages, cytokine levels, and perhaps, the probability of an acute coronary event. Reducing the degree of stenosis is not the only or most important therapeutic objective; just stabilizing the plaque to prevent rupture is. Aspirin is used to prevent blood clots and as an anti-inflammatory drug. In the Physicians Health Study, the use of aspirin significantly decreased the risk of MI in more then 1000 healthy men, with the greatest benefit in those with the highest levels of CRP. CRP level also strongly correlated with risk of MI or stroke (Figure 5). 14 More recently, the Women s Health Study compared the predictive value of hscrp and LDL cholesterol in healthy women. 15 Although hscrp and LDL cholesterol were minimally correlated, each Figure 4. hscrp, Lipids, and Risk of Coronary Events: Results from the Women s Health Study hscrp = high-sensitivity C-reactive protein. Adapted with permission from Ridker et al. N Engl J Med. 2000;342(12): Copyright 2000 Massachusetts Medical Society. All rights reserved. Figure 5. CRP,Aspirin, and Risk of MI: Results from the Physicians Health Study CRP = C-reactive protein; MI = myocardial infarction. Adapted with permission from Ridker et al. N Engl J Med. 1997; 336(14): Copyright 1997 Massachusetts Medical Society. All rights reserved. Advanced Studies in Medicine S861

6 was a strong predictor of future cardiovascular events based on mean 8-year follow-up. These results were also seen in subgroup analyses of users and nonusers of hormone therapy (Figure 6). These results suggest that hscrp and LDL cholesterol levels identified 2 different groups of women who are at risk for cardiovascular events, and that hscrp provides prognostic information that is additional to that found in the Framingham risk score. If hscrp levels appear to predict cardiovascular event risk and provide additive prognostic value, what effect do statins have on hscrp, given their profound beneficial effects on LDL cholesterol levels? A review of the major statin trials shows that statins also have a beneficial effect on hscrp, with decreases of 15% to 20% from baseline (Figure 7). 16 This suggests that statins may also attenuate the inflammatory process in the complex atheroma, although this remains to be proven. Given the strong evidence linking hscrp to the prediction of future cardiovascular events, who should be screened? Earlier this year, the American Heart Association (AHA) released guidelines on the role of hscrp for screening patients at risk for cardiovascular disease. 17 According to the AHA, there is no need to screen the entire adult population for hscrp levels as a public health measure; however, hscrp can be an independent marker of risk and may be useful as a discretionary tool for evaluating individuals with moderate risk. There is not yet enough evidence to support using hscrp to track the efficacy of treatment, despite the effect of statins on hscrp levels. However, the AHA does identify cutoff points for hscrp blood levels to determine the level of risk: low risk, below 1.0 mg/l; average risk, 1.0 to 3.0 mg/l; and high risk, above 3.0 mg/l. Given the effect of statins on hscrp and the unclear relationship between LDL cholesterol and hscrp levels, will statin therapy prevent cardiovascular events in patients with relatively low LDL levels but elevated hscrp? This is currently under investigation in the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study. This randomized placebo-controlled trial is designed to determine whether rosuvastatin (20 mg daily) can decrease coronary events in patients with LDL cholesterol levels below Figure 6. Cardiovascular Event-Free Survival Using Combined hscrp and LDL Cholesterol Measurements hscrp = high-sensitivity C-reactive protein; LDL = low-density lipoprotein. Adapted with permission from Ridker et al. N Engl J Med. 2002;347(20): Copyright 2002 Massachusetts Medical Society. All rights reserved. Figure 7. Effects of Statin Therapy on hscrp hscrp = high-sensitivity C-reactive protein; CARE = Cholesterol and Recurrent Events Trial; PRINCE = Pravastatin Inflammation CRP Evaluation; AFCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study; 4S = Scandinavian Simvastatin Survival Study. Data from Ridker. 16 S862 Vol. 3 (9A) October 2003

7 130 mg/dl and hscrp levels above 2 mg/l. Men older than 55 years and women older than 65 years with no history of coronary disease are being studied. Because this is an event-driven trial, the length will be determined by differences in outcomes; however, follow-up is estimated at 3.5 years. Coronary events are defined as death due to cardiovascular disease, nonfatal MI, nonfatal stroke, hospitalization for unstable angina, and coronary revascularization. The results may suggest whether we should be more aggressive in treating cardiovascular disease risk and whether hscrp can be used to identify candidates for aggressive LDL reduction. CONCLUSION Atherosclerosis leading to MI is no longer considered a problem of simple mechanical obstruction. The atheroma is a complex structure created by and perpetuating an inflammatory response, which creates a prothrombotic state. It is the thrombus from a ruptured plaque that causes occlusion and, ultimately, MI, rather than just growth of the fatty plaque. As we understand the key components of this complex atheroma, we appreciate emerging risk factors that can provide information that is additional to that provided by the major risk factors identified by the NCEP ATP III, particularly on an individual level. Although recommended therapies and their targets are not yet changed, testing for certain emerging cardiovascular disease risk factors may help to identify at-risk individuals who may otherwise be overlooked by population-based guidelines. REFERENCES 1. Libby P. The vascular biology of atherosclerosis. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders; 2001: Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989;320(14): Nathan CF. Secretory products of macrophages. J Clin Invest. 1987;79(2): Mackness MI, Abbott C, Arrol S, Durrington PN. The role of high-density lipoprotein and lipid-soluble antioxidant vitamins in inhibiting low-density lipoprotein oxidation. Biochem J. 1993;294(pt 3): Libby P. The pathogenesis of atherosclerosis. In: Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, eds. Harrison s Principle of Internal Medicine. 15th ed. New York: McGraw Hill Companies; 2001: Urbina EM, Srinivasan SR, Tang R, Bond MG, Kieltyka L, Berenson GS. Impact of multiple coronary risk factors on the intima-media thickness of different segments of carotid artery in healthy young adults (The Bogalusa Heart Study). Am J Cardiol. 2002;90(9): Berenson GS. Childhood risk factors predict adult risk associated with subclinical cardiovascular disease. The Bogalusa Heart Study. Am J Cardiol. 2002;90(10C):3L-7L. 8. 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) final report. Circulation. 2002; 106: Castelli WP. Lipids, risk factors, and ischaemic heart disease. Atherosclerosis. 1996;124(suppl):S1-S Castelli WP. Cholesterol and lipids in the risk of coronary artery disease. The Framingham Heart Study. Can J Cardiol. 1988;4:5A. 11. St-Pierre AC, Ruel IL, Cantin B, et al. Comparison of various electrophoretic characteristics of LDL particles and their relationship to the risk of ischemic heart disease. Circulation. 2001;104(19): Cui Y, Blumenthal RS, Flaws JA, et al. Non high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med. 2001;161(11): Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342(12): Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336(14): Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20): Ridker PM. Should statin therapy be considered for patients with elevated C-reactive protein? The need for a definitive clinical trial. Eur Heart J. 2001;22(23): Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice. A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107: Advanced Studies in Medicine S863