CASE STUDY

Physical Exam Height: 74 in Weight: 220 lb Waist circumference: 41 in Blood pressure: 150/88 mm Hg Pulse: 64 bpm Breathing rate : 12 breaths/min Cardiopulmonary exam: Normal Laboratory Data TC: 220 mg/dL HDL-C: 36 mg/dL LDL-C: 140 mg/dL TG: 220 mg/dL Fasting blood sugar (FBS):        130 mg/dL Medications Amlodipine 5 mg/day Sildenafil 50 mg as needed Related information on this website: In the Slide Library section: ATP III Framingham Risk Scoring—Assessing CHD Risk in Men In the Current Literature section: How Generalizable Are Coronary Risk Prediction Models? Comparison of Framingham and Two National Cohorts Liao Y, McGee DL, Cooper RS, Sutkowski MBE. Am Heart J. 1999;137:837-845. New Tools for Coronary Risk Assessment: What Are Their Advantages and Limitations? Pearson TA. Circulation. 2002;105:886-892. Ankle-Brachial Index as a Predictor of the Extent of Coronary Atherosclerosis and Cardiovascular Events in Patients with Coronary Artery Disease Papamichael CM, Lekakis JP, Stamatelopoulos KS, et al. Am J Cardiol. 2000;86:615-618.

Cardiac Risk Assessment in a Middle-Aged Male   Saman Nazarian, MD   Roger S. Blumenthal, MD The following case was provided by Saman Nazarian, MD, Fellow in Cardiovascular Medicine, Johns Hopkins Hospital, and NLEC Faculty Member Roger S. Blumenthal, MD, FACC, Associate Professor of Medicine, and Director, The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, Maryland. Disclosure Information for Dr Nazarian: None. Disclosure Information for Dr Blumenthal: Clinical Research Support: Pfizer Inc, Merck & Co., Inc., Novartis, Bristol-Myers Squibb, Wyeth, KOS; Speaker's Bureau: Pfizer Inc, Merck & Co., Inc., Novartis, Wyeth. WC is a 54-year-old male with hypertension who presents for cardiac risk assessment. Although he is asymptomatic at rest, he finds himself winded after brief attempts to jog a few blocks. He is a successful executive with a busy, stressful schedule. He frequents fast-food restaurants, where he enjoys a burger 2 to 3 times per week. He has had a long-term weight problem. He is not a cigarette smoker, but has a fondness for an occasional cigar. He consumes alcohol socially. Though he reports no family history of premature coronary disease, he doesn't know much about his father's relatives, as his parents lived together for only a short time. Discussion An important step in forming a preventive strategy for the care of WC is an objective assessment of his coronary risk. The Framingham experience allows us to calculate a 10-year coronary heart disease (CHD) risk using age, TC, HDL-C, blood pressure (BP), diabetes, and smoking. Through Framingham risk scoring—adapted by ATP III—WC receives 6 points for his age, 3 points for TC, 2 points for HDL-C level, and 2 points for systolic BP (treated). His total score is 13, translating to a 10-year risk of 12% for hard CHD (myocardial infarction [MI] and coronary death).1, 2 (See Figure 1.) Figure 1. Assessing WC's CHD Risk     With more than two cardiac risk factors (age, elevated BP, low HDL-C) and a 10-year risk of 10%–20%, ATP III guidelines assign an LDL-C goal of <130 mg/dL for WC. With an LDL-C of 140 mg/dL, ATP III advises that WC be considered for drug therapy as well as encouraged to initiate therapeutic lifestyle changes (TLC). (See Figure 2.) Specific recommendations regarding the TLC diet include reducing saturated fats and cholesterol while increasing plant stanols/sterols and viscous fiber. The exercise component of TLC serves to reduce weight through increased physical activity.1 Figure 2. ATP III: LDL-C Treatment Cutpoints     WC repeats his concern about the possibility of coronary disease and inquires about other tests to further evaluate his coronary risk. Several noninvasive tests of silent ischemia are at our disposal:   An inexpensive and widely available test, the ankle-brachial index (ABI) is measured by dividing the systolic BP in the ankle by that in the brachial artery. A ratio of less than 0.90 is a reliable sign for the presence of peripheral arterial disease (PAD). Patients with PAD are known to have increased cardiac risk. While the ABI is extremely sensitive for detection of severe PAD (up to 95% sensitive), it is not as sensitive for detection of subclinical coronary disease and was not used for the evaluation of WC.   Carotid B-mode ultrasound places emphasis on intima-media thickness (IMT)—and is an important test because increased IMT values elevate the risk of CHD fivefold. Typically, ultrasound evaluates the distal straight centimeter of the extracranial common carotid artery, the carotid bifurcation, and the proximal centimeter of the internal carotid artery. Recent studies, however, suggest that measuring the IMT of the far wall of the common carotid artery alone is predictive of future MI.3 This methodology may offer an advantage, since bifurcation and internal carotid artery measurements are more difficult to obtain secondary to depth and tortuousity. However, since carotid IMT is not routinely performed in all laboratories and is not always reliable, this test was not performed on WC.   An exercise treadmill test (ETT) is very helpful not only in terms of electrocardiogram recording and BP response to exercise, but also as a measure of exercise tolerance. Exercise test duration alone is a strong predictor of future cardiovascular disease risk.4 A recent study revealed that each metabolic equivalent (MET) increase in exercise capacity translated to a 12% improvement in 6-year survival.5 However, in an asymptomatic patient, an ETT may be abnormal only if there is >60% stenosis in a major epicardial coronary artery. Understanding that a high burden of atherosclerosis manifesting as subclinical stenoses could be missed by a normal or nonspecific ETT, we elected to use a different modality to assess WC's coronary disease.   Electron beam computed tomography (EBCT) measures calcium deposition in coronary arteries. (See Figure 3.) The extent of coronary calcium determined by EBCT has been correlated with the degree of atherosclerosis through autopsy and angiographic measurements.6 A coronary calcium score (CCS) >75th percentile for age would suggest advanced atherosclerosis and would provide a rationale for intensified lipid-lowering therapy. As proposed by Grundy SM, EBCT may also provide a means of substituting age, which is essentially a surrogate of coronary plaque burden, with a more direct measure of this risk factor.7 A CCS >75th percentile for WC's age would change the number of points assigned in the Framingham risk score for his age to 10, thus elevating his 10-year risk to 30%. (A CCS in the lowest quartile for his age would yield 0 points, resulting in a 10-year risk of 3%.) Thus, EBCT is ideal for detection of subclinical atherosclerosis and risk stratification in patients without a known history of coronary disease, such as WC. Figure 3. EBCT Image: Calcification of Proximal LAD     Our patient was referred for EBCT and was indeed found to have a CCS of 220, which is >75th percentile for his age. To better evaluate contributing factors to his premature atherosclerosis, further laboratory measurements were made. Further Laboratory Data Homocysteine: 18 µmol/L Lp(a): 45 mg/dL hs-CRP: 1.5 mg/L Apo B: 126 mg/dL PlA2: Negative Emerging Risk Factors Several new markers of atheroembolic disease have emerged from recent studies, which may be used to further refine WC's cardiac risk. These markers include homocysteine, lipoprotein(a) (Lp[a]), high- sensitivity C-reactive protein (hs-CRP), apolipoprotein B (apo B), and PlA2 allele.   The amino acid homocysteine results from demethylation of dietary methionine. Patients with rare defects in this metabolic pathway can develop severe hyperhomocysteinemia, leading to premature atherothrombosis. More commonly, patients develop mild hyperhomocysteinemia due to inadequate folate intake. Among patients with average cholesterol and below-average HDL-C levels enrolled in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), those with elevated homocysteine levels had more coronary events than did those with lower levels. The risk of developing acute coronary events increased 15% for each quartile increase in baseline homocysteine. However, homocysteine determination did not help define patients with below-average LDL-C levels who would benefit from statin therapy.8 Therefore, WC's mildly elevated homocysteine (>15 mg/dL) might warrant the use of folate and B-vitamin supplements, but wouldn't influence lipid-lowering therapy.   Lp(a) is formed by a linkage between the apo B-100 of an LDL-C particle and apolipoprotein(a) (apo[a]). Apo(a) is homologous to plasminogen and is thought to competitively inhibit endogenous fibrinolysis. Apo(a) may also induce monocytic chemotactic activity in the vascular endothelium, thereby promoting atherosclerosis. Similar to homocysteine, widespread use of Lp(a) is prevented by the lack of prospective data correlating it to elevated cardiac risk, but measurement in young patients with advanced atherosclerosis is warranted.9 The finding of a borderline-high Lp(a), associated with elevated LDL-C in WC's profile, supports more aggressive LDL-C–lowering therapy.   Elevation (>2 mg/L) of the inflammatory marker CRP has a strong predictive value in determining CHD risk among men and women. Plasma elevation of hs-CRP also appears to add to the predictive value of lipid measurements. Elevated hs-CRP in AFCAPS/TexCAPS participants correlated with coronary events.     Furthermore, therapy with lovastatin reduced hs-CRP levels and was effective at reducing coronary events in patients with normal cholesterol levels and elevated hs-CRP. This finding supports the use of hs-CRP for risk stratification in the primary prevention of CHD.10 In the case of WC, however, a normal level does not affect his management.   Apo B is a component of each LDL-C particle and is therefore correlated in a direct relationship with LDL-C measurements. Since apo B is a direct measurement, and LDL-C is a calculated value, apo B is more reliable in the setting of TG levels >250 mg/dL. An apo B/LDL-C ratio >1 suggests a preponderance of small, dense LDL-C particles, thought to be more atherogenic11 than larger, more buoyant particles. A mildly elevated apo B is not useful in determining WC's management.   The presence of the PlA2 allele and resultant GPIIIa polymorphism results in tighter fibrinogen-platelet binding. A study of 116 siblings of patients with premature CHD revealed the presence of the PlA2 allele in 41% of participants.12 This association was more frequent in Caucasians (53%) than in other races. Aspirin (ASA) appears to decrease the risk associated with the PlA2 allele. WC does not have the PlA2 allele, but given his premature atherosclerosis he should be taking daily ASA anyway. The Metabolic Syndrome Patients with the metabolic syndrome—defined by hypertension, insulin resistance, and the lipid triad of elevated serum TG, low HDL-C, and small, dense LDL-C particles—are at increased risk of developing premature CHD. A comprehensive plan for patients with this syndrome would include treatment of insulin resistance, as well as lipid-lowering therapy and management of other individual risk factors13 (such as ASA for prothrombotic state or antihypertensives). In addition to hypertriglyceridemia and low HDL-C, WC's initial laboratory evaluation revealed elevation of his fasting blood glucose, alerting us to the presence of the metabolic syndrome. Given WC's current risk factors, there is little need to confirm the presence of small, dense LDL-C particles in his serum, but this could easily be accomplished by the use of nuclear magnetic resonance spectroscopy.14 Treatment Plan Given WC's subclinical atherosclerosis confirmed by EBCT, high Lp(a), and his elevated CHD risk due to the metabolic syndrome, HMG-CoA reductase inhibitor (statin) therapy is recommended. He agrees to treatment with 20 mg of simvastatin daily and to more aggressive antihypertensive management, as well as potential addition of oral hypoglycemics should dietary management of his elevated blood glucose fail. However, he asks about the utility of antioxidant therapy. Data from the recent Heart Protection Study showed that use of antioxidants—specifically vitamin E, vitamin C, and beta-carotene—conferred no advantage in terms of mortality, vascular events, or cancer.15 Concluding Remarks Emerging risk factors such as homocysteine, apo B, Lp(a), PlA2, hs-CRP, and LDL-C particle size are useful adjuncts for risk stratification and prevention of premature atherosclerosis. The significant CHD risk reduction achieved with statin therapy in high-risk patients underscores the need for their identification and treatment. References   1. ATP III. JAMA. 2001;285:2486-2496. 2. Wilson PW, D'Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-1847. 3. Iglesias del Sol A, Bots ML, Grobbee DE, Hofman A, Witteman JCM. Carotid intima-media thickness at different sites: relation to incident myocardial infarction. Eur Heart J. 2002;23:934-940. 4. Laukkanen JA, Lakka TA, Rauramaa R, Salonen JT. Cardiovascular fitness as a predictor of mortality. CVR&R. 2002;23:339-344 . 5. Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood E. Exercise capacity and mortality among men referred for mortality testing. N Engl J Med. 2002;346:793-801. 6. Greenland P, Smith SC, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people. Circulation. 2001;104:1863-1867. 7. Grundy SM. Coronary plaque as a replacement for age as a risk factor in global risk assessment. Am J Cardiol. 2001;88(suppl 2-A):8E-11E. 8. Ridker PM, Shih J, Cook TJ, et al, for the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Investigators. Plasma homocysteine concentration, statin therapy, and the risk of first acute coronary events. Circulation. 2002;105:1776-1779. 9. Braunwald E, Zipes D, Libby P. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co. 2001;1027-1028. 10. Ridker PM, Rifai N, Clearfield M, et al, for the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959-1965. 11. Nass CM, Wiviott SD, Allen JK, Post SW, Blumenthal RS. Global risk assessment for lipid therapy to prevent coronary heart disease. Current Cardiology Reports. 2000;2:424-432. 12. Goldschmidt-Clermont PJ, Lindsay DC, Pham YM, et al. Higher prevalence of GPIIIa PlA2 polymorphism in siblings of patients with premature coronary heart disease. Arch Pathol Lab Med. 1999;123:1223-1229. 13. Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol. 1998;81:18B-25B. 14. Otvos DJ, Rifai N. Handbook of Lipoprotein Testing. 2nd ed. Washington, DC: American Association for Clinical Chemistry, Inc. 2000;609-623. 15. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:23-33.