Non High-Density Lipoprotein Cholesterol Versus Low-Density Lipoprotein Cholesterol as a Risk Factor for a First Nonfatal Myocardial Infarction

Transcription

1 Non High-Density Lipoprotein Cholesterol Versus Low-Density Lipoprotein Cholesterol as a Risk Factor for a First Nonfatal Myocardial Infarction Wildon R. Farwell, MD, MPH a,b, Howard D. Sesso, ScD, MPH b,c, *, Julie E. Buring, ScD b,c,e,f, and J. Michael Gaziano, MD, MPH a,b,c,d Low-density lipoprotein (LDL) cholesterol is the primary lipid parameter targeted to prevent myocardial infarction. Alternatively, non high-density lipoprotein (HDL) cholesterol includes LDL cholesterol and other atherogenic particles but does not require a fasting sample. Non-HDL cholesterol and LDL cholesterol as predictors of first nonfatal myocardial infarction were compared in 303 patients and 297 controls matched for age, gender, and community within the Boston Area Health Study. Patients were white men or women aged <76 years living in the Boston area, without a history of myocardial infarction or angina pectoris, in whom symptoms of confirmed myocardial infarction began during the 24 hours before admission. After multivariate adjustment for coronary risk factors in unmatched analyses, the corresponding odds ratios (ORs) of a first nonfatal myocardial infarction for non-hdl cholesterol in the second, third, and fourth quartiles were 1.83 (95% confidence interval [CI] 1.07 to 3.14), 2.07 (95% CI 1.23 to 3.49), and 2.33 (95% CI 1.39 to 3.90) (p trend <0.01). For LDL cholesterol, the ORs were 1.10 (95% CI 0.67 to 1.81), 0.87 (95% CI 0.52 to 1.46), and 1.45 (95% CI 0.90 to 2.35) (p trend 0.16). Including HDL cholesterol in the model increased the ORs and strengthened the test for a trend for LDL cholesterol, whereas the ORs were decreased and the test for a trend was weakened for non-hdl cholesterol. In conclusion, given that non-hdl cholesterol accounts for LDL cholesterol plus other atherogenic particles but does not require a fasting sample, this study suggests that non-hdl cholesterol may be at least as useful as LDL cholesterol to initially screen patients for risk of a first nonfatal myocardial infarction Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Elevated low-density lipoprotein (LDL) cholesterol predicts cardiovascular disease, 1,2 and in 2001, the National Cholesterol Education Program Adult Treatment Panel published guidelines recommending that LDL cholesterol be the primary lipid parameter used in screening for hyperlipidemia. 3 LDL cholesterol is typically calculated with the Friedewald formula, which requires the measurement of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. 4 Because triglyceride levels can fluctuate significantly in relation to a patient s last meal, a patient must fast to accurately calculate LDL cholesterol. Alternatively, non- HDL cholesterol does not require a fasting lipid profile for The methods of the Boston Area Health Study have been described previously. 14,15 Briefly, all admissions to the coronary care and other intensive care units of 6 suburban Boston hospitals from January 1, 1982, to December 31, 1983, were reviewed to identify potentially eligible suba Department of Medicine, Veterans Affairs Medical Center; Divisions of b Aging and c Preventive Medicine and d Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School; e Department of Epidemiology, Harvard School of Public Health; and f Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachusetts. Manuscript received March 4, 2005; revised manuscript received and accepted June 1, This study was supported by research Grants HL and HL from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. * Corresponding author: Tel: ; fax: address: hsesso@hsph.harvard.edu (H.D. Sesso). its calculation. In 2001, for the first time, the National Cholesterol Education Program Adult Treatment Panel guidelines incorporated non-hdl cholesterol as a secondary target for lipid management. 3 Non-HDL cholesterol has been shown to be an effective predictor of cardiovascular disease, including cardiovascular mortality, in patients with 5,6 and without 7,8 cardiovascular disease, with end-stage renal failure, 9 and diabetes mellitus However, few studies have directly compared non-hdl cholesterol with LDL cholesterol for predicting cardiovascular outcomes in patients without previously known cardiovascular disease. 8,13 Therefore, we compared non-hdl cholesterol with LDL cholesterol as a predictor of first nonfatal myocardial infarction using data from the Boston Area Health Study. Methods /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 1130 The American Journal of Cardiology ( jects. Subjects who were white men or women aged 76 years living in the Boston area were eligible if they had been diagnosed with a myocardial infarction. Symptoms must have begun in the 24 hours before admission. The diagnosis of myocardial infarction was based on an elevated creatinine kinase concentration and clinical history. Eligible subjects were discharged alive and had no history of either angina pectoris or myocardial infarction. Eligible subjects were enrolled in the study if they were willing and able to participate and if they and their admitting physicians provided informed consent. For each patient, a control of the same gender and age ( 5 years) was randomly selected from a list of residents from the town in which the patient resided. Subjects with previous angina pectoris or myocardial infarction were ineligible to be controls. A total of 680 subjects (340 patients and 340 controls) participated in the study. Home interviews to assess cardiovascular risk factors and fasting venous blood samples to assess lipids were ascertained from patients approximately 8 weeks after discharge. Controls had home interviews and fasting venous blood samples ascertained on the same day as or 1 week after the patients. Each participating hospital s institutional human subjects committee approved the research protocol, and all participating subjects gave informed consent. Interviews of patients and controls provided detailed information on various potential cardiovascular risk factors in the period of time before the myocardial infarction for patients and during a similar period of time for controls. Information gathered included gender, age, hypertension (defined as reported treatment for hypertension), body mass index, diabetes mellitus, family history of premature ( 60 years of age) myocardial infarction, cigarette smoking, level of physical activity, type A personality, and alcohol consumption. Type A personality was measured with questions adapted from the Framingham Heart Study. 16 Information on alcohol consumption was gathered using a semi-quantitative food-frequency questionnaire. 17 Fasting venous blood samples of patients and controls were collected and analyzed. Venous blood was drawn into tubes with 0.1% ethylenediaminetetraacetic acid, and plasma was obtained by centrifugation at 3,000 rpm for 30 minutes at 4 C. Lipid Research Clinic methods 18,19 were used to determine levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides from fresh plasma. From a total of 607 subjects (307 patients and 300 controls) who provided adequate venous blood samples, 600 subjects (303 patients and 297 controls) had all lipid parameters measured and were therefore included in the present study. A total of 263 matched pairs were included in the 600 subjects. Statistical analyses were performed using SAS version 8 (SAS Institute Inc., Cary, North Carolina). Correlations among non-hdl cholesterol and total cholesterol, HDL cholesterol, and LDL cholesterol were determined using Spearman s rank correlation test. In addition, patients with Table 1 Characteristics of patients and controls with full lipoprotein profiles Risk Factor Patients (n 303) Controls (n 297) p Value Men 77.2% 78.1% 0.79 Age (yrs) (mean SD) Hypertension 35.3% 26.6% 0.02 Body mass index (kg/m 2 ) % 44.4% to % 43.4% % 12.1% Diabetes mellitus 13.2% 8.4% 0.06 Family history of myocardial infarction 23.1% 15.2% 0.01 Smoker Never 24.1% 30.6% 0.01 Former 31.0% 42.8% 1 pack/day 5.3% 7.4% 1 to 2 packs/day 18.8% 11.8% 2 packs/day 20.8% 7.4% Physical activity index 2,500 kcal/week 43.9% 56.9% 0.01 Type A personality 59.4% 51.2% 0.04 Alcohol consumption Nondrinker 15.8% 14.8% drink/day 51.8% 42.1% 1to 3 drinks/day 20.1% 26.6% 3 drinks/day 12.2% 16.5% Total calories consumed per day (mean SD) 2, , Total grams of saturated fat consumed per day (mean SD) Total cholesterol (mean SD) HDL cholesterol (mean SD) LDL cholesterol (mean SD) Triglycerides (mean SD) Non-HDL cholesterol (mean SD) LDL cholesterol levels 160 mg/dl were identified and then compared with patients with non-hdl cholesterol levels 190 mg/dl. A receiver-operating characteristic curve for the prediction of a first nonfatal myocardial infarction was plotted for LDL cholesterol and non-hdl cholesterol. Values of non-hdl and LDL cholesterol were divided into quartiles on the basis of the distribution of each lipid parameter in controls. Of the subjects with all lipid parameters, quartiles were defined for non-hdl cholesterol ( 143, 144 to 172, 173 to 200, and 201 mg/dl) and LDL cholesterol ( 111, 112 to 137, 138 to 159, and 160 mg/dl). Of matched pairs, quartiles were defined for non-hdl cholesterol ( 144, 145 to 175, 176 to 202, and 203 mg/dl) and LDL cholesterol ( 112, 113 to 138, 139 to 160, and 161 mg/dl). Logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals. 20 We calculated ORs for the second, third, and fourth quartiles of each lipid parameter compared with its first quartile. Tests for trends were conducted across lipid parameter quartiles using the

3 Preventive Cardiology/Non-HDL Cholesterol and First Nonfatal Myocardial Infarction 1131 Table 2 Characteristics of controls by quartiles of non-hdl cholesterol Risk Factor Quartiles of Non-HDL Cholesterol p Value, Trend (n 74) (n 74) (n 73) (n 76) Male gender 79.7% 78.4% 71.2% 82.9% 0.90 Age (yrs) (mean SD) Hypertension 24.3% 25.7% 27.4% 29.0% 0.50 Body mass index (kg/m 2 ) % 39.2% 45.2% 39.5% to % 40.5% 45.2% 48.7% % 20.3% 9.6% 11.8% Diabetes mellitus 9.5% 10.8% 5.5% 7.9% 0.49 Family history of myocardial infarction 9.5% 18.9% 19.2% 13.2% 0.55 Smoker Never 31.1% 28.4% 31.5% 31.6% 0.10 Former 35.1% 44.6% 42.5% 48.7% 1 pack/day 6.8% 9.5% 8.2% 5.3% 1 to 2 packs/d 14.9% 10.8% 13.7% 7.9% 2 packs/d 12.2% 6.8% 4.1% 6.6% Physical activity index 2,500 kcal/wk Type A personality Alcohol consumption Nondrinker drink/d to 3 drinks/d drinks/d Total calories consumed per day (mean SD) 2, , , , Total grams of saturated fat consumed per day (mean SD) Total cholesterol (mean SD) HDL cholesterol (mean SD) LDL cholesterol (mean SD) Triglycerides (mean SD) Non-HDL cholesterol (mean SD) median values in each quartile as ordinal variables. Crude models adjusted for age and gender, and multivariate models further adjusted for all clinical and behavioral coronary risk factors. Regression models were compared using the C statistic. As also detailed in the Results section, crude matched and unmatched ORs from logistic regression were compared. Because no meaningful differences were found, matching was disregarded in this analysis. 21 Results Baseline characteristics of patients and controls are presented in Table 1. Traditional cardiovascular risk factors, such as having hypertension, family history of premature cardiovascular death, and smoking history were more common in patients than controls (p 0.05). The crude differences in mean lipid values were statistically significant between patients and controls for each lipid parameter, except total cholesterol and LDL cholesterol. However, total cholesterol and LDL cholesterol still tended to be greater in patients than in controls. Coronary risk factors by each quartile of non-hdl cholesterol level in unmatched control subjects are presented in Table 2. Age significantly increased across quartiles of non-hdl cholesterol. Although not statistically significant, hypertension increased across each quartile, whereas calories consumed per day decreased across each quartile. Each lipid variable increased significantly in crude analyses across increasing quartiles of non-hdl cholesterol, except for HDL cholesterol, which decreased. The Spearman correlation between LDL and non-hdl cholesterol was 0.82 (p 0.01). The Spearman correlation between total and non-hdl cholesterol was 0.95 (p 0.01) and between HDL and non-hdl cholesterol was 0.11 (p 0.01). Of those unmatched patients with LDL cholesterol 160 mg/dl, 90% also had non-hdl cholesterol 190 mg/dl. Of those unmatched patients with LDL cholesterol 160 mg/dl, 80% also had non-hdl cholesterol 190 mg/dl. The area under the receiver-operating characteristic curve was larger for non-hdl cholesterol compared with LDL cholesterol (0.582 vs 0.537, respectively; 8.4% improvement; Figure 1). The OR of a first nonfatal myocardial infarction in those in increasing quartiles of LDL cholesterol and non-hdl cholesterol as derived from age- and gender-adjusted mod-

4 1132 The American Journal of Cardiology ( Figure 1. Receiver-operating characteristic curve analysis of LDL cholesterol and non-hdl cholesterol for all 600 patients. The receiver-operating characteristic curve for the maximal values of LDL cholesterol and non-hdl cholesterol for a first nonfatal myocardial infarction is shown. The true-positive fraction (sensitivity) is plotted against the false-positive fraction (1 specificity) to quantify the diagnostic accuracy of each lipid parameter for a first nonfatal myocardial infarction. els was compared between matched and unmatched subjects. Odds ratios were calculated in matched subjects for non-hdl cholesterol (1.52, 1.80, and 2.04) and LDL cholesterol (1.16, 0.76, and 1.39). Odds ratios were also calculated in unmatched subjects for non-hdl cholesterol (1.58, 1.98, and 2.27) and LDL cholesterol (1.06, 0.80, and 1.38). Because the differences between crude matched and unmatched ORs were minimal, with no change to the overall interpretation of the ORs, matching was disregarded in this analysis. 21 The ORs of a first nonfatal myocardial infarction in subjects with all lipid parameters are listed in Table 3. Going from age- and gender-adjusted to multivariateadjusted models did not result in substantial changes to the ORs for the lipid parameters. In the multivariate model, the ORs of a first nonfatal myocardial infarction were statistically significant in each quartile compared with the first quartile for non-hdl cholesterol but not LDL cholesterol. The trend across quartiles in the multivariate model demonstrated a statistically significant increase for non-hdl cholesterol (p trend 0.01) but not LDL cholesterol (p trend 0.16). The addition of HDL cholesterol into the multivariate model for non-hdl cholesterol attenuated the ORs for non-hdl cholesterol (p trend 0.06), whereas the addition of HDL cholesterol to the multivariate model for LDL cholesterol resulted in greater ORs (p trend 0.03). C statistics for the multivariate models, including HDL cholesterol of non-hdl cholesterol and LDL cholesterol, were 0.78 and 0.78, respectively. Discussion In this case-control study, we found increasing levels of LDL cholesterol and non-hdl cholesterol to be significantly associated with a greater risk for a first nonfatal myocardial infarction. On the basis of the ORs for first nonfatal myocardial infarction, non-hdl cholesterol was at least as strong of a multivariate predictor for first nonfatal myocardial infarction as LDL cholesterol. The C statistic, 1 measurement of a model s predictability, was nearly equivalent between LDL cholesterol and non-hdl cholesterol multivariate models, including HDL cholesterol. These data from the Boston Area Health Study

5 Preventive Cardiology/Non-HDL Cholesterol and First Nonfatal Myocardial Infarction 1133 Table 3 Odds ratios and 95% confidence intervals of a first nonfatal myocardial infarction by lipid quartiles Variable Quartiles of Each Lipid Parameter p Value, Trend LDL cholesterol (mg/dl) Age- and gender-adjusted model 1.00 Referent 1.06 ( ) 0.80 ( ) 1.38 ( ) 0.21 Multivariate-adjusted model* 1.00 Referent 1.10 ( ) 0.87 ( ) 1.45 ( ) 0.16 Multivariate-adjusted model with HDL cholesterol 1.00 Referent 1.11 ( ) 0.98 ( ) 1.81 ( ) 0.03 Non-HDL Cholesterol (mg/dl) Age- and gender-adjusted model 1.00 Referent 1.58 ( ) 1.98 ( ) 2.27 ( ) 0.01 Multivariate-adjusted model* 1.00 Referent 1.83 ( ) 2.07 ( ) 2.33 ( ) 0.01 Multivariate-adjusted model with HDL cholesterol 1.00 Referent 1.57 ( ) 1.81 ( ) 1.77 ( ) 0.06 * Adjusted for gender, age, hypertension, body mass index ( 25, 25 to 30, and 30 kg/m 2 ), history of diabetes mellitus, family history of myocardial infarction, smoking (never, former, 1 pack/day, 1 to 2 packs/day, 2 packs/day), physical activity, type A personality, and alcohol consumption (nondrinker, 1 drink/day, 1 to 3 drinks/day, 3 drinks/day). therefore suggest that non-hdl cholesterol appears to predict a first nonfatal myocardial infarction at least as well as LDL cholesterol. One reason that non-hdl cholesterol may be at least as good as LDL cholesterol at predicting cardiovascular outcomes is that non-hdl cholesterol includes LDL cholesterol and triglyceride-rich lipoproteins. It is well established that LDL cholesterol is a significant risk factor for coronary heart disease, 1 3 along with other lipid parameters, such as triglycerides 14,22,23 and triglyceride-rich lipoproteins Non-HDL cholesterol has previously been shown to be significantly associated with the risk for cardiovascular disease, 5 13 but few epidemiologic studies have directly compared non-hdl cholesterol and LDL cholesterol for predicting cardiovascular disease. In a study of patients who underwent coronary procedures, after adjusting for multiple cardiovascular risk factors, non-hdl cholesterol, but not LDL cholesterol, was found to be a significant independent predictor of subsequent nonfatal myocardial infarction and angina pectoris. 6 When compared with LDL cholesterol, non-hdl cholesterol has also been found to be more predictive of cardiovascular disease in patients with diabetes mellitus. 11,12 In a primary prevention setting, non-hdl cholesterol was shown to be a better predictor than LDL cholesterol for cardiovascular mortality. 8 None of these previous studies controlled for HDL cholesterol in their models comparing non-hdl cholesterol with LDL cholesterol. In postmenopausal women without known coronary heart disease, non-hdl cholesterol and LDL cholesterol have been found to be significantly associated with coronary heart disease. 13 HDL cholesterol was found to be the primary contributor in a prediction model including LDL cholesterol as well as further improve a prediction model, including non- HDL cholesterol. In our study, when controlled for HDL cholesterol, the trend across quartiles became nonsignificant for non-hdl cholesterol and significant for LDL cholesterol. This likely reflects the inverse relation between triglycerides and HDL cholesterol, whereas it shows the direct relation between LDL cholesterol and HDL cholesterol. One should consider several limitations when assessing results of this study. First, only myocardial infarction survivors were included in this study. The selection of survivors allowed more detailed information on lifestyle variables to be collected as well as transient alterations in lipoproteins to normalize before a fasting venous blood sample was obtained. By only selecting survivors, we likely underestimated the impact of all lipid parameters equally for a first nonfatal myocardial infarction. Second, we measured lipid parameters approximately 8 weeks after myocardial infarction, because previous studies have shown that a myocardial infarction may acutely affect lipid metabolism. During this post-hospitalization period, dietary changes, exercise, and pharmacologic treatment may have altered lipoprotein levels. However, statins and other lipid-lowering medications were not widely available or used in this study, reflecting treatment patterns in the early 1980s. We would expect any modification of lipids secondary to changes in the posthospitalization period to affect LDL cholesterol and non- HDL cholesterol similarly. In addition, we would expect any effect from these changes to bias the ORs for LDL cholesterol and non-hdl cholesterol toward the null, thereby making our estimates conservative. The Boston Area Health Study was primarily composed of white male participants. However, we think that our results remain potentially generalizable to minorities and women, warranting confirmation in other studies. This study shows that non-hdl cholesterol and LDL cholesterol seem to predict first nonfatal myocardial infarction to a similar extent. Because non-hdl cholesterol does not require a fasting sample for measurement, it may represent an alternative strategy by which to screen for lipid abnormalities.

6 1134 The American Journal of Cardiology ( Acknowledgment: We would like to thank all the subjects and the 6 Boston area hospitals that participated in this study. 1. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62: Jacobs DR Jr, Mebane IL, Bangdiwala SI, Criqui MH, Tyroler HA. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics prevalence study. Am J Epidemiol 1990;131: NCEP Expert Panel. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285: Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low density lipoprotein cholesterol in plasma without use of the preparative ultracentrifuge. Clin Chem 1972;18: Pedersen TJ, Olsson AG, Faergeman O, Kjekshus J, Wedel H, Berg K, Wilhelmsen L, Haghfelt T, Thorgeirsson G, Pyorala K, et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97: Bittner V, Hardison R, Kelsey SF, Weiner BH, Jacobs AK, Sopko G, Bypass Angioplasty Revascularization Investigation. Non-high-density lipoprotein cholesterol levels predict five-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI). Circulation 2002;106: Frost PH, Davis BR, Burlando AJ, Curb JD, Guthrie GP, Isaachsohn JL, Wassertheil-Smoller S, Wilson AC, Stamler J. Serum lipids and incidence of coronary heart disease. Findings from the systolic hypertension in the elderly program (SHEP). Circulation 1996;94: Cui Y, Blumenthal RS, Flaws JA, Whiteman MK, Langenberg P, Bachorik PS, Bush TL. Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality. Arch Intern Med 2001;161: Nishizawa Y, Shoji T, Kakiya R, Tsujimoto Y, Tabata T, Ishimura E, Nakatani T, Miki T, Inaba M. Non-high-density lipoprotein cholesterol (non-hdl-c) as a predictor of cardiovascular mortality in patients with end-stage renal disease. Kidney Int 2003;63:S117 S Lehto S, Ronnemaa T, Haffner SM, Pyoralla K, Kallio V, Laakso M. Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM. Diabetes 1997;46: Lu W, Resnick HE, Jablonski KA, Jones KL, Jain AK, Howard WJ, Robbins DC, Howard BV. Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes. Diabet Care 2003;26: Jiang R, Schulze MB, Li T, Rifai N, Stampfer MJ, Rimm EB, Hu FB. Non-HDL cholesterol and apolipoprotein B predict cardiovascular disease events among men with type 2 diabetes. Diabet Care 2004; 27: Shai I, Rimm EB, Hankinson SE, Curhan G, Manson JE, Rifai N, Sampfer MJ, Ma J. Multivariate assessment of lipid parameters as predictors of coronary heart disease among postmenopausal women. Circulation 2004;110: Gaziano JM, Hennekens CH, O Donnell CJ, Breslow JL, Buring JE. Fasting triglycerides, high-density lipoprotein, and risk of myocardial infarction. Circulation 1997;96: Sesso HD, Gaziano JM, Buring JE, Hennekens CH. Coffee and tea intake and the risk of myocardial infarction. Am J Epidemiol 1999; 149: Haynes SG, Levin S, Scotch N, Feinleib M, Kannel WB. The relationship of psychosocial factors to coronary heart disease in the Framingham Study, I: methods and risk factors. Am J Epidemiol 1978; 107: Giovannucci E, Colditz G, Stampfer MJ, Rimm EB, Litin L, Sampson L, Willett WC. The assessment of alcohol consumption by a single self administered questionnaire. Am J Epidemiol 1991;133: Lipid Research Clinics Program. Manual of Operations. Vol. 1. Lipid and Lipoprotein Analysis (DHEW Publication No ). Bethesda, Maryland: National Institutes of Health, National Heart, Lung, and Blood Institute, 1975: Lipid Research Clinics Program. Lipid Research Clinics Population Studies Data Book, Vol. 1. The Prevalence Study (NIH Publication No ). Bethesda, Maryland: National Institutes of Health, 1980: Kleinbaum DG, Kupper LL, Muller KE, Nizam A. Applied Regression Analysis and Other Multivariable Methods. Pacific Grove, California: Brooks/Cole, Schlesselman JJ. Case-Control Studies. New York: Oxford University Press, Castelli WP. Epidemiology of triglycerides a view from Framingham. Am J Cardiol 1992;70(suppl):H3 H Assmann G, Schulte H, von Eckardstein A. Hypertriglyceridemia and elevated levels of lipoprotein (a) are risk factors for major coronary events in middle-aged men. Am J Cardiol 1996;77: Simons LA, Dwyer T, Simons J, Berstein L, Mock P, Poonia S, Balasubramaniam S, Baron D, Branson J, Morgan J. Chylomicrons and chylomicron remnants in coronary-artery disease a case-control study. Atherosclerosis 1987;65: Hodis HN, Mack WJ, Azen SP, Alaupovic P, Pogoda JM, LaBree L, Hemphill LC, Kramsch DM, Blankenhorn DH. Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/moderate and severe lesion progression as assessed by quanitative coronary angiography in a controlled trial of lovastatin. Circulation 1994;90: Rapp JH, Lespine A, Hamilton RL, Colyvas N, Chaumeton AH, Tweedie-Hardman J, Kotite L, Kunitake ST, Havel RJ, Kane JP. Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb Vasc Biol 1994;14: Hodis HN, Mack WJ. Triglyceride-rich lipoproteins and progression of atherosclerosis. Eur Heart J 1998;19:A40 A44.