Break the Fast: “Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study.” Journal Club 9/10/08

Background Coronary Heart Disease is now the major cause of death worldwide Brunzell JD, et al. JACC 2008; 51: 1513

Clinically Important Lipoprotein Parameters Parameters should be easily measured, have available treatment strategies and strategies should reduce cardiovascular events LDL cholesterol : major predictor of CVD and lowering LDL lowers CVD events but limitations: LDL cholesterol is estimated (Friedewald equation) which progressively underestimates LDL cholesterol as TG levels , not as predictive in the elderly, individual variability, influenced by disease states, AND even with adequate lowering, significant residual risk remains; requires fasting HDL : strong inverse predictors of CVD events; non- fasting Non-HDL cholesterol : ATP III guidelines suggest using this as secondary goal after LDL in patients with hypertriglyceridemia; non-fasting

Some New Parameters LDL particle number: shown to be better predictor of risk and can be calculated using nuclear magnetic resonance (NMR) but not widely available and currently $$$ ApoB-100: found in atherogenic VLDL, IDL, and LDL with each particle containing single apoB molecule; non-fasting sample; found to be a better predictor of CVD risk than LDL cholesterol, especially on-treatment one as statins lower non-HDL cholesterol more than they lower apoB

An LDL particle A low-density lipoprotein (LDL) particle contains a core of about 1500 cholesterol molecules bonded to long-chain fatty acids that is surrounded by a lipid monolayer. A single molecule of a 500,000-dalton protein (an apolipoprotein) organizes the particle and mediates the specific binding of LDL to its receptor on other cells. Of note, there is a 1:1 relationship between protein and the LDL particle. Alberts, et. al. Molecular Biology of the Cell, 4 th edition, 2002

Properties of Plasma Lipoproteins LipoproteinApoproteins ChylomicronB-100, B-48, C, E VLDL (very low density)B-100, C, E IDL (intermediate density)B-100, E LDL (low density)B-100 Lipoprotein (a)B-100 HDL (high density)A Adapted from Berg, et. al. Biochemistry, 5 th ed. 2002: 727.

Consensus Statement of the ADA and ACC “Because apoB appears to be a more sensitive index of residual CVD risk when LDL cholesterol or non-HDL cholesterol are < 130 mg/dl or < 160 mg/dl, respectively, measurement of apoB, using a standardized assay, is warranted in patients with CMR on pharmacologic treatment. In particular, apoB levels should be used to guide adjustments of therapy.” Brunzell JD, et al. JACC 2008; 51: 1513

Study Outline Hypothesis: lipoproteins are better markers than lipids for risk of coronary heart disease Study Design: case-control Setting: hospital admissions from 262 centers in 52 countries Participants: –CASES: 12, 461 individuals admitted with a first acute MI screened within 24 hours of initial symptoms –CONTROLS: 14, 637 age-matched and sex-matched Hospital-based (58%): admitted to same hospital as matched cases without known CAD Community based (36%): attendants or relatives of patients from a non-cardiac ward or unrelated attendant of a cardiac patient 3% from WHO MONICA study, 3% undocumented source

Study Outline Continued Data Collection: non-fasting blood samples obtained and concentrations of TC, HDL cholesterol, ApoA1 and ApoB-100 measured Analytic Method: odds ratio and population- attributable risk, using ANOVA logistic regression

Study participants with myocardial infarction and controls by ethnic origin

Concentrations of Lipids and their Ratios in Cases and Controls

Figure 1: Risk of myocardial infarction for increasing decile medians (adjusted for age, sex, and region) of (A) lipids, lipoproteins, and apolipoproteins and (B) ratios of apolipoprotein B/apolipoprotein A1 and total cholesterol/HDL cholesterol Note the doubling scale on the y axis for both fi gures. ApoA1=apolipoprotein A1. ApoB=apolipoprotein B100.

TCHDLNon- HDL ApoA1ApoBTC / HDL ApoB / ApoA1 1 SD change 1.16 (1.13 – 1.19) 0.85 (0.83 – 0.88) 1.21 (1.17 – 1.24) 0.67 (0.65 – 0.70) 1.32 (1.28 – 1.36) 1.17 (1.13 – 1.20) 1.59 (1.52 – 1.64) Change in risk of MI (Odds ratios, 95% CI) with 1 SD change in parameter

Stratification by Age

A Look at Population Attributable Risk (PAR)

Conclusions ApoB/ApoA1 ratio was better risk marker of myocardial infarction than ratio of total cholesterol/HDL cholesterol This was seen in nearly all ethnic groups, both sexes and all age groups Depending on costs and added risk to expanding treatment, ApoB and ApoA1 may replace lipid measures especially in older age groups or in non- fasting patients These measures can be used in clinical practice for assessment of risk of vascular disease and to determine adequacy of cholesterol-lowering treatment

What It’ll Cost You – at JHH Lipid profile - $31.42 Apo B - $24.81 Apo A1 - $24.81

Strengths Large number of study patients Inclusion of many ethnic groups Large generalizability

Weaknesses Controls – concern for selection bias; no baseline characteristics table to determine effectiveness of matching Retrospective Cholesterol measurement in different labs Small percentage of Africans in this study

References Brunzell JD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008; 51: 1512 – 24. Berg, JM, et al. Biochemistry, 5 th edition, 2002: 727. Alberts, B et. al. Molecular Biology of the Cell, 4 th edition, McQueen, MJ, et. al. Lipids, lipoproteins and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancent 2008; 372: 224 – 232.