The joint effects of apolipoprotein B, apolipoprotein A1, LDL cholesterol, and HDL cholesterol on risk: 3510 cases of acute myocardial infarction and 9805 controls

Abstract

AimsPlasma levels of apolipoprotein B (apoB), the main surface protein on LDL particles, and LDL-C, the amount of cholesterol in those particles, are closely correlated and, considered separately, are positive risk factors. Plasma levels of apolipoprotein A1, the main surface protein on HDL particles, and HDL-C, the amount of cholesterol in those particles, are also closely correlated with each other and, considered separately, are negative risk factors. The interdependence of these four risk factors is unclear.Methods and resultsCase–control study among 3510 acute myocardial infarction patients (without prior vascular disease, diabetes, or statin use) in UK hospitals and 9805 controls. Relative risks (age, sex, smoking, and obesity-adjusted) were more strongly related to apoB than to LDL-C and, given apoB, more strongly negatively related to apoA1 than to HDL-C. The ratio apoB/apoA1 was uncorrelated with time since symptom onset in cases, was reproducible in samples collected a few years apart in controls (correlation 0.81), and encapsulated almost all the predictive power of these four measurements. Its effect was continuous, substantial throughout the UK normal range [relative risk, top vs. bottom decile of this ratio, 7.3 (95% CI 5.8–9.2)] and varied little with age. The ratio apoB/apoA1 was substantially more informative about risk (χ12 = 550) than were commonly used measures such as LDL-C/HDL-C, total/HDL cholesterol, non-HDL cholesterol, and total cholesterol (χ12 = 407, 334, 204, and 105, respectively). Given apoB and apoA1, the relationship with risk of LDL-C was reversed, and this reversal was strengthened by appropriate allowance for random measurement errors in two correlated variables. Given usual apoB, lower LDL-C (consistent with smaller LDL particles) was associated with higher risk (P < 0.0001). During the first 8 h after symptom onset HDL-C increased by about 10%, precluding reliable assessment of the joint relationship of apoA1 and pre-onset HDL-C with risk in such retrospective case–control studies.ConclusionApolipoprotein ratios are more informative about risk than lipid fractions are. This suggests that, among lipoprotein particles of a particular type (LDL or HDL), some smaller and larger subtypes differ in their effects on risk. Direct measurements of even more specific subtypes of lipoprotein particles may be even more informative about risk.

Lipids and Lipoproteins and Risk of Different Vascular Events in the MRC/BHF Heart Protection Study

“…2 This finding, however, differs from those of earlier large retrospective case-control studies in acute MI, which reported that apolipoproteins were superior predictors of MI than cholesterol fractions, 28,29 but this difference may be explained by distortions of HDL-C levels in the hours after an acute MI when apolipoproteins may be more robust measures. The HR for major occlusive coronary event per unit of non-HDL-C (1.22 per 0.34 mg/dL in the statin arm) in the present study was low compared with that found in the ERFC meta-analysis (1.56 per 0.29 mg/dL after correction for within-person variation).…”

Opening a New Lipid “Apo-thecary”: Incorporating Apolipoproteins as Potential Risk Factors and Treatment Targets to Reduce Cardiovascular Risk

“…Select epidemiologic and clinical studies have suggested that either Apo A-1 levels or the Apo B:A-1 ratio would be superior to traditional cholesterol values or ratios (eg, total cholesterol:HDL cholesterol) in predicting cardiovascular events. 8,11,24,25,30,31,35,45,48,[104][105][106]111,112 However, at this time, the potential benefits of introducing Apo A-1 to routine lipid/lipoprotein panels do not seem to outweigh their incremental costs. In the Emerging Risk Factors Collaboration, the largest pooled epidemiologic study to date, no advantage in risk prediction was found for Apo A-1 over HDL cholesterol.…”

“…[24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] In the 52-country INTERHEART study, the Apo B:A-1 ratio accounted for 54% of the population-attributable risk of acute myocardial infarction (MI). Apo B was also superior to LDL cholesterol and non-HDL cholesterol in predicting coronary heart disease (CHD) ( Table 1).…”

Feedback inhibition of apolipoprotein A-I synthesis by its propeptide in hepatocyte cell culture and in the cell-free system

“…The major protein associated with high density lipoproteins is apoA-I and the apoB/apoA-I ratio is superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infarction [47,48]. ApoA-I is synthesized in the liver as preproprotein.…”