Background: Low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol are established risk factors for vascular disease, but lipoprotein particle concentrations may be stronger determinants of risk.
Methods and results: Associations between vascular events and baseline concentrations of cholesterol fractions, apolipoproteins B and A(1), and lipoprotein particles assessed by nuclear magnetic resonance were considered in the Heart Protection Study randomized trial of simvastatin versus placebo (>5000 vascular events during 5.3 years of follow-up among 20 000 participants). Major occlusive coronary events were equally strongly associated with the cholesterol- and particle-based total LDL measures; adjusted hazard ratios per 1-SD-higher level were 1.25 (95% confidence interval [CI], 1.16-1.34) for LDL cholesterol, 1.22 (95% CI, 1.14-1.32) for non-HDL cholesterol, 1.23 (95% CI, 1.15-1.33) for apolipoprotein B, and 1.25 (95% CI, 1.16-1.35) for LDL particle number. Given the total LDL particle number, the distribution between small and large particles did not add predictive value. Associations of these different LDL-related measures were similar with arterial revascularization procedures but much weaker or nonexistent with ischemic stroke and other cardiac events (mainly heart failure). After adjustment for LDL particle number, the hazard ratios for major occlusive coronary event per 1-SD-higher level were 0.91 (95% CI, 0.86-0.96) for HDL cholesterol and 0.89 (95% CI, 0.85-0.93) for HDL particle number. Other cardiac events were inversely associated with total (hazard ratio, 0.84; 95% CI, 0.79-0.90) and small (0.82; 95% CI, 0.76-0.89) HDL particle number but only very weakly associated with HDL cholesterol (0.94; 95% CI, 0.88-1.00).
Conclusions: In a population at 2% average coronary event risk per year, cholesterol, apolipoprotein, and particle measures of LDL were strongly correlated and had similar predictive values for incident major occlusive vascular events. It is unclear whether the associations between HDL particle numbers and other cardiac events represent a causal or reverse-causal effect.