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

Abstract

on behalf of the Heart Protection Study Collaborative Group 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 (Ͼ5000 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. Clinical Trial Registration-URL: http://www.isrctn.org/. Unique identifier: ISRCTN48489393. arge observational studies indicate strong positive associations between low-density lipoprotein (LDL) particles, which carry cholesterol, and the risk of coronary heart disease (CHD). 1,2 Randomized trials have demonstrated that lowering LDL cholesterol (LDL-C) with statins reduces the risk of CHD death, nonfatal myocardial infarction (MI), ischemic stroke, and the need for revascularization procedures, with less benefit apparent on deaths resulting from other cardiac disease (including sudden death, arrhythmia, and heart failure). [3][4][5] Observational studies, however, have typically reported weaker associations of LDL-C (or related measures) with ischemic stroke than with CHD, 1,2 which is discordant with the findings of randomized tri...

LDL and HDL transfer rates across peripheral microvascular endothelium agree with those predicted for passive ultrafiltration in humans

“…in two population studies, one of 27,673 subjects ( 11 ) and another of 20,021 subjects ( 40 ). HDL size by NMR has been shown to agree with those by gradient gel electrophoresis (GGE) ( 10,44 ) and compositional analysis ( 41 ).…”

“…Our primary measure of HDL particle number was apo AI concentration. As apo AI is present in all HDLs and is unique to this lipoprotein class in fasted healthy humans, its concentration in plasma refl ects HDL particle number ( 10,40 ). As the number of apo AI molecules per particle varies, most containing three or four ( 41 ), and the relative proportions of different particles varies between subjects, the correlation between plasma apo AI concentration and HDL particle number in populations is nonlinear ( 42 ).…”

Associations between intensive diabetes therapy and NMR-determined lipoprotein subclass profiles in type 1 diabetes

“…In the general population, lipoprotein particle concentrations and sizes are established predictors of future cardiovascular events, and are at least comparable in this regard to the cholesterol content of lipoproteins ( 18,19 ). Smaller LDL and HDL particle diameters, low particle numbers of large HDL, and high particle numbers of large VLDL, small HDL, total LDL, and small LDL have all been associated with CVD risk in large prospective studies in the general population ( 18,41,42 ).…”

“…Circulating levels of these subclasses can predict CVD events (17)(18)(19). LDL particle concentration has demonstrated comparable, but not greater, CVD predictive power to LDL-C in some large studies ( 20,21 ), but these studies do not involve people with type 1 diabetes.…”

Dyslipidemia in diabetic nephropathy

“…In the UKPDS, 50 % of patients with type 2 diabetes had high serum levels of TG [6]. The Heart Protection Study (HPS) showed that the prevalence of low HDL-C was higher in diabetic individuals (21 % in males and 25 % in females) compared to non-diabetic individuals (12 % in males and 10 % in females) [8].…”