HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the lipoprotein investigators collaborative

High-density lipoprotein (HDL) is highly heterogeneous and the link of its subclasses to prognosis remains controversial. We aimed to rigorously examine the associations of HDL subclasses with prognosis in secondary prevention. We collaboratively analysed data from two, complementary prospective cohorts: the TRIUMPH study of 2465 acute myocardial infarction patients, and the IHCS study of 2414 patients who underwent coronary angiography. All patients had baseline HDL subclassification by vertical-spin density gradient ultracentrifugation. Given non-linearity, we stratified by tertiles of HDL-C and its two major subclasses (HDL2-C, HDL3-C), then compared multivariable-adjusted hazard ratios for mortality and mortality/myocardial infarction. Patients were middle-aged to elderly (TRIUMPH: 58.2 +/- 12.2 years; IHCS: 62.6 +/- 12.6 years), and the majority were men (TRIUMPH: 68.0%; IHCS: 65.5%). IHCS had lower mean HDL-C levels (34.6 +/- 10.1 mg/dL) compared with TRIUMPH (40 +/- 10.6 mg/dL). HDL3-C accounted for > 3/4 of HDL-C (mean HDL3-C/HDL-C 0.78 +/- 0.05 in both cohorts). During 2 years of follow-up in TRIUMPH, 226 (9.2%) deaths occurred, while death/myocardial infarction occurred in 401 (16.6%) IHCS patients over 5 years. No independent associations with outcomes were observed for HDL-C or HDL2-C. In contrast, the lowest tertile of HDL3-C was independently associated with > 50% higher risk in each cohort (TRIUMPH: with middle tertile as reference, fully adjusted HR for mortality of HDL3-C, 1.57; 95% CI, 1.13-2.18; IHCS: fully adjusted HR for mortality/myocardial infarction, 1.55; 95% CI, 1.20-2.00). In secondary prevention, increased risk for long-term hard clinical events is associated with low HDL3-C, but not HDL2-C or HDL-C, highlighting the potential value of subclassifying HDL-C.