Eur J Clin Invest 2010; 40 (6): 483–489

Background  We recently reported high high‐density lipoprotein (HDL) cholesterol as a predictor of recurrent risk in a subgroup of postinfarction patients defined by hypercholesterolemia and high C‐reactive protein (CRP) levels. We investigated whether a similar high‐risk subgroup might exist for incident cardiovascular disease.

Material and Methods  A graphical exploratory data analysis tool was used to identify high‐risk subgroups in a male population‐based cohort (n = 3405) from the prevention of renal and vascular end‐stage disease study by generating 3‐dimensional mappings of risk over the HDL‐cholesterol/CRP domain with subsequent use of Kaplan–Meier analysis to verify high‐risk. Within‐subgroup risk was assessed using Cox proportional hazards regression and Kaplan–Meier analysis.

Results  Mappings revealed two high‐risk subgroups: a low HDL‐cholesterol/high CRP subgroup and a high HDL‐cholesterol/high CRP subgroup. The low HDL‐cholesterol subgroup demonstrated a pattern of metabolic syndrome dyslipidemia contrasted with a predominantly unremarkable biomarker pattern for the high HDL‐cholesterol subgroup. However, in the high HDL‐cholesterol subgroup, CRP levels were higher than the low HDL‐cholesterol subgroup; and within the high HDL‐cholesterol subgroup, CRP predicted risk. Moreover, in the high HDL‐cholesterol subgroup, risk was associated with lower triglyceride levels in conjunction with presumptively larger HDL particles.

Conclusions  High HDL‐cholesterol and high CRP levels define a subgroup of men at high‐risk for incident cardiovascular disease. High HDL cholesterol‐associated risk likely relates to impaired HDL particle remodelling in the setting of inflammation. This approach may facilitate identification of additional inflammation‐related mechanisms underlying high HDL cholesterol‐associated risk; and potentially influence management of such patients.