Characterization of the clinical importance of the anti-inflammatory activity of high density lipoproteins (HDL) – prognostic significance, association with atherosclerotic lesion composition and identification of essential functional determinants

Bakgrund: Based on recent results from genetic studies and pharmacological intervention trials a causal relationship between plasma high density lipoprotein (HDL) cholesterol and atherosclerotic cardiovascular disease is disputed. Therefore, the concept of cardiovascular disease (CVD) risk prediction has been shifting from measuring the static biomarker HDL cholesterol (HDL-C) towards determining functional properties of HDL particles.

HDL have potent anti-inflammatory functions, which could conceivably be etiologically tied to the pathogenesis of atherosclerosis, an inflammatory disease.

Målsättning: The main hypothesis of this proposal is that the anti-inflammatory function of HDL is prospectively associated with incident CVD events in the general population independent of HDL-C and therefore has the potential to serve as a novel CVD biomarker.

Arbetsplan: The project is structured into three subprojects. First, the prospective association of the baseline HDL anti-inflammatory function with incident CVD events will be determined in two large general population cohorts, one including middle-aged (PREVEND, mean age 59-years) another older participants (BIS, mean age 80-years). The second subproject investigates, whether the HDL anti-inflammatory function relates to histological features of actual atherosclerotic plaques, particularly with respect to an inflammatory lesion phenotype (Carotid Plaque Imaging Project).

Finally, using proteomics and lipidomics subproject 3 will comprehensively identify essential compositional constituents of HDL determining the anti-inflammatory function of the particle using a discovery-validation cohort set-up in subjects from PREVEND matched for several clinical variables, importantly including HDL-C.

Betydelse: We expect that the results of the proposed studies can establish the HDL anti-inflammatory function as a novel biomarker for CVD risk prediction. By understanding, which components of HDL are responsible for their anti-atherogenic function this project also conceivably contributes to the identification of potential new targets for future pharmacological intervention.