High-Density Lipoproteins (HDL) Functionality in Degenerative Cardiac Disease - 
\nNovel Cardioprotective Roles of HDL and Strategies to Target HDL Dysfunction

Background: The recent failure of drugs targeted to high-density lipoprotein (HDL) cholesterol levels has led to the conclusion that HDL function rather than HDL quantity is the key player in cardiovascular pathologies.The augmentation of functional HDL through administration of reconstituted HDL (rHDL) or apolipoprotein A-I (apoA-I) seems a promising strategy to in coronary artery disease (CAD) and aortic valve stenosis (AVS).However, clinically applicable biomarkers reflecting functionality of HDL are lacking.In addition, little is known on the mechanisms governing the cardioprotective effects of HDL-based approaches as well as rHDL and apoA-I possible conversion into dysfunctional molecules.Finally, data regarding potential secondary effects of such therapy are sparse.Thus, the present project explored the value of cholesterol esterification as biomarker for cardioprotective HDL effects, assessed whether rHDL exerts beneficial effects in endothelial repair, and investigated potential side-effects of HDL-based therapies as well as HDL-preserving strategies in AVS. Method and results:We explored the value of cholesterol esterification during maturation of HDL particles, as a biomarker for cardioprotective HDL effects in 267 patients with stable CAD.In addition, the effect of rHDL on vascular repair mechanism was assessed in 33 patients with a recent acute coronary syndrome (ACS), and the contribution of different plasma proteases to apoA-I degradation was compared in patients with AVS as well as in a rabbit model of AVS.Using the same population and experimental model, we also assessed possible impact of apoA-I administration on haemorrhagic disorders in patients with AVS.Cholesterol esterification was found to be a strong and independent predictor of atherosclerotic burden in patients with CAD.Administration of rHDL prevented endothelial progenitor cells decline in patients with a recent ACS.While apoA-I administration did not negatively affect haemorrhagic disorders in AVS, it was found that the cysteine protease cathepsin S is the key protease responsible for 70% of apoA-I degradation in humans. Conclusion:The present data indicate that cholesterol esterification is a useful biomarker mirroring severity of atherosclerotic disease.Thus, targeting cholesterol esterification might be a promising therapeutic strategy to reduce cardiovascular v risk.Our data further indicate that an improvement of cardiovascular repair mechanisms following myocardial injury might be amongst the mechanisms by which exogenous HDL exerts its cardioprotective actions.The latter is also a particularly promising strategy in the treatment of AVS and its efficacy could be further enhanced by inhibition of the cysteine protease cathepsin S.

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