Increasing levels of circulating HDL (“good cholesterol”) has been targeted as an important therapeutic goal in reducing the risk of patients with coronary disease. HDL has been shown to have a variety of potentially beneficial effects including cholesterol efflux from foam cells, promotion of endothelial repair mechanisms and stimulation of the enzyme eNOS to increase nitric oxide (NO) production. Unfortunately, though a variety of therapies have been shown to be able to increase HDL levels, none have demonstrated significant clinical benefit with the CETP inhibitor torcetrapib even demonstrating harm, although off-target effects on blood pressure may have contributed to this. The reasons for this profound lack of efficacy remain obscure, but in this mechanistic study the authors examine this question in greater detail.
Using HDL cholesterol from patients with stable coronary artery disease (CAD), patients with a recent acute coronary syndrome and matched healthy controls, the effects of HDL were compared in a series of lab-based experiments. In contrast to HDL from healthy subjects, HDL from patients with stable CAD or an acute coronary syndrome (HDLCAD) was found not to have endothelial anti-inflammatory effects and did not stimulate endothelial repair, failing to induce endothelial NO production. The HDLCAD particles were found to have gained the ability to activate a specific endothelial receptor known as LOX-1 which in fact inhibited NO production and the other beneficial effects that were seen in healthy controls. In fact raising levels of HDLCAD was found to be potentially detrimental to overall risk profile, actually favouring the development and progression of atherosclerotic cardiovascular disease and this finding may go some way towards explaining the negative results in clinical trials.
In patients with known coronary artery disease, HDL particles failed to show beneficial effects on endothelial function in contrast from that in healthy volunteers. These findings suggest that the biological function of HDL – and not simply its plasma levels – should be assessed in future studies of HDL raising agents.
- Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, Chroni A, Yonekawa K, Stein S, Schaefer N, Mueller M, Akhmedov A, Daniil G, Manes C, Templin C, Wyss C, Maier W, Tanner FC, Matter CM, Corti R, Furlong C, Lusis AJ, von Eckardstein A, Fogelman AM, Lüscher TF and Landmesser U. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest. 2011 Jul 1;121(7):2693-708.