Dyslipidemia and cardiovascular diseases (2009)

Introduction Despite the progress made in the management of hypercholesterolemia with statins, events are reduced by only 30% [1••]. Protecting the other 70% requires, additionally, interventions including adjunctive use of anti-inflammatory or immunologic treatments. The results of the statin trials seriously underestimate the ultimate potential of cholesterol-lowering therapy. Experts suggest continuing and more extensive use of lipid-improving regimens and intervention at an earlier stage [1••]. HDL therapy HDL, which is a major target for therapy in CAD, is highly heterogeneous, has a variety of functions that may contribute to its cardiovascular protective effects, including promotion of reverse cholesterol transport (RCT), anti-inflammatory and nitric oxide-promoting effects [2]. Under the inflammatory pressure, however, HDL can become dysfunctional [3]. Normal HDL has high levels of antioxidants and active antioxidant proteins/enzymes and is anti-inflammatory (aiHDL). Proinflammatory HDL (piHDL) has high levels of prooxidant molecules, which interfere with HDL removal of cellular toxic waste and HDL delivery of this metabolic waste for elimination. HDL from individuals with coronary artery disease (CAD) was not able to prevent LDL lipid oxidation [4] and HDL from obese individuals was unable to maintain vascular relaxation [5]. In renal patients, the survival rate for those with aiHDL was four-fold than for those with piHDL [6•]. Women with systemic lupus erythematosus (SLE) have increased risk of coronary artery disease (CAD). McMahon et al. [7] showed that SLE patients had high levels of piHDL, which correlated with the levels of oxidized LDL. SLE patients with CAD had higher piHDL scores than those without CAD. Patients with Crohn's disease had piHDL, which improved upon standard therapy [8]. Among other factors, the failure of torcetrapib has fuelled speculation that in addition to raising HDL-cholesterol, the quality and function of HDL needs to be improved [9]. Statins were shown to improve HDL quality and function in patients with CAD [10]. Patients with rheumatoid arthritis (RA) have increased risk of myocardial infarction. Charles-Schoeman et al. [11•] showed that in a group of patients with active RA, unlike HDL from healthy individuals, HDL from patients with RA was proinflammatory. This piHDL was rendered anti-inflammatory by high-dose atorvastatin [11•]. Novel compounds and approaches Several compounds are being tested in clinical trials including an extended-release niacin, which does not produce flushing and increases HDL–apoA1 and decreases triglycerides and VLDL/LDL [12]; a PPAR-α agonist LY518674, affecting the production and clearance of apoA-I and HDL [13]; the apoA-I mimetic peptide 4F, which was shown to be safe and well tolerated and improved the HDL anti-inflammatory index [4]; and a microsomal triglyceride transfer protein inhibitor (AEGR-733) [14]. In addition, it is recommended [15,16] that efforts be directed toward promotion of RCT and its robust measures. As obesity and metabolic syndrome have become a serious global health issue [17], therapeutic strategies are needed that directly target adipose tissue to optimally reduce cardiometabolic risk. Conclusion Certain lipoproteins and the renin–angiotensin–aldosterone system are important in the pathogenesis of atherosclerotic cardiovascular disease. Understanding how risk factors such as high blood pressure, dysregulated blood lipids and diabetes contribute to atherosclerotic disease, as well as elucidation of the molecular pathogenesis of atherosclerotic plaques, are leading to new targets for therapy [18••].