Dysfunction of high-density lipoprotein and its apolipoproteins: new mechanisms underlying cardiometabolic risk in the population at large.

We review the metabolic and residual cardiovascular risk existing in populations with prevailing metabolic syndrome (MetS) or in people prone to impaired glucose tolerance. Evidence is presented that enhanced systemic inflammation, or oxidative stress associated with elevated plasma triglyceride-rich lipoproteins and their remnants, and excess oxidized lipoprotein(a) phospholipids underlie this risk. The adverse risk profile is augmented by loss of the anti-inflammatory, anti-oxidative and atheroprotective properties of high-density lipoprotein and its apolipoproteins (apo). Common clinical manifestations are atherogenic dyslipidemia and hypertriglyceridemia with elevated apoB or hypertriglyceridemic waist phenotype. These manifestations are often accompanied by such inflammatory mediators/markers as elevated serum apoE, C-reactive protein, complement C3, and uric acid levels. Compared with men, peri- and postmenopausal women are more commonly and more strongly affected by multiple inflammation mediators. The long-term effects of cigarette smoking are not adverse in such women, but instead, serve as protection against obesity and other health issues. ApoA-I may become dysfunctional in either gender, even in the absence of MetS and diabetes. The public health implications of this cardiometabolic risk are huge. Much research is needed on this topic to further clarify the impact of apoA-I dysfunction, to elucidate the underlying genetics and mechanisms, and to determine preventive measures and optimal management. Avoiding (abdominal) obesity via lifestyle modifications, including dietary changes, improving physical inactivity, and limiting smoking and alcohol consumption, are mainstay measures in the prevention and management of pro-inflammatory states and HDL dysfunction. Omega-3 fatty acids are a good adjunct to lower plasma triglycerides. When further treatment is needed, extended-release niacin or fibrates, with or without statins, are the best options.