Hyperlipidemias: Acampa M

Puccetti L, Acampa M, Auteri A. · Department of Clinical Medicine and Immunological Sciences, Section of Internal Medicine, University of Siena, Siena, Italy. · Recent Pat Cardiovasc Drug Discov. · Pubmed #18221122 No free full text.

Abstract: Cardiovascular disease has become the global leading cause of death worldwide, representing the most frequent cause of morbidity and mortality in the developed world. Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Meta-analyses from several primary and secondary intervention studies have clearly shown that cholesterol-lowering medication, significantly reduces cardiovascular events, mortality, and morbidity, but considerable interindividual variation exists in response to statin therapy. Pharmacogenomics can provide important insights into statins therapy through elucidation of the genetic (or genomic) contribution to variable response for these drugs. The search for genetic polymorphisms may enable us to identify novel determinants of drug responsiveness by means of the study of three candidate genes groups: (1) genes encoding proteins involved in metabolism or drug transport, or both, that influence drug pharmacokinetics; (2) genes encoding proteins involved in mechanism of action and/or metabolic pathways on which drugs operate (that influence pharmacodynamics); (3) genes encoding proteins involved in the underlying disease condition or intermediate phenotype. This review briefly summarizes the recent pharmacogenomic and pharmacogenetic patents and the potential contributions of genetic variations in candidate genes related to lipid and lipoprotein metabolism and statins efficacy.

Puccetti L, Bruni F, Pasqui AL, Pastorelli M, Ciani F, Palazzuoli A, Acampa M, Auteri A. · Department of Clinical Medicine and Immunology, Internal Medicine Division, Centre for Atherosclerosis Research, University of Siena, Siena, Italy. · Eur J Clin Invest. · Pubmed #18173546 No free full text.

Abstract: BACKGROUND: Recent data indicate that statins could offer coronary artery disease (CAD) benefit even by mechanisms beyond lipid lowering. Genetic influence has been shown for some antithrombotic actions of statins via oxidized-low-density lipoprotein cholesterol (ox-LDL) receptors and nitric oxide synthase (NOS) activity modulation. The present study was designed to evaluate the influence of ox-LDL lectin-like receptor-1 (LOX-1) and NOS polymorphisms in the incidence of cardiovascular events in pure hypercholesterolaemic subjects during statin treatment. MATERIALS AND METHODS: A prospective 4-year study involving 1039 event-free subjects (643 males, 396 females) treated with atorvastatin (10-40 mg day(-1)) to reach the appropriate Adult Treatment Panel-III LDL target of 3.36 mmol L(-1). Enrolled subjects were evaluated every 6 months or at a clinical event. LOX-1 3'UTR/T-C and NOS G894T polymorphisms were detected by allelic discrimination assays (polymerase chain reaction), lipid profile by enzymatic-colorimetric method, ox-LDL by enzyme linked immunosorbent assay, platelet activation by P-selectin (P-sel) expression (FACScan), NOS activity (by intracellular citrullin recovery) and homocysteine (high performance liquid chromatography), C-reactive protein (CRP) by sensitive nephelometric technique. RESULTS: LOX-1 3'UTR/T showed the strongest association with events in the whole cohort with respect to each other variable including LDL reduction and NOS G894T (OR 4.90, 95% CI 3.19-6.98, P < 0.00001). Smoking influenced events in LDL-targeted subjects (P < 0.0001). Ox-LDL and P-sel were better indicators than LDL or other variables according to 3'UTR/C genotype regardless of the magnitude of LDL reduction (OR 4.21, 95% CI 2.29-6.70 P < 0.0001). CONCLUSIONS: LOX-1 polymorphisms could influence statin effectiveness in CAD prevention by induction of sensitivity to antithrombotic mechanisms such as antiplatelet activity.