Statin-associated myopathy: from genetic predisposition to clinical management.

Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of individual statin molecules (e.g. lipophilicity, excretion pathways) and patients´ characteristics influence the likelihood of SAM development. This review summarizes current data as well as our own results.

Impact of variants within seven candidate genes on statin treatment efficacy.

Statins are the most commonly used drugs in patients with dyslipidemia. Among the patients, a significant inter-individual variability with supposed strong genetic background in statin treatment efficacy has been observed. Genome wide screenings detected variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes that are among the candidates potentially modifying response to statins. Ten variants (SNPs) within these genes (rs599838, rs646776, rs16996148, rs693, rs515135, rs4420638, rs12654264, rs6511720, rs6235, rs11206510) were analyzed in 895 (46 % men, average age 60.3+/-13.1 years) patients with dyslipidemia treated with equipotent doses of statins (~90 % on simvastatin or atorvastatin, doses 10 or 20 mg) and selected 672 normolipidemic controls (40 % men, average age 46.5 years). Lipid parameters were available prior to the treatment and after 12 weeks of therapy. Statin treatment resulted in a significant decrease of both total cholesterol (7.00+/-1.53-->5.15+/-1.17 mmol/l, P<0.0001) and triglycerides (2.03+/-1.01-->1.65+/-1.23 mmol/l, P<0.0005). Rs599838 variant was not detected in first analyzed 284 patients. After adjustment for multiple testing, there was no significant association between individual SNPs and statin treatment efficacy. Only the rs4420638 (APOE/C1/C4 gene cluster) G allele carriers seem to show more profitable change of HDL cholesterol (P=0.007 without and P=0.06 after adjustment). Results demonstrated that, although associated with plasma TC and LDL cholesterol per se, variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes do not modify therapeutic response to statins.

Omega-3 fatty acids and cardiovascular disease risk: do we understand the relationship?

There is a large body of evidence documenting the effects of long-chain polyunsaturated fatty acids with the first double bond at the third position from methyl-terminal (so called omega-3 fatty acids (FAs)) on different components of cardiovascular disease (CVD) risk. However, it may seem the more answers on the topic we learn, the more questions remain to be elucidated. There are three levels of evidence documenting the impact of fish omega-3 FAs on CVD risk. Epidemiological data have shown unequivocally the increased intake of fish is associated with lower CVD morbidity and mortality. Numerous experimental studies have shown (almost always) positive effects of omega-3 FAs on lipoprotein metabolism, coagulation and platelet function, endothelial function, arterial stiffness etc. Most importantly, there are a few prospective clinical endpoint trials (DART, JELIS, GISSI Prevenzione and GISSI-HF) that have examined the impact of omega-3 FAs supplementation on cardiovascular outcomes in different patient populations. Recent meta-analyses of these and other clinical studies have yielded somewhat conflicting results. In this review we will summarize current evidence of omega-3 FAs effects on cardiovascular risk focusing on new data from recent clinical trials as well as possible practical implications for clinical practice.

Lipoprotein(a) and its position among other risk factors of atherosclerosis.

Lipoprotein(a) [Lp(a)] comprises of an LDL particle and apolipoprotein(a) [apo(a)] and its elevated levels are considered a risk factor for atherosclerosis. The aim of our study was to find out whether elevated Lp(a) levels are associated with increased risk of atherosclerosis in patients with multiple other risk factors. We further tested the association of three polymorphisms of the apo(a) gene promoter with Lp(a) levels. No significant correlation was detected between Lp(a) levels and lipid and clinical parameters tested. The study demonstrated a significantly (p=0.0219) elevated Lp(a) level (mean 28+/-35 mg/dl, median 0.14) in patients with coronary heart disease (CHD). In a group with premature CHD the correlation was not significant anymore. There was a significant correlation between polymorphic loci of the promoter region of apo(a) gene and Lp(a) levels (+93C T, p=0.0166, STR, p<0.0001). Our study suggests that elevated Lp(a) level is an independent risk factor of CHD in carriers of other important CHD risk factors. Observed association of sequence variants of the promoter of apo(a) gene with Lp(a) levels is caused in part due to linkage to a restricted range of apo(a) gene length isoforms.