ABSTRACT
Self-perceived statin-associated muscle symptoms (SAMS) are prevalent, but only a minority is drug-dependent. Diagnostic biomarkers are not yet identified. The local statin exposure in skeletal muscle tissue may correlate to the adverse effects. We aimed to determine whether atorvastatin metabolites in blood reflect the corresponding metabolite levels in skeletal muscle, and whether genetic variants of statin transporters modulate this relationship. We also addressed atorvastatin metabolites as potential objective biomarkers of SAMS. Muscle symptoms were examined in patients with coronary disease and self-perceived SAMS during 7 weeks of double-blinded treatment with atorvastatin 40 mg/day and placebo in randomized order. A subset of 12 patients individually identified with more muscle symptoms on atorvastatin than placebo (confirmed SAMS) and 15 patients with no difference in muscle symptom intensity (non-SAMS) attended the present follow-up study. All received 7 weeks of treatment with atorvastatin 40 mg/day followed by 8 weeks without statins. Biopsies from the quadriceps muscle and blood plasma were collected after each treatment period. Strong correlations (rho > 0.7) between muscle and blood plasma concentrations were found for most atorvastatin metabolites. The impact of the SLCO1B1 c.521T>C (rs4149056) gene variant on atorvastatin's systemic pharmacokinetics was translated into muscle tissue. The SLCO2B1 c.395G>A (rs12422149) variant did not modulate the accumulation of atorvastatin metabolites in muscle tissue. Atorvastatin pharmacokinetics in patients with confirmed SAMS were not different from patients with non-SAMS. In conclusion, atorvastatin metabolite levels in skeletal muscle and plasma are strongly correlated, implying that plasma measurements are suitable proxies of atorvastatin exposure in muscle tissue. The relationship between atorvastatin metabolites in plasma and SAMS deserves further investigation.
Subject(s)
Coronary Disease , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Atorvastatin/adverse effects , Atorvastatin/pharmacokinetics , Biomarkers , Coronary Disease/drug therapy , Follow-Up Studies , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Liver-Specific Organic Anion Transporter 1/genetics , Muscle, SkeletalABSTRACT
PURPOSE: Paroxysmal atrial fibrillation is often suspected as a probable cause of cryptogenic stroke. Continuous long-term ECG monitoring using insertable cardiac monitors is a clinically effective technique to screen for atrial fibrillation and superior to conventional follow-up in cryptogenic stroke. However, more studies are needed to identify factors which can help selecting patients with the highest possibility of detecting atrial fibrillation with prolonged rhythm monitoring. The clinical relevance of short-term atrial fibrillation, the need for medical intervention and the evaluation as to whether intervention results in improved clinical outcomes should be assessed. METHOD: The Nordic Atrial Fibrillation and Stroke Study is an international, multicentre, prospective, observational trial evaluating the occurrence of occult atrial fibrillation in cryptogenic stroke and transient ischaemic attack. Patients with cryptogenic stroke or transient ischaemic attack from the Nordic countries are included and will have the Reveal LINQ® Insertable cardiac monitor system implanted for 12 months for atrial fibrillation detection. Biomarkers which can be used as predictors for atrial fibrillation and may identify patients, who could derive the most clinical benefit from the detection of atrial fibrillation by prolonged monitoring, are being studied. CONCLUSION: The primary endpoint is atrial fibrillation burden within 12 months of continuous rhythm monitoring. Secondary endpoints are atrial fibrillation burden within six months, levels of biomarkers predicting atrial fibrillation, CHA2DS2-VASc score, incidence of recurrent stroke or transient ischaemic attack, use of anticoagulation and antiarrhythmic drugs, and quality of life measurements. The clinical follow-up period is 12 months. The study started in 2017 and the completion is expected at the end of 2020.
