Calcium handling proteins gene variants and the risk of ventricular arrhythmias in ICD recipients with heart failure: focus on extremely opposing phenotypes

Introduction: Genetic predisposition to ventricular arrhythmias in heart failure (HF) has been suggested. Ca2+ plays a crucial role in cardiac electrical stability. We investigated whether variants of the genes encoding Ca2+ handling proteins are associated with ventricular tachycardia (VT) or ventricular fibrillation (VF) in HF patients with a primary prevention ICD. Methods: 107 patients with severe HF of ischaemic and non-ischaemic origin were followed from ICD implantation to the time of first ICD-treated or recorded sustained VT/VF, death, or last follow-up visit. Patients were then divided into a high-risk group (VT/VF occurring within 6 months after ICD implantation) and a low-risk group (no VT/VF after at least 4 years from ICD implantation). Subjects were genotyped with respect to the following SNPs: SERCA2 rs1860561 and rs56243033; RYR2 rs4142933; Calsequestrin 2 rs4074536; Na(+)-Ca(2+) exchanger C/A substitution -2349; phospholamban rs12198461; calstabin 2 rs7568163. The primary endpoint was the time to the occurrence of the first VT/VF. Hazard ratios were derived from Cox proportional-hazards regression analysis. Results: After a mean follow-up of 724 days (IQ range, 195-1099), 38 patients (36%) had at least one sustained VT/VF. History of ICD-recorded non-sustained VT (NSVT) (HR: 3.6; 95% CI: 1.4-9.1; p= 0.01) and coronary artery disease (CAD) (HR: 2.1; 95% CI: 1.0-4.4; p= 0.04) predicted VT/VF occurrence. Prevalence of the SERCA2 variant rs1860561 was 17% in patients without VT/VF and 7% in subjects with sustained ventricular arrhythmias (p=0.04). After adjustment for NSVT and CAD, the rs1860561 gene variant remained independently associated with lower incidence of VT/VF (HR: 0.4; 95% CI: 0.1-0.9; p= 0.04).We identified 17 patients with VT/VF occurring <6 months after ICD implantation (high risk group; mean time-to-event: 2.3±1.9 months) and 14 patients without VT/VF after at least 4 years from ICD implantation (low-risk group; mean follow-up without events: 63±12 months). Prevalence of the SERCA2 rs1860561 variant was 6% in the high-risk group and 25% in the low-risk group (p=0.03). Conclusions: The SERCA2 rs1860561 variant is associated with lower incidence of life-threatening arrhythmias in HF and may help to identify patients who will benefit most from ICD therapy. Comparison of allelic/genotypic distributions between extremely opposing phenotypes provided reliable information on genetic contributors to arrhythmia occurrence in a complex disease.