Genetic variants associated to reverse remodelling after cardiac resynchronization therapy

Background: Reverse remodelling (RR) may occur as a beneficial effect of cardiac resynchronization therapy (CRT). RR, defined in most studies as a decrease . 15% in left ventricular end systolic volume (LVESV) with respect to pre-procedural values, is associated to clinical outcome in heart failure (HF) patients. There are currently no data on the association of genetic factors with RR after CRT. We aimed to assess genetic variants in patients with chronic systolic HF and different degrees of RR. Method: We sampled blood from 156 patients implanted with CRT since at least 12 months. Lack of RR after CRT (RR-) was defined as a LVESV decrease at follow-up echo 6 to 12 months after CRT from baseline ,15%. RR- patients were compared to RR+ controls matched by age, gender, NYHA class and etiology. DNA, prepared from mononuclear blood cells, was genotyped for 44 genetic variants using TaqMan technology. Relative allelic frequencies were compared by chi-square test between RR- patients and RR+ controls. Results: RR- (n ¼ 76) and RR+ (n ¼ 80) subjects were well matched for variables known to impact on CRT outcomes such as age (RR- 61 [56-70] vs RR+ 64 [57-71], p ¼ ns),symptom severity (NYHA class III-IV RR- 72% vs RR+ 71%, p=ns) and ischemic etiology (RR- 53% vs RR+ 49%, p ¼ ns). Lack of RR was significantly associated with C allele of rs5443 within the heterotrimeric GTP-binding protein (GNB3) (RR- 74% vs RR+ 58%, p ¼ 0.004), C allele of rs3766031 within the b-subunit of Na+/K+- ATPase (ATP1B1) (RR- 92% vs RR+ 82%, p=0.011), and the C allele of rs5522 that encodes for the mineralocorticoid receptor (NR3C2) (RR- 16% vs RR+ 6%, p ¼ 0.006). Conclusion: We identified three genetic variants significantly associated with the CRT non-responder phenotype. These variants reside either within genes involved in signal transduction processes (GNB3 and ATP1B1), suggesting reduced benefit from CRT due to altered protein activity, or in cellular receptor structures (NR3C2). These findings have potential implications for optimized drug treatment after CRT.