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 preprocedural 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 whether genetic variants within systems known to be involved in ventricular remodelling was associated to different degrees of RR in patients with chronic systolic HF. 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 using Taq-Man technology. The association of clinical factors and genetic variants within the renin-angiotensin and adrenergic systems with the RR- phenotype was assessed by multivariable logistic regression analysis and expressed by odds ratios (OR) and their 95% confidence interval (CI). Results: RR- (n=76) and RR+ (n=80) patients were well matched for age (RR- 61 [56-70] vs RR+ 64 [57-71], years, p=ns), symptom severity (NYHA class IIIIV RR- 72% vs RR+ 71%, p=ns) and ischemic etiology (RR- 53% vs RR+ 49%, p=ns). LVESV decreased by -1 [-6, 5] % in RR- and -32 [-46, -23] % in RR+, while left ventricular ejection fraction (LVEF) increased by 2.5 [-2, 5] units in RRand 11 [6, 16] units in RR+ (p<0.001). By multivariable logistic regression analysis, after adjustment for age, gender, LVEF and previous myocardial infarction, the RR- phenotype was independently associated with diabetes (OR 3.29, 95% CI 1.20-9.02), the CC genotype of rs5443 within the heterotrimeric GTP-binding protein (GNB3, OR 3.0, 95% CI 1.43-6.28) and the CC genotype of rs3766031, within the ?-subunit of Na+/K+-ATPase (ATP1B1, OR 2.67, 95% CI 1.14-6.26). The combined presence of the CC genotype in both rs 5443 and rs3766031 gave an OR of 8.07 (95% CI 2.60-25) for lack of RR. Conclusion: Genetic variants residing within genes involved in signal transduction processes (GNB3 and ATP1B1) were significantly associated with the CRT non-responder phenotype. These findings suggest altered protein activity as a contributory factor to reduced benefit from CRT.