Prognostic value of two polymorphisms in non-sarcomeric genes for the development of atrial fibrillation in patients with hypertrophic cardiomyopathy.

Background: Several non-sarcomeric genes have been postulated to act as modifiers in the phenotypic manifestations of hypertrophic cardiomyopathy (HCM). The development of atrial fibrillation (AF) in HCM has adverse prognostic implications with increased thromboembolism and functional class impairment. Aim: We tested the hypothesis that 2 non-sarcomeric genes [CYP11B2 (-344T>C) and COL1A1 (2046G>T)] are associated with the development of AF. Design: Prospective study. Methods : Two polymorphisms in non-sarcomeric genes [CYP11B2 (-344T>C) and COL1A1 (2046G>T)] were analyzed in 159 HCM patients (49.3±14.9 years, 70.6% male) and 136 controls. All subjects were clinically stable and in sinus rhythm at entry in the study, without ischemic heart disease or other significant co-morbidities that could mask the effect of the analyzed polymorphisms (i.e. previous AF). Thirty-nine patients (24.4%) developed AF during a median follow-up of 49.5 months. Results : Patients with the -344T>C polymorphism in CYP11B2 gene had a higher risk for AF development (HR: 3.31(95%CI 1.29-8.50); p=0.008). In a multivariate analysis, the presence of the C allele in CYP11B2 gene [HR: 3.02(1.01-8.99); p=0.047], previous AF [HR: 2.81(1.09-7.23) p=0.033] and a left atrial diameter of ≥42mm [HR: 2.69(1.01-7.18) p=0.048] were independent predictors of AF development. The presence of the polymorphic allele was associated with higher aldosterone serum levels. Conclusion: We have shown for the first time that the CYP11B2 polymorphism is an independent predictor for AF development in HCM patients. This highlights the importance of non-sarcomeric genes in the phenotypic heterogeneity of HCM. The association with higher aldosterone serum levels could relate to greater fibrosis and cardiac remodelling.