Abstract P2046: The Role Of A Novel Alpha-crystallin B Chain Variant In Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation. While mutations in sarcomere genes can account for a substantial proportion of familial cases, 40-50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYAB R123W ) in a pair of homozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYAB R123W promotes HCM phenotype remains unclear. Here, we generated mice carrying the Cryab R123W -knockin allele and demonstrated that hearts from these animals exhibit increased maximal elastance, reduced diastolic function and are more susceptible to ventricular tachycardia with programmed stimulation. Upon transverse aortic constriction, mice carrying the Cryab R123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYAB R123W despite its potent effect on driving cellular hypertrophy. Unexpectedly, CRYAB R123W appears to enhance calcium signaling by promoting nuclear localization of NFAT through direct interaction with calcineurin. Studies on isolated adult cardiomyocytes reveal altered fractional shortening, calcium dyshomeostasis, prolonged action potential duration, and T-wave alternans. Crossing of CRYAB R123W mice with a mybpc3 knock-in model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in this model are independent of the sarcomere. Thus, our data establish the Cryab R123W allele as a novel genetic model of HCM that potentially unveils additional sarcomere-independent mechanisms of cardiac pathological hypertrophy and sudden cardiac death.