Abstract P402: Caveolin-1 Upregulation Leads To Decreased Erg And Stress-induced Ventricular Tachycardia In Cystic Fibrosis Hearts

Abstract

Background: Cardiac manifestations of cystic fibrosis are classically accepted as cor pulmonale, yet emerging evidence supports that cardiac abnormalities can develop early when respiratory function is preserved. Myocardial cystic fibrosis transmembrane regulator (CFTR) channels, inactive in normal conditions, are activated in response to catecholamine stress. Methods and Results: In multiple mouse models of homozygous CFTR mutations (S489X or F508d), we demonstrate increased susceptibility to ventricular tachycardia (VT) in response to epinephrine, and this is associated with prolongation of QTc intervals (repolarization). Despite having normal left ventricular ejection fraction and histology, CF S489X mut/mut hearts showed 460 proteins significantly altered compared with WT hearts by tandem mass tag (TMT) proteomics. The Ingenuity Pathway Analysis of proteomics data revealed mitochondrial dysfunction and increased caveolin-1 signaling among the top pathways affected in CF S489X mut/mut hearts. In mouse hearts and human induced pluripotent stem cells derived cardiomyocytes (iPS-CM) with CFTR mutations, we observed increased ER stress and caveolin-1 (cav-1). These changes are concomitant with reduced levels of the ERG channel, a K+ channel contributing to phase 3 repolarization, mutations of which cause long QT syndrome II and VT. Patch clamp analysis showed decreased phase 2-3 repolarization current (including hERG current) in CF F508d iPS-CM compared with control iPS-CM, consistent with the findings of decreased membranous hERG and elevated Cav-1. Suppression of Cav-1 successfully restores membranous hERG in two separate lines of mutant iPS-CM generated from CF patients with F508d mutation. In F508d mut/mut mice, suppression of cardiac Cav-1 upregulation by reducing ER stress using TUDCA or crossing with heterozygous Cav-1 +/- abolished the stress-induced VT. Our analysis of a large-scale real-world clinical database from TriNetX, including 4520 CF men, 3510 CF women and the same number of well-matched controls demonstrated novel findings of increased risk for QT prolongation and VT in CF patients. Retrospective analysis of 126 CF patients with available EKG in our hospital revealed significant QTc prolongation in CF patients compared with matched controls, for both males (CF 447.8±4.5 vs cont. 429.2±2.5) and females (CF 454.0±3.5 vs cont.437.5±2.4). The QTc interval is not affected by lung function (%predicted FEV1) and is an independent predictor of survival in CF patients. Conclusions: In mice and iPS-CM models of CF, we demonstrated impaired repolarization and increased susceptibility to stress-induced VT. This is mediated by ER-stress-induced upregulation of Cav-1, which leads to internalization of ERG and subsequent decrease in repolarization current.