Abstract 15529: Transgenic Short QT Syndrome Type 1 Rabbits (HERG-N588K) Mimic the Human Phenotype with Shortened Cardiac Repolarization, Ventricular Fibrillation, and Sudden Death

Abstract

Introduction and Hypothesis: Short QT syndrome is an inherited ion channelopathy with an accelerated cardiac repolarization due to gain-of-function mutations in K+ channel genes. Patients are prone to ventricular tachycardia and sudden cardiac death (SCD). Detailed knowledge about mechanisms of arrhythmogenesis is lacking. We aimed at generating transgenic SQT1 rabbits as novel tool to investigate these mechanisms. Methods: FLAG-HA-tagged HERG-N588K cDNA and the b-MyHC promoter were integrated into a pBSII SK vector and microinjected into rabbit oocytes. SQT1 rabbits and their wildtype (WT) littermates were subjected to in vivo ECG and ex vivo monophasic action potential (AP) measurements. Electrical remodeling was investigated using real-time PCR. Results: We successfully generated 3 transgenic SQT1 founder rabbits. One of the founders died suddenly at the age of 60 days. In SQT1 rabbits (F1) not subjected to any experiments 3/11 died around day 40 vs. 0/8 WT rabbits (p<0.05). SQT1 founder rabbits and their offspring demonstrated a shortened QT interval compared to WT (QT, ms, SQT1, n=44, 147.8±1.7 vs. WT, n=24, 166.4±2.9, p<0.0001, heart-rate corrected QTi, %, 91.6±0.7 vs. 98.1±1.1, p<0.0001) with no gender differences among SQT1 rabbits. Moreover, in SQT1, AP duration was shortened in all segments of LV base, mid, and apex (LV base-lat, APD90, ms, SQT1, n=7, 118.6±5.1 vs. WT, n=9, 154.4±2.2, p<0.0001; APD75, 93.1±6.8 vs. 127.1±1.9, p<0.0001). Ventricular fibrillation (VF) occurred more often during AP measurements in SQT1 than in WT rabbits (SQT1, 5/13 vs. WT, 0/8, p<0.05). FLAG-HA-HERG-N588K channels expressed in HEK cells demonstrated increased IKr steady currents and impaired inactivation indicative of a gain-of-function. Remodeling of ion channels and Ca2+ handling proteins occurred in SQT1 rabbits with a downregulation of L-type Ca2+ channel mRNA in LV septum-mid (SQT1, n=4, 0.84±0.1 vs. WT, n=6, 1.03±0.1, p<0.05) and of RyR2 in LV septum-apex (0.85±0.1 vs. 1.08±0.1, p<0.05). Conclusion: These first transgenic SQT1 rabbits over-expressing a HERG-N588K gain-of-function mutation mimic the human phenotype with shortening of QT and APD, a high rate of VF and SCD. These models are thus a useful tool to explore arrhythmogenic mechanisms in SQTS.