PO-455617-5 ANTI-ARRHYTHMIC EFFECTS OF BIOINSPIRED MODIFIED Y RNA IN RATS WITH HEART FAILURE AND PRESERVED EJECTION FRACTION

Abstract

Exosomes secreted from cardiosphere-derived cells (CDCs) attenuate ventricular arrhythmias and prolong survival of rats with heart failure and preserved ejection fraction (HFpEF). Y RNA fragments were abundant in exosomes secreted from CDCs, and they mediate the anti-inflammatory and anti-fibrotic effects of CDCs. We tested the hypothesis that bioinspired modified Y RNA decrease ventricular arrhythmias in rats with HFpEF by reversing electrical remodeling. Dahl salt-sensitive (DSS) rats (n=19) were fed a high-salt diet (8% NaCl) from 7 weeks of age to induce HFpEF. Echocardiogram was performed at 14 weeks of age to confirm the development of diastolic dysfunction (increased E/E’ ratio). Symptomatic rats with diastolic dysfunction were diagnosed with HFpEF. TY1 (Therapeutic Y RNA1, a modified Y RNA in transfection reagent) was injected via the tail vein (twice weekly for 4 weeks) to rats with HFpEF (n=7). Vehicle (phosphate-buffered saline in transfection reagent) and scramble (in transfection reagent) were also injected via the tail vein as placebo (n=8 and 4, respectively). Echocardiogram and programmed electrical stimulation (PES) were performed after 4 weeks of TY1 vs. vehicle or scramble injections. Electrocardiogram was performed to measure QTc intervals as a marker for adverse electrical remodeling. Ventricular arrhythmias were induced in 80% of vehicle-injected and 100% of scramble-injected HFpEF rats by PES, as compared to only 33% of TY1-injected HFpEF rats (p=0.036). The duration of ventricular arrhythmias was significantly lower in TY1-injected HFpEF rats as compared to vehicle-injected and scramble-injected HFpEF rats (4 [IQR 0-5] beats in TY1 vs. 30 [IQR 8-54] beats in vehicle, p=0.034; vs. 21 [16-48] beats in scramble; p=0.031). QTc interval was reduced in TY1-injected HFpEF rats as compared to vehicle or scramble-injected HFpEF rats (QTc interval 238±16 ms in TY1 vs. 271±24 ms in vehicle, p=0.034; vs. 280±7 ms in scramble, p=0.017). Survival was prolonged in TY1-injected HFpEF rats as compared to vehicle or scramble-injected HFpEF rats, although statistically insignificant due to a low number of rats (86% in TY1 vs. 63% in vehicle or 75% in scramble). TY1, a modified Y RNA, reduced ventricular arrhythmias in rats with HFpEF by reversing adverse electrical remodeling of HFpEF (as manifested by a shortened QTc interval). Given these encouraging data, TY1 merits further investigation as a novel therapeutic candidate for ventricular arrhythmias.