Abstract 1404: Ventricular Arrhythmias and Altered QT/RR Relations in Transgenic Rabbit Models of LQT1 and LQT2
To establish the cause of death in transgenic rabbits with LQTS, we monitored 5 LQT1, 5 LQT2 and 7 littermate male rabbits aged 17 to 27 months for 6 weeks using a DSI telemetry system, and analyzed for PQ, QT, RR, QRS intervals and arrhythmic events. The mean QT(±SD) of control littermates was 140±11.8 ms while those of LQT1 and LQT2 rabbits were 159±8ms for and 160±10ms (p <0.001). Scatterplots of QT/RR intervals showed linear relations for wild-type (WT), LQT-1 and LQT2 rabbits. However, the slope of the QT/RR relation of LQT1 rabbits was shallower suggesting blunted shortening of the QT interval in response to faster heart rates. Monitoring of male LQT1 and control littermates did not reveal any substantial ventricular arrhythmias. By contrast, monitoring of LQT2 rabbits documented sudden death due to polymorphic ventricular tachycardia and fibrillation. This observation correlates with the significantly shorter life expectancy for LQT2 rabbits with 17 sudden deaths out of 33 rabbits, while no sudden death was observed in 26 LQT1 and 1 of the 60 control rabbits (p<0.01). Echocardiogram revealed normal cardiac function without any abnormalities in all 3 groups. A transvenous programmed electrical stimulation (PES) protocol was established and validated in a total of 10 male LQT1 and WT rabbits. In LQT1 and WT atrial refractory period was significantly longer in LQT1 than in WT (152.0 ±31ms vs. 104.0±22ms); differences in ventricular refractory period at the apex and the base were not significant. Of note, the QT intervals of LQT1 rabbits did not shorten in response to ISO despite faster heart rates. Ventricular arrhythmias were inducible in 2 WT and 2 LQT1 after stimulation at the apex, no animal was inducible at the base. Similarly, PES of the first LQT2 rabbit did not result in inducible arrhythmias, but revealed a significant infra-Hisian block. In conclusion, monitoring and PES of LQT1 rabbits revealed a blunted response to ISO and a shallower QT/RR slope likely due to the elimination of IKs currents. Initial monitoring of LQT2 rabbits suggests that the cause of SCD is polymorphic ventricular tachycardia and fibrillation. Thus, the LQT2 model mimics the human phenotype of prolonged QT, spontaneous torsade de pointes and sudden cardiac death.