Electrophysiological Studies of Transgenic Long QT Type 1 and Type 2 Rabbits 1 Reveal Genotype - Specific Differences in Ventricular Refractoriness and His 2 Conduction 3 4

31 Background and Objective: We have generated transgenic rabbits lacking cardiac 32 IKs (LQT1) or IKr (LQT2). Rabbits with either genotype have prolonged APD and QT intervals; 33 however, only LQT2 rabbits develop AV blocks and polymorphic ventricular tachycardia. We 34 therefore sought to characterize the genotype-specific differences in AV conduction and 35 ventricular refractoriness in LQT1 and LQT2 rabbits. 36 Methods: We carried out in vivo electrophysiological studies (EPS) in LQT1, LQT2, 37 and littermate control (LMC) rabbits at baseline, during isoproterenol-infusion, and after a 38 bolus of dofetilide, and ex vivo optical mapping studies of the AV-node/His-region at baseline 39 and during dofetilide perfusion. 40 Results: Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, 41 decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 42 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra43 His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV 44 block. The ventricular effective refractory period (VERP) in RV apex and base were 45 significantly longer in LQT2 than LQT1 (p<0.05) or LMC (p<0.01), with a greater VERP 46 dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 47 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP 48 in LQT1. 49 Conclusions: EPS and optical mapping experiments demonstrated genotype-specific 50 differences in AV conduction and ventricular refractoriness. The occurrence of infra-His 51 blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide 52 suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking 53 IKr and IKs. 54 55 Words: 250 56 57 58 59