Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

Abstract

studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction. Am J Physiol Heart Circ Physiol 299: H643-H655, 2010. First published June 25, 2010; doi:10.1152/ajpheart.00074.2010.-We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K ϩ current [IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayedrectifier K ϩ current [IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/ His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block. The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 (P Ͻ 0.05) or LMC (P Ͻ 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.long QT syndrome; His-Purkinje conduction; rapidly activating delayed-rectifier potassium current; slow delayed-rectifier potassium current; transgenic rabbit model; pharmacogenomics; ventricular effective refractory period dispersion; in vivo electrophysiological study THE INHERITED LONG-QT SYNDROME (LQTS) is a genetically heterogeneous arrhythmic disease characterized by impaired cardiac repolarization leading to QT prolongation, polymorphic ventricular tachycardia (pVT), and sudden cardiac death (SCD) (reviewed in Ref. 34). The most common forms of LQTS, type 1 and type 2 (LQT1 and LQT2), account for Ͼ90% of the genotyped cases and are due to loss-of-function mutations in KvLQT1 [␣-subunit of slow delayed-rectifier K ϩ current (I Ks )] (11) or HERG [␣-subunit of rapidly activating delayed-rectifier K ϩ current (I Kr )] (9), respectively. The known triggers for pVTs in LQTS vary f...

Pronounced Effects of HERG-Blockers E-4031 and Erythromycin on APD, Spatial APD Dispersion and Triangulation in Transgenic Long-QT Type 1 Rabbits

“…Using this method, we demonstrated that at baseline, spatial APD dispersion did not differ significantly between LQT1 and LMC rabbits as also shown in vivo (ventricular refractory periods) and ex vivo in previous studies in LQT1 rabbits [16], [25], [28] – albeit there was a non-significant trend towards an even less pronounced APD dispersion in LQT1. The lack of differences in APD dispersion at baseline matches data of electrophysiological studies in LQT1 patients, who similarly did not yield greater APD dispersion compared to a healthy control group [34].…”

Electromechanical and structural alterations in the aging rabbit heart and aorta

“…Young (aged 5-7 mo, n ϭ 6) and old (aged 3.5-5.5 yr, n ϭ 8) female NZW rabbits were subjected to transvenous electrophysiological studies (EPS) as described (41). Briefly, rabbits were anesthetized with ketamine/xylazine (25 mg·kg Ϫ1 ·3.75 mg Ϫ1 ·kg Ϫ1 im) and buprenorphine (0.03 mg/kg sq), intubated, and ventilated with isoflurane (1-2%, FI O 2 0.5).…”

“…EPS were performed at a stimulation cycle length (CL) of 200 and 240 ms. The following electrophysiological parameters were analyzed as previously described (41): sinus node recovery time (SNRT) was evaluated at pacing drive rates of 200 and 240 ms after 200 beats, and the heart rate-corrected SNRT (SNRT Ϫ sinus CL) was calculated. Atrium-to-His (AH) and His-to-ventricle (HV) intervals that reflect conduction from the atrium to the proximal His bundle (AH) and from the His bundle via Purkinje fibers to the ventricle (HV) were measured.…”

A novel, minimally invasive, segmental myocardial infarction with a clear healed infarct borderzone in rabbits

“…The protocol was modified from a previously published protocol from our laboratory (45). Rabbits were anesthetized and monitored as described for MI induction.…”

“…Atrium to His (AH) and His to ventricle (HV) intervals were measured. Programmed ventricular stimulation was performed with one, two, and three extra stimuli in apical and basal positions to examine inducibility of monomorphic ventricular tachycardia or ventricular fibrillation (45). We strictly defined all ventricular tachycardia or ventricular fibrillation as sustained ventricular arrhythmias requiring cardioversion or defibrillation respectively.…”