Background and Objective Postpubertal women with inherited long-QT syndrome 2 (LQT2) are at increased risk for polymorphic ventricular tachycardia (pVT) and sudden cardiac death (SCD), particularly during the postpartum. We aimed at investigating whether sex hormones directly modulate the arrhythmogenic risk in LQTS. Methods and Results Prepubertal ovariectomized transgenic LQT2 rabbits were treated with estradiol (EST), progesterone (PROG), dihydrotestosterone (DHT), or placebo (OVX). During eight weeks of treatment, major cardiac events – spontaneous pVT or SCD – occurred in 5/7 EST rabbits, contrasting with 2/9 in OVX (p<0.05) and no events in 9 PROG and 6 DHT rabbits (p<0.01 vs. PROG, p<0.05 vs. DHT). Moreover, EST increased the incidence of pVT (p<0.05 vs. OVX), while PROG reduced PVCs, bigeminy, couplets, triplets, and pVT (p<0.01 vs. OVX, p<0.001 vs. EST). In vivo ECG monitoring, in vivo electrophysiological and ex vivo optical mapping studies revealed that EST promoted SCD by steepening the QT/RR slope (p<0.05), by prolonging cardiac refractoriness (p<0.05), and by altering the spatial pattern of APD dispersion. Isoproterenol-induced Ca2+ oscillations resulted in early afterdepolarisations (EAD) in EST-treated hearts (4/4), while PROG prevented SCD by eliminating this EAD formation in 4/7 hearts (p=0.058 vs. EST, p<0.05 vs. OVX). Analyses of ion currents demonstrated that EST increased the density of ICa,L compared to OVX (p<0.05), while PROG decreased it (p<0.05). Conclusion This study reveals the pro-arrhythmic effect of EST and the anti-arrhythmic effect of PROG in LQT2 in vivo, outlining a new potential anti-arrhythmic therapy for LQTS.
of anesthetic drugs in transgenic LQT1 and LQT2 rabbits reveal genotype-specific differential effects on cardiac repolarization. Am J Physiol Heart Circ Physiol 295: H2264 -H2272, 2008. First published October 3, 2008 doi:10.1152/ajpheart.00680.2008.-Anesthetic agents prolong cardiac repolarization by blocking ion currents. However, the clinical relevance of this blockade in subjects with reduced repolarization reserve is unknown. We have generated transgenic long QT syndromes type 1 (LQT1) and type 2 (LQT2) rabbits that lack slow delayed rectifier K ϩ currents (IKs) or rapidly activating K ϩ currents (IKr) and used them as a model system to detect the channel-blocking properties of anesthetic agents. Therefore, LQT1, LQT2, and littermate control (LMC) rabbits were administered isoflurane, thiopental, midazolam, propofol, or ketamine, and surface ECGs were analyzed. Genotype-specific heart rate correction formulas were used to determine the expected QT interval at a given heart rate. The QT index (QTi) was calculated as percentage of the observed QT/expected QT. Isoflurane, a drug that blocks IKs, prolonged the QTi only in LQT2 and LMC but not in LQT1 rabbits. Midazolam, which blocks inward rectifier K ϩ current (IK1), prolonged the QTi in both LQT1 and LQT2 but not in LMC. Thiopental, which blocks both IKs and IK1, increased the QTi in LQT2 and LMC more than in LQT1. By contrast, ketamine, which does not block IKr, IKs, or IK1, did not alter the QTi in any group. Finally, anesthesia with isoflurane or propofol resulted in lethal polymorphic ventricular tachycardia (pVT) in three out of nine LQT2 rabbits. Transgenic LQT1 and LQT2 rabbits could serve as an in vivo model in which to examine the pharmacogenomics of drug-induced QT prolongation of anesthetic agents and their proarrhythmic potential. Transgenic LQT2 rabbits developed pVT under isoflurane and propofol, underlining the proarrhythmic risk of IKs blockers in subjects with reduced I Kr . repolarization reserve; long QT syndrome types 1 and 2; sudden cardiac death; ventricular fibrillation COMMONLY USED ANESTHETIC AGENTS influence cardiac repolarization, with effects on surface ECG such as changes in QT interval duration and T-wave morphology (23,26,37,41). Drug-induced QT prolongation is known to precede potentially lethal arrhythmias such as polymorphic ventricular tachycardia (pVT) (reviewed in Refs. 3 and 15). The risk for anesthesiainduced malignant pVT is particularly pronounced in individuals with congenital long QT (LQT) syndromes (LQTS) (2,14,17,18,31,35,40) (12) are responsible for the LQT1 and LQT2 phenotypes, respectively. Furthermore, subtle mutations in LQT-related genes can predispose healthy individuals to drug-induced QT prolongation and ventricular arrhythmia (20,22,29,51). Therefore, anesthetic agents might have more serious implications for apparently healthy individuals in the general population.In vitro patch-clamp experiments have revealed that several anesthetic drugs block cardiac repolarizing ion currents; isoflurane (47) and pro...
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...
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