Long QT syndrome (LQTS) is a heritable disease associated with ECG QT interval prolongation, ventricular tachycardia, and sudden cardiac death in young patients. Among genotyped individuals, mutations in genes encoding repolarizing K + channels (LQT1:KCNQ1; LQT2:KCNH2) are present in approximately 90% of affected individuals. Expression of pore mutants of the human genes KCNQ1 (KvLQT1-Y315S) and KCNH2 (HERG-G628S) in the rabbit heart produced transgenic rabbits with a long QT phenotype. Prolongations of QT intervals and action potential durations were due to the elimination of I Ks and I Kr currents in cardiomyocytes. LQT2 rabbits showed a high incidence of spontaneous sudden cardiac death (>50% at 1 year) due to polymorphic ventricular tachycardia. Optical mapping revealed increased spatial dispersion of repolarization underlying the arrhythmias. Both transgenes caused downregulation of the remaining complementary I Kr and I Ks without affecting the steady state levels of the native polypeptides. Thus, the elimination of 1 repolarizing current was associated with downregulation of the reciprocal repolarizing current rather than with the compensatory upregulation observed previously in LQTS mouse models. This suggests that mutant KvLQT1 and HERG interacted with the reciprocal wild-type α subunits of rabbit ERG and KvLQT1, respectively. These results have implications for understanding the nature and heterogeneity of cardiac arrhythmias and sudden cardiac death.

Sirtuin 3 (SIRT3) is a mitochondrial NAD(+)-dependent deacetylase that regulates energy metabolic enzymes by reversible protein lysine acetylation in various extracardiac tissues. The role of SIRT3 in myocardial energetics and in the development of mitochondrial dysfunction in cardiac pathologies, such as the failing heart, remains to be elucidated. To investigate the role of SIRT3 in the regulation of myocardial energetics and function SIRT3(-/-) mice developed progressive age-related deterioration of cardiac function, as evidenced by a decrease in ejection fraction and an increase in enddiastolic volume at 24 but not 8 weeks of age using echocardiography. Four weeks following transverse aortic constriction, ejection fraction was further decreased in SIRT3(-/-) mice compared to WT mice, accompanied by a greater degree of cardiac hypertrophy and fibrosis. In isolated working hearts, a decrease in cardiac function in SIRT3(-/-) mice was accompanied by a decrease in palmitate oxidation, glucose oxidation, and oxygen consumption, whereas rates of glycolysis were increased. Respiratory capacity and ATP synthesis were decreased in cardiac mitochondria of SIRT3(-/-) mice. HPLC measurements revealed a decrease of the myocardial ATP/AMP ratio and of myocardial energy charge. Using LC-MS/MS, we identified increased acetylation of 84 mitochondrial proteins, including 6 enzymes of fatty acid import and oxidation, 50 subunits of the electron transport chain, and 3 enzymes of the tricarboxylic acid cycle. Lack of SIRT3 impairs mitochondrial and contractile function in the heart, likely due to increased acetylation of various energy metabolic proteins and subsequent myocardial energy depletion.

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...

Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of

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Enhanced dispersion of repolarization has been proposed as an important mechanism in long QT related arrhythmias. Dispersion can be dynamic and can be augmented with the occurrence of spatially out-of-phase action potential duration (APD) alternans (discordant alternans; DA). We investigated the role of tissue heterogeneity in generating DA using a novel transgenic rabbit model of type 2 long QT syndrome (LQT2). Littermate control (LMC) and LQT2 rabbit hearts (n = 5 for each) were retrogradely perfused and action potentials were mapped from the epicardial surface using di-4-ANEPPS and a high speed CMOS camera. Spatial dispersion ( APD and slope of APD restitution) were both increased in LQT2 compared to LMC ( APD: 34 ± 7 ms vs. 23 ± 6 ms; slope:1.14 ± 0.23 vs. 0.59 ± 0.19). Onset of DA under a ramp stimulation protocol was seen at longer pacing cycle length (CL) in LQT2 compared to LMC hearts (206 ± 24 ms vs. 156 ± 5 ms). Nodal lines between regions with APD alternans out of phase from each other were correlated with conduction velocity (CV) alternation in LMC but not in LQT2 hearts. In LQT2 hearts, larger APD dispersion was associated with onset of DA at longer pacing CL. At shorter CLs, closer to ventricular fibrillation induction (VF), nodal lines in LQT2 (n = 2 out of 5) showed persistent complex beat-to-beat changes in nodal line formation of DA associated with competing contribution from CV restitution and tissue spatial heterogeneity, increasing vulnerability to conduction block. In conclusion, tissue heterogeneity plays a significant role in providing substrate for ventricular arrhythmia in LQT2 rabbits by facilitating DA onset and contributing to unstable nodal lines prone to reentry formation.