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.

After LVAD placement, there is a significant rise in the incidence of de novo MVT. By contrast, the incidence of PVT/VF was unaffected by LVAD placement.

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.

Non-technical summary Long QT syndrome (LQTS) is a genetic disorder characterized by recurrent syncope and sudden cardiac death (SCD). Type 1 (LQT1) and Type 2 (LQT2) LQTS account for 90% of the genotyped mutations in patients with this disorder. These syndromes have been associated with different sympathetic modes for initiation of cardiac arrest. Using isolated cardiomyocytes and Langendorff-perfused hearts from transgenic rabbit models of LQT1 and LQT2, we have identified differential conditions and cellular mechanisms for the generation of early afterdepolarizations (EADs), abnormal depolarizations during the plateau and repolarization phase of action potentials and the hallmark of the arrhythmias in LQTS. These differences explain why different types of increased autonomic nervous system activity, i.e. sympathetic surge vs. high sympathetic tone, are associated with the initiation of polymorphic ventricular tachycardia in LQTS patients with different genetic background.Abstract Early after-depolarization (EAD), or abnormal depolarization during the plateau phase of action potentials, is a hallmark of long-QT syndrome (LQTS). More than 13 genes have been identified as responsible for LQTS, and elevated risks for EADs may depend on genotypes, such as exercise in LQT1 vs. sudden arousal in LQT2 patients. We investigated mechanisms underlying different high-risk conditions that trigger EADs using transgenic rabbit models of LQT1 and LQT2, which lack I Ks and I Kr (slow and fast components of delayed rectifying K + current), respectively. Single-cell patch-clamp studies show that prolongation of action potential duration (APD) can be further enhanced by lowering extracellular potassium concentration ([K + ] o ) from 5.4 to 3.6 mM. However, only LQT2 myocytes developed spontaneous EADs following perfusion with lower [K + ] o , while there was no EAD formation in littermate control (LMC) or LQT1 myocytes, although APDs were also prolonged in LMC myocytes and LQT1 myocytes. Isoprenaline (ISO) prolonged APDs and triggered EADs in LQT1 myocytes in the presence of lower [K + ] o . In contrast, continuous ISO perfusion diminished APD prolongation and reduced the incidence of EADs in LQT2 myocytes. These different effects of ISO on LQT1 and LQT2 were verified by optical mapping of the whole heart, suggesting that ISO-induced EADs are genotype specific. Further voltage-clamp studies revealed that ISO increases L-type calcium current (I Ca ) faster than I Ks (time constant 9.2 s for I Ca and 43.6 s for I Ks ), and computer simulation demonstrated a high-risk window of EADs in LQT2 during ISO perfusion owing to mismatch in the time courses of I Ca and I Ks , which may explain why a sympathetic surge rather than high sympathetic tone can be an effective trigger of EADs in LQT2 perfused hearts. In summary, EAD formation is genotype specific, such that EADs can be elicited in LQT2 myocytes simply by lowering [K + ] o , while LQT1 myocytes require sympathetic stimulation. Slower activation of I Ks than of I Ca by ISO may expla...