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.

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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.

Permanent cardiac pacing is the treatment of choice in severe and symptomatic bradycardia. To determine factors associated with longer survival we analysed the survival times and baseline characteristics of 6505 patients after pacemaker implantation. This longitudinal study with 30 years of follow-up was performed in a single centre university hospital with all-cause mortality as the end-point. In 6505 patients we analysed a total of 30948 years of patient follow-up, median survival was 101.9 months ( approximately 8.5 years), with 44.8% of patients alive after 10 years and 21.4% alive after 20 years. In all subgroups women had a significantly longer survival than men (118 vs 91.7 months, P<0.0001), despite a markedly higher age at implantation (73.2 years vs 71 years, P<0.0001). Survival of patients with sick-sinus-syndrome was significantly better than in patients with high degree AV-block, which in turn, was better than survival of patients with atrial fibrillation (132.9 months vs 94.2 months vs 85.1 months, P<0.0001). Multivariate analysis revealed several independent factors: age, gender, decade of implantation, type of pacemaker, index arrhythmia and initial symptoms. Interestingly, if only the patients of the last decade were analysed multivariately, neither pacing mode nor index arrhythmia were independently associated with survival. In conclusion, survival of patients with pacemakers is independently influenced by several baseline characteristics which can identify patients with very long survival.

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