Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome

Abstract

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.

Rescue of Aberrant Gating by a Genetically Encoded PAS (Per-Arnt-Sim) Domain in Several Long QT Syndrome Mutant Human Ether-á-go-go-related Gene Potassium Channels

“…Loss of hERG function, and thus, loss of I Kr (11), can occur through a number of mechanisms, including defects in channel opening and closing (gating), ion permeation, or protein trafficking (12). hERG channels containing LQT2 mutations in the PAS domain (hERG PAS-LQT2) exhibit robust currents when studied in Xenopus oocytes (6,(13)(14)(15); however, most channels with LQT2 mutations located outside the PAS domain do not have measurable currents and show defects in maturation and trafficking when studied in mammalian cells (12, 16 -21).…”

Properties of WT and mutant hERG K+ channels expressed in neonatal mouse cardiomyocytes

“…A few transgenic animal models have also been created for specific mutations (5,8,23,37). In the present work, we studied the biochemical, biophysical, and pharmacological properties of wild-type (WT) hERG channels and three LQT2-linked channels expressed in native neonatal mouse cardiomyocytes.…”

How Can we Study Cardiopulmonary Resuscitation and Cardiac Arrest in Animals: a Review

“…In the same way, knock-out mice for cardiac connexin-43 died prematurely from sustained ventricular tachyarrhythmias, with a mean lifespan of 43.9±2.4 days [55]. In rabbits, the cardiac expression of KCNQ1 and KCNH2 human genes also induced a long QT syndrome [56], increasing the chance of ventricular tachycardia.…”