In the 3D wedge, disopyramide and quinidine at clinically-relevant concentrations decreased the dominant frequency of re-entrant excitations and exhibited anti-fibrillatory effects; preventing formation of multiple, chaotic wavelets which developed in SQT1, and could terminate arrhythmias.
The human ether-à-go-go related gene (hERG) potassium channel is an obligatory anti-target for drug development on account of its essential role in cardiac repolarization and its close association with arrhythmia.
The present work uncovered a novel molecular mechanism underlying HERG protein expression and indicated that PML SUMOylation is a critical step in the development of drug-acquired arrhythmia.
The sodium channel gene SCN5A and potassium channel genes KCNQ1 and KCNH2 have been widely reported to be genetic risk factors for arrhythmia including Brugada syndrome and long QT syndrome (LQTS).
The long QT-related arrhythmia torsades de pointes (TdP) can arise with mutations in HERG and during treatment with drugs that block cardiac I Kr, the current encoded by HERG.
The level of inhibition of the human Ether-à-go-go-related gene (hERG) channel is one of the earliest preclinical markers used to predict the risk of a compound causing Torsade-de-Pointes (TdP) arrhythmias.
Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed.
To determine what role genetic variation in the hERG gene plays in drug-induced arrhythmias, we screened DNA samples collected from 105 atrial-fibrillation patients treated with dofetilide for polymorphisms, seven of whom developed TdP.
Electrophysiological analysis of patient-derived LQT2 hiPSC cardiomyocytes treated with mutation-specific siRNAs showed normalized action potential durations (APDs) and K(+) currents with the concurrent rescue of spontaneous and drug-induced arrhythmias (presented as early-afterdepolarizations).
Mutations that inhibit Kv11.1 ion channel activity contribute to abnormalities of cardiac repolarization that can lead to long QT2 (LQT2) cardiac arrhythmias and sudden death.
Prolonged action potential is present in LQT2-specific cardiomyocytes derived from a mutation carrier and arrhythmias can be triggered by a commonly used drug.
The rapid component of the delayed rectifier potassium current (I(Kr)), encoded by the ether-a-go-go-related gene (ERG1, officially denominated as KCNH2), is a major contributor to repolarization in the mammalian heart.Acute (e.g. drug-induced) and chronic (e.g. inherited genetic disorder) disruptions of this current can lead to prolongation of the action potential and potentiate occurrence of lethal arrhythmias.
QT prolongation, a classic risk factor for arrhythmias, can result from a mutation in one of the genes governing cardiac repolarization and also can result from the intake of a medication acting as blocker of the cardiac K(+) channel human ether-a-go-go-related gene (HERG).
Reduced levels of the cardiac human (h)ERG ion channel protein and the corresponding repolarizing current <i>I</i><sub>Kr</sub> can cause arrhythmia and sudden cardiac death, but the underlying cellular mechanisms controlling hERG surface expression are not well understood.
In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias.
We have previously reported that in female rabbits, estrogen increases arrhythmia risk in drug-induced LQTS2 by upregulating L-type Ca<sup>2+</sup> (I<sub>Ca,L</sub>) and sodium-calcium exchange (I<sub>NCX</sub>) currents at the base of the epicardium by a genomic mechanism.