Aims
Current treatment for congenital long QT syndrome Type 2 (cLQTS2), an electrical disorder that increases the risk of life-threatening cardiac arrhythmias, is aimed at reducing the incidence of arrhythmia triggers (beta-blockers) or terminating the arrhythmia after onset (implantable cardioverter-defibrillator). An alternative strategy is to target the underlying disease mechanism, which is reduced rapid delayed rectifier current (IKr) passed by Kv11.1 channels. Small molecule activators of Kv11.1 have been identified but the extent to which these can restore normal cardiac signalling in cLQTS2 backgrounds remains unclear. Here, we examined the ability of ICA-105574, an activator of Kv11.1 that impairs transition to the inactivated state, to restore function to heterozygous Kv11.1 channels containing either inactivation enhanced (T618S, N633S) or expression deficient (A422T) mutations.
Methods and results
ICA-105574 effectively restored Kv11.1 current from heterozygous inactivation enhanced or expression defective mutant channels in heterologous expression systems. In a human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of cLQTS2 containing the expression defective Kv11.1 mutant A422T, cardiac repolarization, estimated from the duration of calcium transients in isolated cells and the rate corrected field potential duration (FPDc) in culture monolayers of cells, was significantly prolonged. The Kv11.1 activator ICA-105574 was able to reverse the prolonged repolarization in a concentration-dependent manner. However, at higher doses, ICA-105574 produced a shortening of the FPDc compared to controls. In vitro and in silico analysis suggests that this overcorrection occurs as a result of a temporal redistribution of the peak IKr to much earlier in the plateau phase of the action potential, which results in early repolarization.
Conclusion
Kv11.1 activators, which target the primary disease mechanism, provide a possible treatment option for cLQTS2, with the caveat that there may be a risk of overcorrection that could itself be pro-arrhythmic.
Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease; characterised by left ventricular wall thickening, cardiomyocyte disarray, and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to the structural changes in the myocardium, or as a result of intrinsic properties of the HCM cardiomyocyte. In this study, we used an induced pluripotent stem cell model of the Arg403Gln variant in myosin heavy chain 7 (MYH7) to study ′tissue level′ electrophysiological properties of HCM cardiomyocytes. For the first time, we show significant slowing of conduction velocity and an increase in local spatial dispersion of repolarisation – both well established substrates for arrhythmia – in monolayers of HCM cardiomyocytes. Analysis of rhythmonome protein expression in R403Q cardiomyocytes revealed dramatically reduced connexin-43, sodium channels, and inward rectifier channels, a three-way hit that combines to reduce electrotonic coupling between HCM cardiomyocytes and slow cardiac conduction. Our data therefore represent a novel, biophysical basis for arrhythmia in HCM, that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic electrical phenotypes may be accentuated by fibrosis and myocyte disarray to contribute to sudden death in HCM patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.