Restricting Excessive Cardiac Action Potential and QT Prolongation

Abstract

Background-Although pharmacological block of the slow, delayed rectifier potassium current (I Ks ) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of I Ks block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of I Ks in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline. Methods and Results-Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 mol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 mol/L) produced a Ͻ12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the I Kr blockers sotalol and E-4031 markedly lengthened APD.

Human ex-vivo action potential model for pro-arrhythmia risk assessment

“…Various academic groups have used, to a very limited extent, cardiac tissues from healthy donors (Boukens et al, 2015;Jost et al, 2005Jost et al, , 2013 and patients (Brandenburger et al, 2015;Näbauer, Beuckelmann, Überfuhr, & Steinbeck, 1996;Näbauer & Kääb, 1998;Nawrath & Eckel, 1979;Sivagangabalan et al, 2014;Wettwer et al, 1993;Wettwer, Amos, Posival, & Ravens, 1994) to investigate the role of ion channels, specifically potassium channels, in human ventricular repolarization. Additionally, dofetilide, Sotalol and quinidine have been found to prolong ventricular repolarization in healthy human hearts (QT duration;Johannsen et al, 2014;Lande et al, 1998;Vicente et al, 2015) and patients (QT duration (Echt et al, 1982;McComb, McGovern, McGowan, Ruskin, & Garan, 1987); monophasic AP recordings (Melicherick et al, 1999;Nademanee et al, 1990;Yuan, Wohlfart, Rasmussen, Olsson, & Blomstrom-Lundqvist, 1994)).…”

“…While access to animal tissues is typically plentiful, the availability of human cardiac samples is limited. When available, human tissues have typically been limited to fixed or frozen samples or very small amounts of fresh and viable tissues which were obtained from surgical discards (Boukens et al, 2015;Jost et al, 2005Jost et al, , 2013Brandenburger et al, 2015;Näbauer, Beuckelmann, Überfuhr, & Steinbeck, 1996;Näbauer & Kääb, 1998;Wettwer et al, 1993;Wettwer, Amos, Posival, & Ravens, 1994). However, in the past, tissue recovery procedures, as well as tissue quality and quantity have been extremely variable, resulting in an unreliable source for robust and reproducible drug safety data.…”

Inherited heart disease – what can we expect from the second decade of human iPS cell research?

“…the slow I Ks , and the rapid I Kr components of the delayed rectifier potassium currents, the sodium current I Na , and the L‐type calcium current I CaL ) varying widely even among wild‐type control hiPSC‐CMs 55, 56. Most notably, very different levels of I Ks have been described (ranging from ~ 0.3 to ~ 2.5 pA/pF 5, 57), variable observation leading to controversial conclusions: on the one hand, I Ks recapitulates physiological behaviour in playing a major role when repolarisation reserve is attenuated 58, 59; on the other, it seems to contribute to repolarisation in hiPSC‐CMs even in the absence of sympathetic stimulation 5, 36, 60, 61. The immature phenotype of all stem cell derivatives including hiPSC‐CMs is probably the reason for this variability but, independent of the cause, it is a limitation to extrapolating results obtained using hiPSC‐CMs to native – healthy and diseased – adult human CMs as discussed below.…”

Pharmacological and therapeutical basis of torsades de pointes

“…Mutations of KCNH2, KCNQ1, KCNE2 and ANKB genes have been identified in some patients with drug induced torsades de pointes of which KCNQ1 mutation is the most common one whose expression results into variability of IKs channel functioning. [12][13][14] Furthermore IKs amplitude variability majorly contributes to variability in response to IKr block. More is the IKs amplitude; more is its efficiency to counteract the IKr blocking drugs i.e, QT prolonging drugs.…”