Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations

Abstract

Drug-induced block of the cardiac rapid delayed rectifying potassium current (IKr), carried by the human ether-a-go-go-related gene (hERG) channel, is the most common cause of acquired long QT syndrome. Indeed, some, but not all, drugs that block hERG channels cause fatal cardiac arrhythmias. However, there is no clear method to distinguish between drugs that cause deadly arrhythmias and those that are clinically safe. Here we propose a mechanism that could explain why certain clinically used hERG blockers are less proarrhythmic than others. We demonstrate that several drugs that block hERG channels, but have favorable cardiac safety profiles, also evoke another effect; they facilitate the hERG current amplitude in response to low-voltage depolarization. To investigate how hERG facilitation impacts cardiac safety, we develop computational models of IKr block with and without this facilitation. We constrain the models using data from voltage clamp recordings of hERG block and facilitation by nifekalant, a safe class III antiarrhythmic agent. Human ventricular action potential simulations demonstrate the ability of nifekalant to suppress ectopic excitations, with or without facilitation. Without facilitation, excessive IKr block evokes early afterdepolarizations, which cause lethal arrhythmias. When facilitation is introduced, early afterdepolarizations are prevented at the same degree of block. Facilitation appears to prevent early afterdepolarizations by increasing IKr during the repolarization phase of action potentials. We empirically test this prediction in isolated rabbit ventricular myocytes and find that action potential prolongation with nifekalant is less likely to induce early afterdepolarization than action potential prolongation with dofetilide, a hERG channel blocker that does not induce facilitation. Our data suggest that hERG channel blockers that induce facilitation increase the repolarization reserve of cardiac myocytes, rendering them less likely to trigger lethal ventricular arrhythmias.

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

“…2Aa,Ba, red line). Reducing the %g Na,LM by 65%, corresponding to , and pre-junctional membrane (pre-JM) segments, and each membrane segment comprises a modified O'Hara-Rudy dynamic (mORd) ventricular myocyte model [10][11][12] and membrane capacitance, C m,l , for l = post-JM, LM, and pre-JM (c). In (d), V k j represents extracellular cleft potential just after the kth myocyte.…”

“…Allocating Na + channel conductances to each membrane segment and changing those individually, we altered the subcellular expression of Na + channels. The electrophysiological property of each membrane segment was represented by a modified O'Hara-Rudy dynamic (mORd) model 10,11 , which is the most sophisticated human ventricular AP model to date that extensively validated against experimental data from more than 100 non-diseased human hearts. For better correspondence with the experimental CV of human RV epicardium 52 , the formula of fast I Na in the O'Hara-Rudy dynamic model was replaced with that of the ten Tusscher-Panfilov (TP) model 12 .…”

Model based estimation of QT intervals in non-invasive fetal ECG signals

“…The latter equation is similar to the equation obtained in this study. Another study performed by K. Furutani et al [43] discusses a model for I K . K. Furutani et al [43] mention two equations that model the activation and inactivation of the I K channels and both equations have exponential expressions on them.…”

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

“…Allocating Na + channel conductances to each membrane segment and changing those individually, we altered the subcellular expression of Na + channels. The electrophysiological property of each membrane segment was represented by the O'Hara-Rudy dynamic (ORd) model (16,17), which is the most sophisticated human ventricular AP model to date that extensively validated against experimental data from more than 100 non-diseased human hearts. For better correspondence with the experimental conduction velocity of human RV epicardium (18), the formula of fast I Na in the ORd model was replaced with that of the ten Tusscher-Panfilov (TP) model (19).…”

“…Electrophysiological properties of each membrane segment composing the ventricular myocyte were described by a modified O'Hara-Rudy dynamic (mORd) model (16). The mORd model consisted of a membrane capacitance and several ion channel currents, including our modification (17) to the original currents of a potassium channel (I Kr ). Furthermore, the fast I Na in the original ORd model was replaced with that of the ten Tusscher-Panfilov (TP) model (19).…”