Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species

Abstract

BACKGROUND: The slow and rapid delayed rectifier K+ currents (IKs and IKr, respectively) are responsible for repolarizing the ventricular action potential (AP) and preventing abnormally long APs that may lead to arrhythmias. Although differences in biophysical properties of the two currents have been carefully documented, the respective physiological roles of IKr and IKs are less established. In this study, we sought to understand the individual roles of these currents and quantify how effectively each stabilizes the AP and protects cells against arrhythmias across multiple species. METHODS: We compared 10 mathematical models describing ventricular myocytes from human, rabbit, canine, and guinea pig. We examined variability within heterogeneous cell populations, tested the susceptibility of cells to proarrhythmic behavior, and studied how IKs and IKr responded to changes in the AP. RESULTS: We found that: (1) models with higher baseline IKs exhibited less cell-to-cell variability in action potential duration (APD); (2) models with higher baseline IKs were less susceptible to early afterdepolarizations (EADs) induced by depolarizing perturbations; (3) as APD is lengthened, IKs increases more profoundly than IKr, thereby providing negative feedback that resists excessive AP prolongation; and (4) the increase in IKs that occurs during β-adrenergic stimulation is critical for protecting cardiac myocytes from EADs under these conditions. CONCLUSIONS: Slow delayed rectifier current is uniformly protective across a variety of cell types. These results suggest that IKs enhancement could potentially be an effective antiarrhythmic strategy.

Time Course of Low-Frequency Oscillatory Behavior in Human Ventricular Repolarization Following Enhanced Sympathetic Activity and Relation to Arrhythmogenesis

“…The important role of I Ks during β-AS has been pointed out in numerous studies (Volders et al, 2003;Johnson et al, 2010Johnson et al, , 2013Hegyi et al, 2018;Varshneya et al, 2018). Reduced I Ks responsiveness to β-AS has been suggested to increase arrhythmia susceptibility in a heart failure animal model (Hegyi et al, 2018).…”

“…Reduced I Ks responsiveness to β-AS has been suggested to increase arrhythmia susceptibility in a heart failure animal model (Hegyi et al, 2018). In ventricular myocytes, loss of I Ks current has been experimentally shown to exaggerate beat-to-beat APD variability in response to β-AS (Johnson et al, 2010(Johnson et al, , 2013 and computationally proved to facilitate the generation of proarrhythmic early afterdepolarizations (Varshneya et al, 2018). Our results provide additional support to the role of I Ks during β-AS, as reduced I Ks shortens the oscillatory latency and thus facilitates the occurrence of LF oscillations of APD.…”

Investigational Treatments for COVID‐19 may Increase Ventricular Arrhythmia Risk Through Drug Interactions

“…Once baseline models for the different patient groups had been created, we generated virtual populations to simulate physiological variability between individuals. 24,25,26 All maximal conductances in the…”

Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation

“…In addition, since no direct or personalized therapeutics have been developed to target the channelopathies that lead to LQTS, particularly important is understanding the structure–function relationship of ion channels (such as KCNQ1/KCNE1 channels) and the drug–channel interaction (such as the activation of KCNQ1/KCNE1 by PUFA and PUFA analogs). In addition, in a recent simulation study, activators of KCNQ1/KCNE1 channels were proposed as the safest strategy for the development of LQTS treatments [ 7 ]. On the other hand, development of selective blockade of KCNQ1/KCNE1 channels has been studied as a strategy for providing more effective class III antiarrhythmic agents [ 23 , 151 ].…”

“…Mutations of KCNQ1/KCNE1 channels that reduce IKs currents prolong the QT interval by lengthening the duration of the ventricular action potential [ 3 ]. The KCNQ1/KCNE1 channel has been proposed as a potential target for the development of LQTS treatment [ 7 ]. One study [ 8 ] suggested that the repolarization reserve of KCNQ1/KCNE1 channels is important to prevent the development of ischemia- and reperfusion-induced arrhythmias.…”