Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure

Abstract

Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na+ current (INaL) is relevant and is currently under investigation. In this study we examined the role of INaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of INaL. A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human INaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for INaL in the prolongation of action potential duration (APD), triangulation of the shape of the AP, and changes in Ca2+ transient. A mechanistic investigation of intracellular Na+ accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na+/K+ pump, the Na+/Ca2+ exchanger and INaL. The results of the simulations also showed that in failing myocytes, the enhancement of INaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the INaL prolong APD and alter Ca2+ transient facilitating the development of early afterdepolarizations. An enhanced INaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca2+]i homeostasis of failing myocytes.

In silico assessment of drug safety in human heart applied to late sodium current blockers

“…In control conditions, GS967 had a slight tendency to decrease APD, with the effect being larger for APD 50 than for APD 90 . 10 There is also ample experimental and theoretical evidence that I NaL enhancement can have opposite pro-arrhtyhmic effects, including an increase of triangulation, 54 reverse rate-dependence of APD prolongation measured in transgenic mice with LQT3 48 or the peak to end interval of the T-wave, which closely approximates TDR, in rabbit ventricular wedges. 5 Perhaps more importantly, many experimental studies have shown that inhibition of I NaL can markedly reduce the risk of drug-induced TdP, e.g., by I Kr blockers.…”

Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

“…The analysis of the different Na + flux pathways further suggested that the reduced Na/K flux during acute myocardial ischemia plays the largest role in exacerbated Na + overload during reperfusion, and therefore in the possible development of reperfusion injury [54]. Mechanistic investigations using computational models have also evidenced that intracellular Na + accumulation in heart failure is mainly driven by the electrophysiological remodeling of the Na/K pump current, consequently contributing to the deregulation of intracellular Ca 2+ homeostasis in the failing cardiac myocytes [50,67].…”

An Emerging Antiarrhythmic Target: Late Sodium Current

“…The contribution of BM and LSM to INa,L is equal at the beginning of this phase, then monotonic reduction of BM leaves LSM the only gating mode shaping the plateau sodium current. Shifts in the relative magnitudes of the different gating modes caused by channel mutations or pathologic conditions have been implicated in cardiac electric disorders [33][34][35][36][37][38][39][40][41][42]. Targeted pharmacological modulation of different gating modes is hoped to exert cardioprotective and antiarrhythmic effects [43][44][45] .…”

“…It is now well established that the upregulation of INa,L results in pathologic cardiac function including contractile dysfunction, arrhythmia and structural heart disease [5,6,41,44,57,77,100]. There are several conditions (mutation, hypoxia, ischemia, carbon monoxide, CaMKII or angiotensin II activation, etc.)…”

“…Role of I Na,L in arrhythmogenesis Acquired or inherited increase of INa,L is associated with enhanced risk for cardiac arrhythmia and inhibition of INa,L was demonstrated to prevent or abolish arrhythmic electric activity of the heart [1,3,5,6,41,57,123,214,215]. There are multiple mechanisms INa,L might lead to manifest arrhythmic activity.…”