Late Sodium Current Inhibition in Acquired and Inherited Ventricular (dys)function and Arrhythmias

Abstract

The late sodium current has been increasingly recognized for its mechanistic role in various cardiovascular pathologies, including angina pectoris, myocardial ischemia, atrial fibrillation, heart failure and congenital long QT syndrome. Although relatively small in magnitude, the late sodium current (I(NaL)) represents a functionally relevant contributor to cardiomyocyte (electro)physiology. Many aspects of I(NaL) itself are as yet still unresolved, including its distribution and function in different cell types throughout the heart, and its regulation by sodium channel accessory proteins and intracellular signalling pathways. Its complexity is further increased by a close interrelationship with the peak sodium current and other ion currents, hindering the development of inhibitors with selective and specific properties. Thus, increased knowledge of the intricacies of the complex nature of I(NaL) during distinct cardiovascular conditions and its potential as a pharmacological target is essential. Here, we provide an overview of the functional and electrophysiological effects of late sodium current inhibition on the level of the ventricular myocyte, and its potential cardioprotective and anti-arrhythmic efficacy in the setting of acquired and inherited ventricular dysfunction and arrhythmias.

Human iPSC-Derived Cardiomyocytes for Investigation of Disease Mechanisms and Therapeutic Strategies in Inherited Arrhythmia Syndromes: Strengths and Limitations

“…Although the initial large inward I Na that contributes to the AP upstroke is for the most part rapidly inactivated, a small fraction of the current (designated the late sodium current, I NaL ) persists throughout the duration of the AP plateau. Enhanced I NaL is typically found during heart failure and long QT syndrome type 3 (LQT3, see “ Pharmacological Studies for Inherited Arrhythmia Syndromes Using hiPSC-CMs ” section) [ 42 ]. I NaL in freshly isolated healthy human CMs is small [ 38 ]; in some hiPSC-CMs studies, I NaL was observed to be similarly small [ 31 , 35 ], while in other studies, it was reported to be absent [ 37 , 40 ].…”

Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects

“…However, β‐blockers may not be ideal in LQT3 (since cardiac events occur mostly during rest or sleep), and the effects of sodium channel blockers are probably mutation specific. More recently, the late sodium current inhibitor ranolazine has been proposed as a potential pharmacological therapy for cardiac sodium channel disease related to gain of sodium current function, including LQT3 (Fredj et al 2006, Moss et al 2008; Remme & Wilde, 2013). Indeed, in a small set of five patients carrying the SCN5A ‐ΔKPQ mutation, short‐term ranolazine infusion significantly decreased QTc‐intervals in the absence of adverse effects (Moss et al 2008), indicating a potential beneficial effect of late sodium current inhibition in LQT3 (discussed further below).…”

“…Interestingly, the late sodium current blocker ranolazine was effective in reducing or preventing intracellular calcium overload in vitro (Lindegger et al 2009). Thus, pharmacological late sodium current inhibition by compounds such as ranolazine may prove a useful and beneficial therapeutic approach in LQT3 patients, not only through stabilizing repolarization abnormalities, but also by preventing more long‐term detrimental effects of intracellular calcium overload (see Remme & Wilde, 2013). Moreover, increased sodium influx with subsequent activation of CAMKII was observed in cardiomyocytes from mice overexpressing the human SCN5A ‐N1325S gain‐of‐function mutation (Yao et al 2011), providing another potential therapeutic target.…”

The transient receptor potential melastatin 4 channel inhibitor 9‐phenanthrol modulates cardiac sodium channel

“…Enhanced I NaL has been linked with excessive prolongation of APD, the occurrence of EADs and increased transmural dispersion of repolarization, especially under pathophysiological conditions, such as LQT3, heart failure, oxidative stress and ischaemia–reperfusion (Remme and Wilde, ; Belardinelli et al, ; Fei et al, ). In our study, we used the known I NaL enhancer ATX‐II to increase this persistent current which resulted in prolonged APD and occurrence of EADs and TdP.…”