Pathophysiology of the cardiac late Na current and its potential as a drug target

Abstract

A pathological increase in the late component of the cardiac Na(+) current, I(NaL), has been linked to disease manifestation in inherited and acquired cardiac diseases including the long QT variant 3 (LQT3) syndrome and heart failure. Disruption in I(NaL) leads to action potential prolongation, disruption of normal cellular repolarization, development of arrhythmia triggers, and propensity to ventricular arrhythmia. Attempts to treat arrhythmogenic sequelae from inherited and acquired syndromes pharmacologically with common Na(+) channel blockers (e.g. flecainide, lidocaine, and amiodarone) have been largely unsuccessful. This is due to drug toxicity and the failure of most current drugs to discriminate between the peak current component, chiefly responsible for single cell excitability and propagation in coupled tissue, and the late component (I(NaL)) of the Na(+) current. Although small in magnitude as compared to the peak Na(+) current (~1-3%), I(NaL) alters action potential properties and increases Na(+) loading in cardiac cells. With the increasing recognition that multiple cardiac pathological conditions share phenotypic manifestations of I(NaL) upregulation, there has been renewed interest in specific pharmacological inhibition of I(Na). The novel antianginal agent ranolazine, which shows a marked selectivity for late versus peak Na(+) current, may represent a novel drug archetype for targeted reduction of I(NaL). This article aims to review common pathophysiological mechanisms leading to enhanced I(NaL) in LQT3 and heart failure as prototypical disease conditions. Also reviewed are promising therapeutic strategies tailored to alter the molecular mechanisms underlying I(Na) mediated arrhythmia triggers.

Figure 1. Mechanisms of late I_Na

A) Schematic of an increased window current (shaded region) in the LQT3 linked N1325S. The dotted lines represent the wild-type. Note the minimal overlap between steady-state inactivation and the activation curve normally exists outside the voltage range of repolarization. Adapted from [8]. B) Modal gating of I_NaL. A simulation demonstrating three modes (left panels) of gating, transients, late scattered, and bursts comprise the total I_Na current (right panel) (simulation time course is shown). Adapted from [1]. C) Non-equilibrium gating of I1768V. A schematic of a negative ramp protocol. Persistent current was measured at the end of a 100ms depolarizing pulse (arrow) and was not significantly different between wild-type and the I1768V mutation. Ramp currents were measured as the peak inward current during the negative ramp protocol and were significantly larger in the mutant Na⁺ channel (summary data in bar graph on right). Adapted from [38].

Figure 2. Electrical gradients within the myocardium detected on the ECG, and action potential prolongation via mutation induced late I_Na

A. and B. Schematic representation of the relationship between an action potential and the ECG detected as spatial and temporal gradients for one cardiac cycle. The P wave represents atrial depolarization, the QRS complex represents ventricular activation, and the T wave represents the gradient of ventricular repolarization. Dotted lines indicate the link between deflections on the ECG and underlying cellular level electrical events. B. Schematic of the cellular electrical activity underlying the ECG. C and D: Simulated action potential (top) and I_Na (bottom) for wild-type (C) and ΔKPQ (D). In the wild-type, Na⁺ channels activate, followed quickly by inactivation; ΔKPQ mutant channels fail to inactivate and cause a small, persistent (<5% peak) Na⁺ current (panel D, bottom) that prolongs the action potential and can lead to arrhythmogenic early afterdepolarizations (EADs) shown in the top panel of D. Note, in both C and D bottom panels, peak I_Na is off scale. Figure adapted from [59, 60].

Figure 3. Cascade of I_NaL induced dysfunction

Congenital and acquired conditions exhbit an increased late Na⁺ current, which can both cause electrical and mechanical instability. Blocking I_NaL, may effectively blunt the cascade of I_NaL induced cardiac dysfunction. See text for details. Figure adapted from [42, 105].

Figure 4. Pharmacological targeting of I_NaL normalizes APs in a pharmacological model of LQT3 and in heart failure

(A) Superimposed recordings of 10 consecutive action potentials from a guinea pig myocyte in the presence of 10nM ATX-II, and (B) in the presence of 10nM ATX-II and 10 μM ranolazine. Modified from [121]. (C) Ranolazine (RAN) reduces APD variability in left ventricular myocytes isolated from canine failing hearts. (A) Twelve consecutive APs recorded at a pacing rate of 0.25 Hz are superimposed. (B) APs recorded in the presence of 10 μM ranolazine. From [98].