Review article
Late sodium current inhibition as a new cardioprotective approach

https://doi.org/10.1016/j.yjmcc.2008.03.019Get rights and content

Abstract

There is increasing evidence that the late sodium current of the sodium channel in myocytes plays a critical role in the pathophysiology of myocardial ischemia and thus is a potential therapeutic target in patients with ischemic heart disease. Ranolazine, an inhibitor of the late sodium current, reduces the frequency and severity of anginal attacks and ST-segment depression in humans, and unlike other antianginal drugs, ranolazine does not alter heart rate or blood pressure. In experimental animal models, ranolazine has been shown to reduce myocardial infarct size and to improve left ventricular function after acute ischemia and chronic heart failure. This article reviews published data describing the role of late sodium current and its inhibition by ranolazine in clinical and experimental studies of myocardial ischemia.

Introduction

This review presents evidence that inhibition of the late sodium current (late INa; see Glossary) in the heart is beneficial to reduce electrical and mechanical dysfunction during ischemia. The pathophysiological role of late INa to increase Na+ and Ca2+ overload during myocardial ischemia is summarized. Studies showing that ranolazine, the first selective late INa inhibitor approved for human use, is beneficial in preclinical models of ischemia, infarction, heart failure and arrhythmias are discussed, and clinical trials of the efficacy and safety of ranolazine are reviewed. For additional reviews of the cardioprotective and neuroprotective roles of Na+-channel blockers the reader is referred to [1], [2], [3], [4], [5], [6], [7].

Ranolazine is an antianginal drug that acts to reduce the late (i.e., persistent), but not the early (i.e., peak or transient), influx of sodium through cardiac sodium channels in myocardial cells. In patients, ranolazine reduces the frequency of anginal attacks, increases time to ST-segment depression during a treadmill exercise test, and improves exercise tolerance. Ranolazine is the first antianginal agent capable of producing anti-ischemic effects without altering heart rate or blood pressure. In experimental animal studies, the drug has been shown to reduce myocardial infarct size and to improve left ventricular function both after acute ischemia and during chronic heart failure.

Section snippets

Dysregulation of intracellular Na+ and Ca2+ homeostasis during ischemia: The role of the late sodium current

Myocardial ischemia is characterized by an imbalance of oxygen supply and demand that leads to a dysregulation of ionic homeostasis in myocardial cells, which when severe and prolonged, is followed by marked cellular depolarization and death [8]. An early event during ischemia is a rise in the cytosolic Na+ concentration [1], [9], [10], [11]. Increases of late INa and Na+ influx via sodium–hydrogen exchange (NHE) in response to intracellular acidification both contribute to the rise of

Inhibition of the late sodium current by ranolazine

Ranolazine, by inhibiting late INa, is believed to alter the pathophysiology associated with cellular Ca2+ overload. The evidence that ranolazine, at concentrations within its proposed therapeutic range (≤ 10 µM), significantly reduces late INa and reverses or prevents the consequences of an increase of late INa is substantial. Inhibition of late INa by ranolazine has been demonstrated both indirectly and directly, in heart tissues and single myocytes. Ranolazine reduced late INa in mouse

Calcium channels, NCX, and NHE

Ranolazine at therapeutic concentrations (≤ 10 µM) causes minimal or no inhibition of peak [69], [71], [78] or late Ca2+ channel current (ICa) [70], NCX [70], or NHE [20]. Thus, the effect of ranolazine to reduce Ca2+ overload is not dependent on reduction of Ca2+ entry through Ca2+ channels, inhibition of NCX, or inhibition of NHE, but is rather by an indirect mechanism [i.e., reduction of late INa; see Fig. 1]. Further evidence supporting an indirect effect on intracellular Ca2+ concentrations

Isolated heart preparations

Considerable data from animal studies suggest that ranolazine treatment during ischemia reduces cell death and improves left ventricular function. In the early nineties, in one of the first studies of ranolazine treatment during acute myocardial ischemia, Clarke et al. described the cardioprotective effects of ranolazine on ischemic myocardium in isolated guinea pig hearts during low-flow ischemia [80]. They noted that in the presence of ranolazine cellular ATP was better preserved, and release

Clinical perspective

It has been some time since a new antianginal therapy has been introduced in the United States. Nitrates (1867) and beta blockers (1962) were the standard of care for treatment of chronic angina for many years. Coronary artery bypass surgery was introduced in 1967 and percutaneous transluminal coronary angioplasty in 1977 (in Switzerland). Calcium channel blockers were approved in the early 1980s. Ranolazine is the first new pharmacologic agent specifically developed in the United States to

Early clinical studies

To demonstrate that an agent is effective in reducing angina pectoris requires evidence that the agent is superior to placebo and/or at least equivalent to approved comparators in improving certain objective parameters during exercise testing, e.g., time to onset of angina, total exercise duration, time to 0.1 mV (1 mm) ST-segment depression. These measures are usually coupled with questions regarding the number of anginal episodes a patient develops during a week or the number of times a week

Conclusions and future directions

Late sodium current inhibition with ranolazine has been demonstrated to reduce myocardial ischemia and to be safe and effective in the relief of symptoms of angina and myocardial ischemia in multiple studies. Initial concerns regarding the possible proarrhythmic consequences of the QTc prolongation (2–6 ms at therapeutic doses) observed with ranolazine have been addressed in the MERLIN study in which ranolazine use was associated with a reduction in the numbers of both tachy- and

Glossary

ACS
acute coronary syndrome
AP
action potential
APD
action potential duration
ATX-II
anemone toxin-II
CK
creatine kinase
EAD
early after-depolarization
ICa
calcium current
INa
sodium current
LV
left ventricle
NCX
sodium–calcium exchange
NHE
sodium–hydrogen exchange
PCI
percutaneous coronary intervention
TdP
torsades de pointes
VT
ventricular tachycardia

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