Role of NCX1 and NHE1 in Ventricular Arrhythmia

Abstract

Lethal ventricular arrhythmias are one of the primary causes of high mortality among patients with a variety of cardiac diseases, like acute ischemia-reperfusion injury, chronic ischemic heart disease (IHD), all major forms of heart failure (HF), and congenital cardiomyopathies. Perturbations in intracellular Ca²⁺ and Na⁺ homeostasis leading to massive intracellular Ca²⁺ overload are frequently found in the background of cardiac arrhythmogenesis. Recent data explicitly demonstrate that these perturbations are tightly connected to enhanced function and overexpression of two cardiac sarcolemmal ion transporters, the Na⁺/Ca²⁺ exchanger (NCX1), a major regulator of the intracellular Ca²⁺ concentration ([Ca²⁺]_i), and the Na⁺/H⁺ exchanger (NHE1), the primary regulator of intracellular pH. Recent efforts to delineate the real therapeutic value of NCX1 modulation were still hampered by the absence of specific and effective inhibitors and the total absence of specific activators. On the other side, several well-established inhibitors of the NHE1 are already in clinical practice or under evaluation but human data—promising in limiting the size of the ischemic injury—are much less convincing in preventing lethal ventricular arrhythmias. In this chapter, we aim to discuss the involvement of these two ion transporters in the regulation of the [Ca²⁺]_i homeostasis in the healthy and diseased heart, to underline their principal contribution to the generation of ventricular arrhythmia, and to summarize experimental results obtained in studies in the direction of their antiarrhythmic and cardioprotective modulation.