Triple threat: the Na+/Ca2+ exchanger in the pathophysiology of cardiac arrhythmia, ischemia and heart failure

Abstract

The Na(+)/Ca(2+) exchanger (NCX) is the main Ca(2+) extrusion mechanism of the cardiac myocyte and thus is crucial for maintaining Ca(2+) homeostasis. It is involved in the regulation of several parameters of cardiac excitation contraction coupling, such as cytosolic Ca(2+) concentration, repolarization and contractility. Increased NCX activity has been identified as a mechanism promoting heart failure, cardiac ischemia and arrhythmia. Transgenic mice as well as pharmacological interventions have been used to support the idea of using NCX inhibition as a future pharmacological strategy to treat cardiovascular disease.

Fig. 1

Role of NCX in cellular Ca²⁺ cycling during excitation-contraction coupling in cardiac myocytes. During the action potential Ca²⁺ enters the myocyte via the voltage dependent sarcolemmal L-type Ca²⁺ channel, and thus triggers further Ca²⁺ release from the sarcoplasmic reticulum via sarcoplasmic Ca²⁺ release channels (ryanodine receptors). The released Ca²⁺ diffuses towards the myofilaments and induces the contraction. During diastole Ca²⁺ is shifted back into sarcoplasmic reticulum by the Ca²⁺ ATPase of the sarcoplasmic reticulum (SERCA). The Na⁺/Ca²⁺ exchanger extrudes Ca²⁺ from the cytosol into the extracellular space.

Fig. 2

Concept of cellular mechanisms of adaptation to reduced and increased NCX activity as modelled from studies in NCX knockout (a, [32, 35]) and overexpressor mice (b, [68]).

Fig. 3

NCX activity regulates AP repolarization in adult cardiac myocytes. Middle column: typical “pyramid”-like mouse AP recorded in a myocyte isolated from a WT animal. Left column: A lack of the plateau phase due to a faster repolarization of the AP is observed in myocytes isolated from NCX KO mice. Right column: In myocytes isolated from mice that homozygously overexpress NCX (HOM), a slowed repolarization with a pronounced plateau phase can be observed (modified from [35, 68]).

Fig. 4

Pathophysiological concept on the role of NCX in the mediation of cardiac arrhythmia (modified from [76]).

Fig. 5

Ca²⁺ entry induced by Na⁺ depletion is absent in NCX KO myocytes: Recording of cytosolic Ca²⁺ concentration in patch clamped cardiac myocytes isolated from NCX KO and WT mice. Ca²⁺ entry via NCX reverse mode was induced in WT myocytes by hyperpolarization and simultaneous rapid removal of external Na⁺. Under these conditions, no increase in cytosolic Ca²⁺ concentration was observed in NCX KO cells. (Modified from [12]).