Clinical potential of sodium-calcium exchanger inhibitors as antiarrhythmic agents

The Na(+)/Ca(2+) exchanger (NaCaX) plays an important role in calcium handling in myocytes, but in the setting of calcium overload NaCaX can also contribute to the activation of an arrhythmogenic transient inward current (I(ti)). Therefore, approaches to inhibit NaCaX could have potential antiarrhythmic effects in pathophysiological states such as heart failure (HF) or myocardial ischaemia and reperfusion. NaCaX typically functions in a forward (Ca(2+) extrusion) mode but can also function in a reverse (Ca(2+) influx) mode. The determining factors for the directionality of NaCaX ion movement are the electrochemical gradients of calcium and sodium, and membrane potential (E(m)). In HF, upregulated NaCaX plays a dual role: it decreases sarcoplasmic reticulum (SR) calcium load, which leads to contractile dysfunction, and it underlies the I(ti) responsible for delayed after-depolarisations (DADs) and ventricular arrhythmias. In myocardial ischaemia and reperfusion, increases in [Na(+)](i) (as a result of acidosis and activation of the Na(+)/H(+) exchanger [NHE]) lead to calcium overload via the NaCaX and arrhythmogenesis is probably mediated by I(ti) activation due to NaCaX. As such, inhibition of NaCaX could provide a novel therapeutic approach to the prevention and treatment of arrhythmias. Unfortunately, it is difficult to assess the efficacy of such an approach since there are no specific NaCaX inhibitors. Currently available agents are hampered by their nonspecific effects on other ion channels and carriers. The potential utility of specific inhibition of forward or reverse mode NaCaX as an antiarrhythmic approach in the settings of HF and ischaemia/ reperfusion is discussed within the context of current knowledge of myocyte calcium and sodium handling. NaCaX is a challenging and complex therapeutic target because of the delicate balance of SR calcium load (too little contributes to contractile dysfunction and too much leads to calcium overload and arrhythmogenesis). Further understanding of NaCaX function, [Na(+)](i) and [Ca(2+)](i) in HF and ischaemia/reperfusion, combined with the development and assessment of specific NaCaX inhibitors, will ultimately define the potential role of NaCaX inhibition in the prevention and treatment of ventricular arrhythmias.