Na/K pump regulation of cardiac repolarization: insights from a systems biology approach

Abstract

The sodium-potassium pump is widely recognized as the principal mechanism for active ion transport across the cellular membrane of cardiac tissue, being responsible for the creation and maintenance of the transarcolemmal sodium and potassium gradients, crucial for cardiac cell electrophysiology. Importantly, sodium-potassium pump activity is impaired in a number of major diseased conditions, including ischemia and heart failure. However, its subtle ways of action on cardiac electrophysiology, both directly through its electrogenic nature and indirectly via the regulation of cell homeostasis, make it hard to predict the electrophysiological consequences of reduced sodium-potassium pump activity in cardiac repolarization. In this review, we discuss how recent studies adopting the Systems Biology approach, through the integration of experimental and modeling methodologies, have identified the sodium-potassium pump as one of the most important ionic mechanisms in regulating key properties of cardiac repolarization and its rate-dependence, from subcellular to whole organ levels. These include the role of the pump in the biphasic modulation of cellular repolarization and refractoriness, the rate control of intracellular sodium and calcium dynamics and therefore of the adaptation of repolarization to changes in heart rate, as well as its importance in regulating pro-arrhythmic substrates through modulation of dispersion of repolarization and restitution. Theoretical findings are consistent across a variety of cell types and species including human, and widely in agreement with experimental findings. The novel insights and hypotheses on the role of the pump in cardiac electrophysiology obtained through this integrative approach could eventually lead to novel therapeutic and diagnostic strategies.

Inter-Subject Variability in Human Atrial Action Potential in Sinus Rhythm versus Chronic Atrial Fibrillation

“…Our findings suggest the need for pharmacological assessment of potential drug effects on the sodium/potassium pump (as is the case of amiodarone, for example) due to its importance on atrial repolarization, in addition to effects on currently evaluated currents such as sodium, potassium and calcium channels [55]–[58].…”

Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6

“…The well described Na + /K + pump contributes to the generation of resting membrane potentials and repolarization of cardiac action potentials. 22 Another electrogenic transporter, Na + /Ca 2+ exchanger (NCX), is not only important in intracellular Ca 2+ homeostasis and cardiac contractility, but also in the regulation of cardiac excitability and arrhythmogenesis. Similar to Slc26a6 −/− , cardiac-specific NCX knockout mice show an abbreviated APD in cardiomyocytes.…”

Association of Perioperative Serum Sodium Level Fluctuation and Postoperative Complications in Coronary Artery Bypass Graft Surgery

“…Although changes in sodium levels in our study did not show any significant differences, patients undergoing CABG might encounter complications in brain and other vital organs which renders information about the mechanism of high level sodium in leading to post-operative complications. 4 Multidiscip Cardio Annal. In Press(In Press):e62857.…”