Role of Intracellular Sodium Overload in the Genesis of Cardiac Arrhythmias

A number of clinical cardiac disorders may be associated with a rise of the intracellular Na concentration (Na(i)) in heart muscle. A clear example is digitalis toxicity, in which excessive inhibition of the Na/K pump causes the Na(i) concentration to become raised above the normal level. Especially in digitalis toxicity, but also in many other situations, the rise of Na(i) may be an important (or contributory) cause of increased cardiac arrhythmias. In this review, we consider the mechanisms by which a raised Na(i) may cause cardiac arrhythmias. First, we describe the factors that regulate Na(i), and we demonstrate that the equilibrium level of Na(i) is determined by a balance between Na entry into the cell, and Na extrusion from the cell. A number of mechanisms are responsible for Na entry into the cell, whereas the Na/K pump appears to be the main mechanism for Na extrusion. We then consider the processes by which an increased level of Nai might contribute to cardiac arrhythmias. A rise of Na(i) is well known to result in an increase of intracellular Ca, via the important and influential Na/Ca exchange mechanism in the cell membrane of cardiac muscle cells. A rise of intracellular Ca modulates the activity of a number of sarcolemmal ion channels and affects release of intracellular Ca from the sarcoplasmic reticulum, all of which might be involved in causing arrhythmia. It is possible that the increase in contractile force that results from the rise of intracellular Ca may initiate or exacerbate arrhythmia, since this will increase wall stress and energy demands in the ventricle, and an increase in wall stress may be arrhythmogenic. In addition, the rise of Na(i) is anticipated to modulate directly a number of ion channels and to affect the regulation of intracellular pH, which also may be involved in causing arrhythmia. We also present experiments in this review, carried out on the working rat heart preparation, which suggest that a rise of Na(i) causes an increase of wall stress-induced arrhythmia in this model. In addition, we have investigated the effect on wall stress-induced arrhythmia of maneuvers that might be anticipated to change intracellular Ca, and this has allowed identification of some of the factors involved in causing arrhythmia in the working rat heart.