Intracellular Na+ and altered Na+ transport mechanisms in cardiac hypertrophy and failure

Abstract

Altered intracellular Na(+) ([Na(+)](i)) is a potentially important factor in the functional adaptation of the hypertrophied and failing heart. We review the currently reported changes in [Na(+)](i) and Na(+) transport in different models of cardiac hypertrophy and heart failure. Direct measurements are limited, but most of these indicate that there is a rise in [Na(+)](i), in particular in hypertrophy. In addition to these direct measurements, several studies report a rise in Na(+) influx or an upregulation of Na(+) influx transporters. The most extensive literature on Na(+) regulating pathways concerns the Na/K-ATPase. Total Na/K-ATPase activity decreases in most models of cardiac hypertrophy and failure, though few measurements were actually performed in intact cells. This decrease can been related to a selective reduction of high-affinity (for cardiac glycosides) Na/K pump alpha-isoforms, across many species and models, including human heart failure. We have used these data to predict changes of [Na(+)](i) in a simulation model, varying the contribution of total Na/K pump capacity and expression of isoforms with different Na(+)(i) affinities, and varying Na(+) influx. A rise in Na(+) in cardiac hypertrophy and failure may improve systolic contractile function, though at the cost of worsening of diastolic function and increased risk of ventricular arrhythmias. The benefit of further increasing [Na(+)](i,) e.g. with cardiac glycosides, is thus compromised. Future therapies may include selective isoform blockers, which could raise [Na(+)](i) in restricted subcellular compartments, drug associations that reduce the arrhythmic risk, or even drugs that lower [Na(+)](i) and thus interfere with the remodelling pathways.