The role of NHE-1 in myocardial hypertrophy and remodelling

Na–H exchange (NHE) is the primary process by which the cardiac cell extrudes protons particularly under conditions of intracellular acidosis. Nine isoforms of NHE have now been identified. Although these antiporters are expressed in virtually all tissues, cardiac cells posses primarily the ubiquitous NHE-1 subtype. It has been well established that NHE-1 is a major contributor to acute ischemic and reperfusion injury although it is now emerging that NHE-1 contributes to chronic maladaptive myocardial responses to injury such as post-infarction myocardial remodelling and likely contributes to the development of heart failure. Experimental studies using both in vitro approaches as well as animal models of heart failure have consistently demonstrated a beneficial effect of NHE-1 inhibitors in attenuating hypertrophy in response to various stimuli as well as inhibiting heart failure in a variety of animal models representing experimentally-induced or genetic models of heart failure. The beneficial effects of NHE-1 inhibitors occur independently of infarct size reduction or on any direct effects on afterload thus implicating a direct antiremodelling influence of these agents. It is proposed that NHE-1 inhibition represents a potentially effective new therapeutic approach for the treatment of heart failure.