NHE-1: still a viable therapeutic target.

The concept of NaH exchange (NHE) involvement in cardiac pathology has been espoused for decades and supported by a plethora of experimental studies demonstrating salutary effects of NHE inhibition in protecting the myocardium against ischemic and reperfusion injury as well as attenuating myocardial remodelling and heart failure. NHE is actually a family of sodium and proton transporting proteins of which 10 isoforms have been identified. Myocardial NHE is represented primarily by the ubiquitous NHE-1 subtype which is expressed in most tissues. The robust positive results seen with NHE-1 inhibitors in experimental studies have led to relatively rapid development of these pharmacological agents for clinical assessment especially as potential cardioprotective therapies. Yet clinical studies have revealed, at best, inconsistent results as evidenced by poor efficacy and serious side effects, the latter revealed with the use of the NHE-1 inhibitor cariporide in high-risk patients undergoing coronary artery bypass grafting and evidenced by an increased incidence of cerebrovascular events of thromboembolic origin. The lack of success in clinical trials coupled with potential for toxicity has had a negative impact on development of cardiac therapeutic agents which have been developed based on the concept of NHE-1 inhibition. Whether this response is justified is open for discussion although a close scrutiny of clinical trial outcomes suggests that it may not be and that NHE-1 inhibition, if applied appropriately continues to represent an effective, if not the most effective approach for myocardial salvage following ischemic insult. Moreover, in addition to its cardioprotective effects, emerging evidence further suggests that NHE-1 inhibition is an effective strategy to minimize myocardial remodelling as well as a potentially effective strategy to improve efficacy of resuscitation following cardiac arrest. Thus, NHE-1 inhibition continues to represent a potentially highly effective therapeutic approach for the treatment of heart disease. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes".