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REVIEW ARTICLE

Na⁺/h⁺ exchange inhibitors for cardioprotective therapy: progress, problems and prospects

^a Centre for Cardiovascular Biology and Medicine and Department of Cardiology, King’s College London, The Rayne Institute, St Thomas’ Hospital, London, United Kingdom

Manuscript received September 25, 2001; revised manuscript received December 4, 2001, accepted December 14, 2001.

^* Reprint requests and correspondence: Professor Metin Avkiran, Centre for Cardiovascular Biology and Medicine, The Rayne Institute, St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom
metin.avkiran{at}kcl.ac.uk

Extensive pre-clinical work indicates that inhibition of the sarcolemmal Na⁺/H⁺ exchanger (NHE) affords significant protection to myocardium subjected to ischemia and reperfusion, predominantly through reduced intracellular accumulation of Na⁺ and consequently Ca²⁺. In contrast, recent clinical studies with the NHE inhibitors cariporide and eniporide in patients with evolving myocardial infarction (MI) and those at risk of MI have provided mixed and somewhat contradictory data. The experimental evidence suggests that the key mechanism through which NHE inhibitors afford protection consists in slowing the progression of myocardial injury during ischemia and thereby enhancing myocardial salvage by reperfusion. It follows from this that, to obtain maximum cardioprotective benefit, 1) the NHE inhibitor must be present in jeopardized myocardium, at a concentration sufficient to inhibit NHE activity, before (or as soon as possible after) the onset of ischemia, and 2) ischemia must be terminated by timely reperfusion. Thus, in the GUARDIAN trial, the cardioprotective efficacy of cariporide was limited to the subset of high-risk patients who underwent coronary artery bypass graft surgery, in whom both prerequisites could be readily fulfilled. In contrast, no cardioprotective benefit was observed in the ESCAMI trial, in which eniporide was administered late as an adjunct to reperfusion therapy in patients with evolving MI. Ongoing clinical studies will determine whether NHE inhibition will find therapeutic application in the setting of cardiac surgery, while pre-clinical investigations continue to test the potential of NHE inhibitors in the treatment of other cardiovascular diseases such as heart failure.

Abbreviations and Acronyms   CABG = coronary artery bypass graft   CK = creatine kinase   CK-MB = creatine kinase-MB isoform   ECG = electrocardiogram   ESCAMI = Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction   EXPEDITION = Na+/H+ Exchange Inhibition to Prevent Coronary Events in Acute Cardiac Conditions   GUARDIAN = Guard During Ischemia Against Necrosis   MI = myocardial infarction   NCX = Na+/Ca2+ exchanger   NHE = Na+/H+ exchanger   PCI = percutaneous coronary intervention

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