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J Thorac Cardiovasc Surg 2003;126:1489-1497
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary support and physiology

Direct inhibition of the sodium/hydrogen exchanger after prolonged regional ischemia improves contractility on reperfusion independent of myocardial viability

^a Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC, USA

Received for publication February 5, 2003; revisions received March 24, 2003; accepted for publication May 19, 2003.

^* Address for reprints: Francis G. Spinale, MD, PhD, Cardiothoracic Research, Strom Thurmond Research Building, 770 MUSC Complex, Suite 625, Medical University of South Carolina, Charleston, SC 29425., USA

BACKGROUND: A mechanism for myocardial dysfunction after ischemia and reperfusion is Na⁺/H⁺ exchanger activation. Although past in vivo models of limited ischemia and reperfusion intervals demonstrate that Na⁺/H⁺ exchanger inhibition confers myocardial protection when administered at the onset of ischemia, the effect of Na⁺/H⁺ exchanger inhibition on myocardial function after prolonged ischemia and reperfusion remains unknown. This investigation tested the hypothesis that Na⁺/H⁺ exchanger inhibition instituted at reperfusion and after prolonged coronary occlusion in pigs would influence myocardial contractility independent of myocardial viability.

METHODS: A coronary snare and sonomicrometry crystals were placed in pigs (n = 21, 32 kg). Coronary occlusion was instituted for 120 minutes followed by reperfusion for 180 minutes. At 105 minutes of ischemia, pigs were randomized to ischemia and reperfusion only (saline solution, n = 11) or Na⁺/H⁺ exchanger inhibition (HOE-642, 3 mg/kg intravenously, n = 10). Myocardial injury was determined by tissue staining and measurement of plasma myocyte–specific enzymes. Myocardial contractility was determined by calculation of the regional end-systolic pressure-dimension relation (millimeters of mercury per centimeter) and by assessment of interregional shortening.

RESULTS: Infarct size was not different between groups (39% ± 6%, P = .26). Moreover, at 180 minutes of reperfusion, plasma troponin-I and creatine kinase MB values had increased to identical levels in the ischemia and reperfusion–only and Na⁺/H⁺ exchanger inhibition groups (300 ± 35 and 50 ± 6 ng/mL, respectively). At 90 minutes of ischemia, regional end-systolic pressure-dimension relation decreased from baseline (5.7 ± 0.5 versus 2.7 ± 0.3, P < .05) in the area at risk. By 30 minutes of reperfusion, regional end-systolic pressure-dimension relation decreased further in the ischemia and reperfusion–only group (1.6 ± 0.2, P < .05), but improved with Na⁺/H⁺ exchanger inhibition (4.4 ± 0.7, P < .05).

CONCLUSIONS: Na⁺/H⁺ exchanger inhibition instituted at reperfusion improved contractility independent of myocardial viability as assessed by absolute infarct size and myocyte-specific enzyme release. Thus, modulation of Na⁺/H⁺ exchanger activity in the setting of prolonged ischemia and reperfusion may hold therapeutic potential.