Blood cardioplegia supplementation with the sodium-hydrogen ion exchange inhibitor cariporide to attenuate infarct size and coronary artery endothelial dysfunction after severe regional ischemia in a canine model☆☆☆★

Background: Activation of the sodium-hydrogen ion exchange mechanism results in accumulation of intracellular calcium through the sodium-calcium ion antiport mechanism. Administration of a sodium-hydrogen ion exchange inhibitor before or during ischemia attenuates myocardial ischemia and reperfusion injury. However, the cardioprotection exerted by sodium-hydrogen ion exchange inhibitors as adjuncts to cardioplegia without perioperative administration has not been tested in a model of surgical reperfusion of acute coronary occlusion with cardiopulmonary bypass. This study tested the hypothesis that sodium-hydrogen ion exchange inhibitor-supplemented blood cardioplegia would reduce postcardioplegia injury after severe regional ischemia. Methods: In anesthetized open-chest dogs, the left anterior descending coronary artery was occluded for 75 minutes, after which total cardiopulmonary bypass was initiated. After crossclamping, cold (4°C) antegrade blood cardioplegia was delivered every 20 minutes for a total of 60 minutes of cardioplegic arrest. In 8 dogs, the blood cardioplegic solution was unsupplemented (vehicle group), whereas in 8 others the solution was supplemented with the sodium-hydrogen ion exchange inhibitor cariporide (10 μmol/L, cariporide group). Results: In the in vitro studies, the direct effects of cariporide on neutrophil function were determined. Isolated canine neutrophils were stimulated by platelet activating factor. Cariporide attenuated superoxide anion production in a concentration-dependent manner, with no appreciable effect at 10 μmol/L (the concentration used in blood cardioplegia) and a peak effect at 100 μmol/L. In the in vivo cardiopulmonary bypass model, infarct size was significantly (P < .05) smaller in the cariporide group than in the vehicle group (22.4% ± 3.5% vs 40.1% ± 5.1% of area at risk), although there were no group differences in postischemic regional wall motion after 2 hours of reperfusion (0.1% ± 0.9% vs −0.2% ± 0.3% systolic shortening). Transmural myocardial edema in the area at risk was significantly decreased in the cariporide group (80.6% ± 0.5%) relative to the vehicle group (83.1% ± 0.6%). Myeloperoxidase activity in the area at risk, an index of neutrophil accumulation, was significantly lower in the cariporide group than in the vehicle group (4.7 ± 0.9 absorbence units/[min · g tissue] vs 10.3 ± 2.3 absorbence units/[min · g tissue]). In isolated postischemic left anterior descending coronary artery rings, maximum relaxation in response to the endothelium-dependent vasodilator acetylcholine was significantly greater in the cariporide group than in the vehicle group (77.5% ± 7.4% vs 51.4% ± 8.0%), whereas smooth muscle relaxation in response to nitroprusside was comparable between groups. Conclusion: In this canine model, supplementation of blood cardioplegia with cariporide, a sodium-hydrogen ion exchange inhibitor, reduced infarct size, attenuated neutrophil accumulation in the area at risk, and reduced postischemic coronary artery endothelial dysfunction without directly inhibiting neutrophil activity. Cariporide as an adjunct to blood cardioplegia without perioperative administration attenuated surgical ischemia-reperfusion injury in jeopardized myocardium.

J Thorac Cardiovasc Surg 2003;125:155-64