Cardioplegic Strategies for Calcium Control

Abstract

Background —Ca 2+ overload plays an important role in the pathogenesis of cardioplegic ischemia-reperfusion injury. The standard technique to control Ca 2+ overload has been to reduce Ca 2+ in the cardioplegic solution (CP). Recent reports suggest that Na + /H + exchange inhibitors can also prevent Ca 2+ overload. We compared 4 crystalloid CPs that might minimize Ca 2+ overload in comparison with standard Mg 2+ -containing CP: (1) low Ca 2+ CP (0.25 mmol/L), (2) citrate CP/normal Mg 2+ (1 mmol/L Mg 2+ ), (3) citrate CP/high Mg 2+ (9 mmol/L Mg 2+ ), and (4) the addition of the Na + /H + exchange inhibitor HOE-642 (Cariporide). We also tested the effect of citrate titration in vitro on the level of free Ca 2+ and Mg 2+ in CPs. Methods and Results —Isolated working rat heart preparations were perfused with oxygenated Krebs-Henseleit buffer and subjected to 60 minutes of 37°C arrest and reperfusion with CPs with different Ca 2+ concentrations. Cardiac performance, including aortic flow (AF), was measured before and after ischemia. Myocardial high-energy phosphates were measured after reperfusion. The in vitro addition of citrate to CP (2%, 21 mmol/L) produced parallel reductions in Mg 2+ and Ca 2+ . Because only Ca 2+ was required to be low, the further addition of Mg 2+ increased free Mg 2+ , but the highest level achieved was 9 mmol/L. Citrate CP significantly impaired postischemic function (AF 58.3±2.5% without citrate versus 41.6±3% for citrate with normal Mg 2+ , P <0.05, versus 22.4±6.2% for citrate with high Mg 2+ , P <0.05). Low-Ca 2+ CP (0.25 mmol/L Ca 2+ ) significantly improved the recovery of postischemic function in comparison with standard CP (1.0 mmol/L Ca 2+ ) (AF 47.6±1.7% versus 58.3±2.5%, P <0.05). The addition of HOE-642 (1 μmol/L) to CP significantly improved postischemia function (47.6±1.7% without HOE-642 versus 62.4±1.7% with HOE-642, P <0.05). Postischemia cardiac high-energy phosphate levels were unaffected by Ca 2+ manipulation. Conclusions —(1) A lowered Ca 2+ concentration in CP is beneficial in Mg 2+ -containing cardioplegia. (2) The use of citrate to chelate Ca 2+ is detrimental in the crystalloid-perfused isolated working rat heart, especially with high Mg 2+ . (3) The mechanism of citrate action is complex, and its use limits precise simultaneous control of Ca 2+ and Mg 2+ . (4) HOE-642 in CP is as efficacious in preservation of the ischemic myocardium as is the direct reduction in Ca 2+ .