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(Circulation. 2000;102:III-319.)
© 2000 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Cardioplegic Strategies for Calcium Control

Low Ca²⁺, High Mg²⁺, Citrate, or Na⁺/H⁺ Exchange Inhibitor HOE-642

Yoshiaki Fukuhiro, MD; Michelle Wowk, BSc(Hons); Ruchong Ou, MBBS; Franklin Rosenfeldt, MD, FRACS; Salvatore Pepe, PhD

From the Cardiac Surgical Research Unit, Alfred Hospital and Baker Medical Research Institute, St Kilda Central, Melbourne, Victoria, Australia. Dr Fukuhiro’s present address is Department of Thoracic and Cardiovascular Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama, Japan.

Correspondence to F.L. Rosenfeldt, MD, Cardiac Surgical Research Unit, Alfred Hospital and Baker Medical Research Institute, PO Box 6492, St Kilda Central, Melbourne, Victoria 8008, Australia. E-mail F.Rosenfeldt{at}alfred.org.au

Background—Ca²⁺ overload plays an important role in the pathogenesis of cardioplegic ischemia-reperfusion injury. The standard technique to control Ca²⁺ overload has been to reduce Ca²⁺ in the cardioplegic solution (CP). Recent reports suggest that Na⁺/H⁺ exchange inhibitors can also prevent Ca²⁺ overload. We compared 4 crystalloid CPs that might minimize Ca²⁺ overload in comparison with standard Mg²⁺-containing CP: (1) low Ca²⁺ CP (0.25 mmol/L), (2) citrate CP/normal Mg²⁺ (1 mmol/L Mg²⁺), (3) citrate CP/high Mg²⁺ (9 mmol/L Mg²⁺), 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 Ca²⁺ and Mg²⁺ 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 Ca²⁺ 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 Mg²⁺ and Ca²⁺. Because only Ca²⁺ was required to be low, the further addition of Mg²⁺ increased free Mg²⁺, 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 Mg²⁺, P<0.05, versus 22.4±6.2% for citrate with high Mg²⁺, P<0.05). Low-Ca²⁺ CP (0.25 mmol/L Ca²⁺) significantly improved the recovery of postischemic function in comparison with standard CP (1.0 mmol/L Ca²⁺) (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 Ca²⁺ manipulation.

Conclusions—(1) A lowered Ca²⁺ concentration in CP is beneficial in Mg²⁺-containing cardioplegia. (2) The use of citrate to chelate Ca²⁺ is detrimental in the crystalloid-perfused isolated working rat heart, especially with high Mg²⁺. (3) The mechanism of citrate action is complex, and its use limits precise simultaneous control of Ca²⁺ and Mg²⁺. (4) HOE-642 in CP is as efficacious in preservation of the ischemic myocardium as is the direct reduction in Ca²⁺.

Key Words: cardioplegia • ischemia • calcium • magnesium • HOE-642