Society of Cardiovascular Anesthesiologists

Na+-H+ Exchanger (NHE) Inhibitor for Myocardial Protection in Cardiac Surgery?

K.W. Tim Park, MD
Beth Israel Deaconess Medical Center
Boston, MA

The Na+-H+ exchanger (NHE) is a sarcolemmal protein that facilitates exchange of intracellular H+ ions for extracellular Na+ ions, as the latter move down the concentration gradient. There are 7 isoforms of the protein identified to date and NHE-1 is believed to be the homolog in the cardiac sarcolemma. The exchanger is normally activated by intracellular acidosis, although a variety of other stimuli such as thrombin (1), angiotensin II (2), and a-1 adrenergic agents (3) may modulate the activation. When activated, the NHE leads to intracellular accumulation of Na+ and secondarily of Ca++. Intracellular overload of Ca++ then leads to cellular injury of the acidotic, ischemic myocardium. Thus, it has been suggested that inhibition of the sarcolemmal NHE may attenuate many of the unfavorable consequences of acute myocardial ischemia.

Amiloride was the first of a family of NHE inhibitors. Many more NHE inhibitors have been developed recently, with marked selectivity for the NHE-1 isoform. These novel NHE inhibitors include cariporide (HOE-642), eniporide (EMD-96785), and zoniporide (CP-597,396). In animal models of myocardial ischemia and reperfusion, cariporide has been shown to markedly reduce intracellular accumulation of Na+ and Ca++ (4, 5). As a result, there is a better preservation of contractile function (6) and reduction of the infarct size (7-10). This effect of NHE inhibition appears to be distinct from and additive to that of ischemic preconditioning (8, 11).

The success of NHE inhibitors in animal models has not been matched in clinical trials. The GUARDIAN (GUARD during Ischemia Against Necrosis) trial was conducted to investigate whether cariporide may reduce the incidence of death and myocardial infarction (MI) at 36 days in high-risk patients due to acute coronary syndrome or a cardiac intervention (PCI or CABG) (12). This international trial enrolled 5,231 patients with unstable angina/non-Q wave MI, 3,441 patients scheduled for high-risk PTCA, and 2,918 clinically high-risk patients scheduled for CABG. Patients were randomized to receive 20, 80, or 120 mg of cariporide or placebo administered over 60 minutes q 8 hours for the period of risk up to 7 days and evaluated at day 36 and at 6 months. There was no difference between the 4 groups in the primary end-point of death or MI at 36 days, although a dose of 120 mg of cariporide was associated with a 10 % (CI: -23 % to +5 %) risk reduction (P=0.12). With the high dose, the benefit in the primary end-point was limited to patients undergoing CABG with a 25 % risk reduction (CI: -3 to -42 %) (P=0.03) and maintained at 6 months. The incidence of Q-wave MI was reduced by 120 mg cariporide across all entry diagnosis groups (relative risk of 0.61, P < 0.05). In the CABG cohort, the risk of non-Q wave MI was also reduced to 0.60 (P < 0.05) by 120 mg cariporide. There were no serious adverse events associated with use of cariporide compared to the placebo. The GUARDIAN trial indicated that in the subgroup of clinically high-risk patients undergoing CABG, a high-dose cariporide may reduce cardiac event rates. Cardiac surgery represents a unique clinical situation in which a period of myocardial ischemia and reperfusion can be clearly identified and a dose of an NHE inhibitor can be precisely timed relative to the period of ischemia and reperfusion. To further investigate the effect of NHE inhibition in cardiac surgery, another trial (EXPEDITION: Na+/H+ EXchange inhibition to Prevent coronary Events in acute cardiac conDITIONs) is now underway in high-risk surgical patients and is to be completed by 2003. The next chapter on the usefulness of NHE inhibition in cardiac surgery should follow shortly thereafter.

References:
1. Yasutake M, Haworth RS, King A, Avkiran M. Thrombin activates the sarcolemmal Na(+)-H(+) exchanger. Evidence for a receptor-mediated mechanism involving protein kinase C. Circ Res 1996; 79:705-15

2. Gunasegaram S, Haworth RS, Hearse DJ, Avkiran M. Regulation of sarcolemmal Na(+)-H(+) exchanger activity by angiotensin II in adult rat ventricular myocytes: opposing actions via AT(1) versus AT(2) receptors. Circ Res 1999; 85:919-30

3. Snabaitis AK, Yokoyama H, Avkiran M. Roles of mitogen-activated protein kinases and protein kinase C in alpha(1A)-adrenoceptor-mediated stimulation of the sarcolemmal Na(+)-H(+) exchanger. Circ Res 2000; 86:214-20

4. Hartmann M, Decking UK. Blocking Na(+)-H(+) exchange by cariporide reduces Na(+)-overload in ischemia and is cardioprotective. J Mol Cell Cardiol 1999; 31:1985-95

5. Stromer H, de Groot MC, Horn M, Faul C, Leupold A, Morgan JP, Scholz W, Neubauer S. Na(+)-H(+) exchange inhibition with HOE642 improves postischemic recovery due to attenuation of Ca(2+) overload and prolonged acidosis on reperfusion. Circulation 2000; 101:2749-55

6. Hendrikx M, Mubagwa K, Verdonck F, Overloop K, Van Hecke P, Vanstapel F, Van Lommel A, Verbeken E, Lauweryns J, Flameng W. New Na(+)-H(+) exchange inhibitor HOE694 improves postischemic function and high-energy phosphate resynthesis and reduces Ca2+ overload in isolated perfused rabbit heart. Circulation 1994; 89:2787-98

7. Garcia-Dorado D, Gonzalez MA, Barrabes JA, Ruiz-Meana M, Solares J, Lidon RM, Blanco J, Puigfel Y, Piper HM, Soler-Soler J. Prevention of ischemic rigor contracture during coronary occlusion by inhibition of Na(+)-H(+) exchange. Cardiovasc Res 1997; 35:80-9

8. Miura T, Ogawa T, Suzuki K, Goto M, Shimamoto K. Infarct size limitation by a new Na(+)-H(+) exchange inhibitor, HOE642: difference from preconditioning in the role of protein kinase C. J Am Coll Cardiol 1997; 29:693-701

9. Linz W, Albus W, Crause P, Jung W, Weichert A, Scholkens BA, Scholz W. Dose-dependent reduction of myocardial infarct mass in rabbits by the NHE-1 inhibitor cariporide (HOE642). Clin Exp Hypertens 1998; 20:733-49

10. Klein HH, Pich S, Bohle RM, Lindert-Heimberg S, Nebendahl K. Na(+)/H(+) exchange inhibitor cariporide attenuates cell injury predominantly during ischemia and not at onset of reperfusion in porcine hearts with low residual blood flow. Circulation 2000; 102:1977-82

11. Shipolini AR, Yokohama H, Galinanes M, Edmondson SJ, Hearse DJ, Avkiran M. Na+/H+ exchanger activity does not contribute to protection by ischemic preconditioning in the isolated rat heart. Circulation 1997; 96:3617-25

12. Theroux P, Chaitman BR, Danchin N, Erhardt L, Meinertz T, Schroeder JS, Tognoni G, White HD, Willerson JT, Jessel A. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Circulation 2000; 102:3032-8

Table of Contents

President's Message -- Cooperation is the Name of the Game
Drug & Innovation Reviews