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(Circulation. 2009;120:S16-S21.)
© 2009 American Heart Association, Inc.

Myocardial Protection, Perioperative Management, and Vascular Biology

Ranolazine as a Cardioplegia Additive Improves Recovery of Diastolic Function in Isolated Rat Hearts

Hyosook Hwang, PhD; Joseph M. Arcidi, Jr, MD; Sharon L. Hale, BS; Boris Z. Simkhovich, MD, PhD; Luiz Belardinelli, MD; Arvinder K. Dhalla, PhD; John C. Shryock, PhD; Robert A. Kloner, MD, PhD

From The Heart Institute (H.H., S.L.H., B.Z.S., R.A.K.), Good Samaritan Hospital, Los Angeles, Calif; Division of Cardiovascular Medicine (B.Z.S., R.A.K.), Keck School of Medicine, University of Southern California, Los Angeles, Calif; Section of Cardiac and Thoracic Surgery (J.M.A.), Good Samaritan Hospital, Los Angeles, Calif; Gilead (formerly Cardiovascular Therapeutics), Inc (L.B., A.K.D., J.C.S.), Palo Alto, Calif.

Correspondence to Robert A. Kloner, MD, Ph.D, The Heart Institute, Good Samaritan Hospital, 1225 Wilshire Boulevard, Los Angles, CA 90017. E-mail rkloner{at}goodsam.org

Background— Ranolazine (Ran), an antianginal agent, inhibits late Na⁺ current. The purpose of this study was to determine whether there was an added benefit of adding Ran to cardioplegia (CP) in a model of global ischemia/reperfusion.

Methods and Results— Isolated rat hearts were Langendorff-perfused and exposed to 40-minute normothermic, cardioplegic global ischemia and 30 minutes of reperfusion. Before ischemia and during reperfusion, hearts were treated with no drug (control) or with the late Na⁺ current inhibitors Ran (5 µmol/L) or tetrodotoxin (1 µmol/L). Ischemic cardioplegic arrest led to an increase of left ventricular end-diastolic pressure (LVEDP) by 20 mm Hg (ie, cardiac contracture). Ten out of 11 hearts treated with CP alone developed contracture, whereas 6 out of 11 hearts treated with CP plus Ran developed contracture. Ran added to CP reduced LVEDP at the end of ischemia from 41±5 mm Hg in CP alone to 26±3 mm Hg in CP plus Ran (P=0.024). Area under the curve for LVEDP during the entire ischemic period was also smaller in CP plus Ran versus CP alone. The percent increase (from baseline) of LVEDP measured at the end of 30-minute reperfusion was smaller for CP plus Ran (66±18%) versus CP alone (287±90%; P=0.035). The area under the curve for LVEDP during reperfusion was smaller in CP plus Ran versus CP alone. Tetrodotoxin (1 µmol/L) also reduced cardiac contracture during ischemia/reperfusion, compared to CP alone.

Conclusions— Our results suggest that Ran may have therapeutic potential as an adjunct to CP and further support a protective role of Na⁺ current inhibition during ischemia/reperfusion.

Key Words: cardiac contractile function • cardiac contracture • cardioplegia • late Na⁺ current • ranolazine