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Ann Thorac Surg 1999;68:1934-1941
© 1999 The Society of Thoracic Surgeons

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I. Pathophysiology of Ischemic Reperfusion Injury

Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest

^a Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina, USA

Address reprint requests to Dr Spinale, Division of Cardiothoracic Surgery, Medical University of South Carolina, 770 MUSC Complex, Rm 625, 171 Ashley Ave, Charleston, SC 29425

Presented at the International Symposium on Myocardial Protection From Surgical Ischemic-Reperfusion Injury, Asheville, NC, Sept 21–24, 1997.

Abstract

Transient left ventricular (LV) dysfunction can occur after hypothermic hyperkalemic cardioplegic arrest. This laboratory has developed an isolated LV myocyte system of simulated cardioplegic arrest and rewarming in order to examine cellular and molecular events that may contribute to the LV dysfunction after cardioplegic arrest. Contractile function was examined using high-speed video microscopy after reperfusion and rewarming. After cardioplegic arrest and reperfusion, indices of myocyte contractility were reduced by over 40% from normothermic control values. The capacity of the myocyte to respond to an inotropic stimulus was examined through ß-adrenergic receptor stimulation with isoproterenol. After cardioplegic arrest, the contractile response to isoproterenol was reduced by over 50% from normothermic values. The next series of studies focused upon preventing these changes in myocyte contractile processes after cardioplegic arrest. First, the cardioplegic solutions were augmented with adenosine or an ATP-sensitive potassium channel opener, aprikalim. Both adenosine and aprikalim augmentation significantly improved myocyte function compared with cardioplegia alone values. A potential intracellular mechanism for the protective effects of either adenosine or the ATP-sensitive potassium channel is the activation of protein kinase C (PKC). A brief period of PKC activation before cardioplegic arrest provided protective effects on myocyte contractility with subsequent reperfusion and rewarming. In another set of studies, the potential protective effects of the active form of thyroid hormone (T₃) were examined. In myocytes pretreated with T₃, myocyte contractile function and ß-adrenergic responsiveness were significantly improved after hypothermic cardioplegic arrest and rewarming. Thus, endogenous means of providing improved myocardial protection during prolonged cardioplegic arrest can be achieved through a brief period of PKC activation or pretreatment with T₃. Future studies, which more carefully deduce the basis for these pretreatment effects, will likely yield novel methods by which to protect myocyte contractile processes during cardioplegic arrest.

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