Coronary artery bypass grafting (CABG) is one of the most commonly performed surgical procedures in the United States. In a prior study of high risk patients undergoing cardiopulmonary bypass for CABG, the applicant observed alterations in thyroid hormone metabolism including a fall in serum triiodothyronine (T3) to levels below normal which was prevented by T3 treatment (1.6 ug/kg/6 hr.). Atrial fibrillation is a common postoperative occurrence and was observed in 46 percent of the untreated patients. In comparison, only 24 percent (p=0.009) of patients receiving T3 treatment developed atrial fibrillation. In this application the applicant will test the hypothesis that T3 can alter atrial cell excitability by modulating atrial gene expression including Na/K-ATPase, Na/Ca exchanger and the K+ channels (including Kv4.2, Kv4.3 and IRK1) that have been linked to atrial rhythm disturbances. In addition, T3 can alter the performance characteristics of these individual ion channels. The latter hypothesis will be tested by electrophysiologic measurements of resting membrane potential, action potential and K+ currents. To model the clinical condition of CABG and cardioplegia, the applicant will study the effects of T3 on cultured rat atrial myocytes subject to hypothermia and hyperkalemia. Secondly, the experimental animal model of myocardial ischemia produced by coronary artery ligation, will be used to test the antiarrhythmic effects of T3 in vivo. To determine the molecular sites of action of T3, the appliant will express the individual Kv channels in the Xenopus oocyte, and study the responses of these channels to T3. Lastly, the applicant proposes to study the effects of T3 on specific gene expression, resting membrane and action potentials, and K+ currents of human atrial myocytes obtained at the time of CABG. These studies will advance our understanding of gene expression and electrophysiologic function of the human atria, and identify the molecular mechanisms by which thyroid hormone acts to prevent postoperative atrial fibrillation in patients undergoing cardiac surgery.
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