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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058849-02
Application #
2735402
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1997-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
North Shore University Hospital
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Danzi, Sara; Klein, Irwin (2005) Posttranscriptional regulation of myosin heavy chain expression in the heart by triiodothyronine. Am J Physiol Heart Circ Physiol 288:H455-60
Danzi, Sara; Ojamaa, Kaie; Klein, Irwin (2003) Triiodothyronine-mediated myosin heavy chain gene transcription in the heart. Am J Physiol Heart Circ Physiol 284:H2255-62
McMahon, Clarie K; Klein, Irwin; Ojamaa, Kaie (2003) Interleukin-6 and thyroid hormone metabolism in pediatric cardiac surgery patients. Thyroid 13:301-4
Sun, Z Q; Ojamaa, K; Nakamura, T Y et al. (2001) Thyroid hormone increases pacemaker activity in rat neonatal atrial myocytes. J Mol Cell Cardiol 33:811-24
Chowdhury, D; Ojamaa, K; Parnell, V A et al. (2001) A prospective randomized clinical study of thyroid hormone treatment after operations for complex congenital heart disease. J Thorac Cardiovasc Surg 122:1023-5
Shenoy, R; Klein, I; Ojamaa, K (2001) Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles. Am J Physiol Heart Circ Physiol 281:H1690-6
Klein, I; Ojamaa, K (2001) Thyroid hormone: targeting the vascular smooth muscle cell. Circ Res 88:260-1
Sun, Z Q; Ojamaa, K; Coetzee, W A et al. (2000) Effects of thyroid hormone on action potential and repolarizing currents in rat ventricular myocytes. Am J Physiol Endocrinol Metab 278:E302-7
Ojamaa, K; Kenessey, A; Klein, I (2000) Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology 141:2139-44
Ojamaa, K; Klein, I; Sabet, A et al. (2000) Changes in adenylyl cyclase isoforms as a mechanism for thyroid hormone modulation of cardiac beta-adrenergic receptor responsiveness. Metabolism 49:275-9

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