Myocardial dysfunction caused by ischemia-reperfusion injuries during cardiac surgery can be life threatening. The elderly patients are at high risk in sustaining myocardial ischemia reperfusion injuries because of their advanced disease and increased susceptibility of the aged myocardium to such injuries. It is important to treat the myocardial dysfunction early to halt the vicious cycle of ischemia-dysfunction- ischemia before it leads to cellular necrosis and irreversible global cardiac dysfunction. However, it may be impossible to wean some high risk patients from cardiopulmonary bypass, despite high doses of multiple conventional inotropes. Catecholamines in high doses may be ineffective or even harmful because of their ability to cause further desensitization of the already impaired beta-adrenezgic system. Truodothyronme (T3) has been shown to be beneficial in animals with prolonged myocardial ischemia. However, its clinical effectiveness in cardiac surgical patients has been debated. The mechanism of acute inotropic action of T3 and the responses of the aged myocardium to T3 are also not clear. We hypothesize: 1. Aging decreases myocardial sensitivity to acute T3 stimulation. 2. Aging decreases myocardial responses to T3 in stunned myocardium. 3. T3 causes minimal increases in O2 consumption in stunned aged myocardium. Myocytes will be isolated from the hearts of young mature (about 6 months of age) and old (3-4 yrs of age) rabbits. We will use a hypoxia-normoxia model of isolated myocytes. Freshly isolated myocytes will be placed in a medium previously equilibrated with 95% N2 and 5% CO2 (hypoxia) for 15 min. The mixture will then be reoxygenated with air (normoxia) for 30 min. The effects of T3, a myofilament Cams sensitizer and beta - adrenergic agonist will be studied. Myocyte contractile function will be measured using a video edge detector. Beta-adrenoceptors, adenylyl cyclase, cAMP, O2 consumption and myofilament Ca2+ binding will be measured. The findings will elucidate the mechanism of myocardial stunning and the isotropic action of T3 on the aged myocardium. This project will also provide new evidence to support the combination of T3 and a myofilament Cams sensitizer as an effective therapeutic modality for post-ischemic dysfunction of the aged heart. This study will provide the basis for a future grant application to investigate probable role of T3 pretreatrnart in gene expression of Cams-regulating proteins and beta-adrenoceptor-cAMP system in stunned aged myocardium and in ischemic preconditioning.
| Tse, James; Gandhi, Ankur; Yan, Lin et al. (2003) Effects of triiodothyronine pretreatment on beta-adrenergic responses in stunned cardiac myocytes. J Cardiothorac Vasc Anesth 17:486-90 |
| Weiss, Harvey R; Lazar, Michael J; Tse, James et al. (2002) Ageing blunts the effects of nitric oxide on myocardial O2 consumption. Clin Exp Pharmacol Physiol 29:924-30 |
