DEVELOPMENT OF A THYROID-HORMONE ANALOG FOR THE TREATMENT OF CONGESTIVE-HEART-FAILURE

The possibility that thyroid hormone or a thyroid hormone analogue tha t improves cardiac performance might be useful in the treatment of hea rt failure has been examined. In the rat postinfarction model of heart failure, treatment with low doses (1.5 mu g/100 g) of thyroxine (T-4) for 3 days produced a positive inotropic response, including an incre ase in left ventricular (LV) dP/dt and a decrease in LV end-diastolic pressure (LVEDP). When treatment with T-4 was continued at the same or higher doses (3 to 15 mu g/100 g) for 10-12 days, heart rate was incr eased and improvement in LVEDP was not sustained. To identify an analo gue with a more favorable hemodynamic profile, single- and double-ring compounds related to T-4 Were screened for thyromimetic activity in h eart cell cultures and for their ability to bind thyroid hormone recep tors. One of the analogues selected, 3,5-diiodothyropropionic acid (DI TPA), was found to have inotropic selectivity in hypothyroid rats. Whe n administered (375 mu g/100 g) to rats with ventricular dysfunction a fter myocardial infarction in combination with captopril, there was im provement of the resting and stressed cardiac index and LV filling pre ssure. Similar improvement in cardiac performance was obtained when DI TPA was administered to rabbits after infarction. Thus a thyroid hormo ne analogue with inotropic selectivity may be a useful adjunct to othe r measures in the treatment of heart failure.