COMBINATION TREATMENT WITH CAPTOPRIL AND THE THYROID-HORMONE ANALOG 3,5-DIIODOTHYROPROPIONIC ACID - A NEW APPROACH TO IMPROVING LEFT-VENTRICULAR PERFORMANCE IN HEART-FAILURE

Background. An agent that improves left ventricular (LV) performance b y non-cAMP-mediated mechanisms would be valuable in the treatment of c hronic heart failure. We have shown earlier that the thyroid hormone a nalogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear recepto rs, alters transcription of T3-responsive genes, and increases +dP/dt( max) in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardio tonic agent. Methods and Results. To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with n ormal saline, captopril (2 g/L), or the combination of DITPA (375 mug/ 100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril tre atment decreased LV end-diastolic pressure compared with controls (21/-2 and 26+/-2 mm Hg, respectively, vs 34+/-3 mm Hg, P<.05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P<.05) and shifted the cardiac function curve upward an d to the left, indicative of enhanced myocardial performance. Also, DI TPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in tau, the time constant of LV pressure decline (17.5+/-1.0 vs 22.2+/-1 .7 milliseconds, P<.05) and a larger absolute value for -dP/dt(max) (- 4561+/-361 vs -3346+/-232 mm Hg/s, P<.05). These changes occurred with out changes in heart rate, LV mass, LV systolic pressure, or periphera l resistance relative to captopril treatment (P>.05). Conclusions. The combination of DITPA and captopril improved cardiac output, increased -dP/dt(max), and increased the rate of LV, relaxation to a greater ex tent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.