TY - JOUR
T1 - Combination treatment with captopril and the thyroid hormone analogue 3,5-diiodothyropropionic acid
T2 - A new approach to improving left ventricular performance in heart failure
AU - Pennock, Gregory D.
AU - Raya, Thomas E.
AU - Bahl, Joseph J.
AU - Goldman, Steven
AU - Morkin, Eugene
PY - 1993/9
Y1 - 1993/9
N2 - Background. An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. Methods and Results. To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 μg/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment 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 and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in τ, 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/dtmax (-4561±361 vs -3346±232 mm Hg/s, P<.05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P>.05). Conclusions. The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent 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.
AB - Background. An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. Methods and Results. To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 μg/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment 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 and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in τ, 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/dtmax (-4561±361 vs -3346±232 mm Hg/s, P<.05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P>.05). Conclusions. The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent 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.
KW - Cardiotonic agents
KW - Heart failure
KW - Thyroid
UR - http://www.scopus.com/inward/record.url?scp=0027199125&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0027199125&partnerID=8YFLogxK
U2 - 10.1161/01.CIR.88.3.1289
DO - 10.1161/01.CIR.88.3.1289
M3 - Article
C2 - 8353891
AN - SCOPUS:0027199125
SN - 0009-7322
VL - 88
SP - 1289
EP - 1298
JO - Circulation
JF - Circulation
IS - 3
ER -