The effects of a thyroid hormone analog on left ventricular performance and contractile and calcium cycling proteins in the baboon.
To determine the biochemical and related functional effects of the thyroid analog diiodothyroproprionic acid (DITPA) on primate myocardium, we examined, both before and after 23 days of DITPA (3.75 mg/kg): myosin heavy-chain (MHC) isoforms and sarcoplasmic reticulum (SR) calcium cycling proteins; left ventricular (LV) function; and the LV force-frequency relation in four baboons chronically instrumented with sonomicrometers and micromanometers. The force-frequency relation was measured as the response of isovolumic contraction (dP/dtmax) to incremental pacing and the critical heart rate (HRcrit) as the rate at which dP/dtmax reached its maximum. DITPA increased basal LV dPt/dtmax (3,300 +/- 378 versus 2,943 +/- 413 mm Hg/sec; p = .09), and velocity of circumferential shortening (1.13 +/- 0.30 versus 0.76 +/- 0.30 circ/sec; p < .01), decreased the basal time constant of isovolumic relaxation (24.2 +/- 1.6 versus 29.9 +/- 2.5 msec; p < .05), and increased the HRcrit (203 +/- 19 versus 168 +/- 20 bpm; p < .05), without effecting significant changes in either basal heart rate (119 +/- 14 versus 111 +/- 17 bpm) or systolic blood pressure (137 +/- 14 versus 126 +/- 8 mm Hg). Quantitative immunoblotting revealed significant decreases in both phospholamban and the ratio of phospholamban to SR Ca2+ adenosine triphosphatase in DITPA-treated animals when compared to four untreated controls. By contrast, alpha-MHC isoform was undetectable in both DITPA treated and control baboons. Thus, DITPA favorably alters the stoichiometry between the SR calcium pump and its inhibitor, phospholamban, and has positive inotropic and lusitropic effects in the normal primate left ventricle, which may be useful in the treatment of heart failure. Unlike thyroid hormone, these changes occur in the absence of detectable alpha-MHC isoform protein expression and without an increase in heart rate.
Hoit
B D
BD
Division of Cardiology, University of Cincinnati Medical Center, OH, USA.
Pawloski-Dahm
C M
CM
Shao
Y
Y
Gabel
M
M
Walsh
R A
RA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D004104:Diiodothyronines / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D010215:Papio; D011422:Propionates / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013963:Thyroid Hormones / Q000494:pharmacology*; D016277:Ventricular Function, Left / Q000187:drug effects*
D004104:Diiodothyronines; D011422:Propionates; D013963:Thyroid Hormones; C082182:3,5-diiodothyropropionic acid; D018995:Myosin Heavy Chains; D000252:Calcium-Transporting ATPases; D002118:Calcium