Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion.
There is emerging evidence that treatment with thyroid hormone (TH) can improve postischemic cardiac function. 3,5-Diiodothyropropionic acid (DITPA), a TH analog, has been proposed to be a safer therapeutic agent than TH because of its negligible effects on cardiac metabolism and heart rate. However, conflicting results have been reported for the cardiac effects of DITPA. Importantly, recent clinical trials demonstrated no symptomatic benefit in patients with DITPA despite some improved hemodynamic and metabolic parameters. To address these issues, dose-dependent effects of DITPA were investigated in mice for baseline cardiovascular effects and postischemic myocardial function and/or salvage. Mice were treated with subcutaneous DITPA at 0.937, 1.875, 3.75, or 7.5 mg·kg(-1)·day(-1) for 7 days, and the results were compared with untreated mice for ex vivo and/or in vivo myocardial ischemia-reperfusion (I/R). DITPA had no effects on baseline body temperature, body weight, or heart rate; however, it mildly increased blood pressure. In isolated hearts, baseline contractile function was significantly impaired in DITPA-pretreated mice; however, postischemic recovery was comparable between untreated and DITPA-treated groups. In vivo baseline cardiac parameters were significantly affected by DITPA, with increased ventricular dimensions and decreased contractile function. Importantly, DITPA-treated mice demonstrated high prevalence of fatal cardiac rhythm abnormalities during in vivo ischemia and/or reperfusion. There were no improvements in myocardial infarction and postischemic fractional shortening with DITPA. Myocardial sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), and heat shock protein (HSP) levels remained unchanged with DITPA treatment. Thus DITPA administration impairs baseline cardiac parameters in mice and can be fatal during in vivo acute myocardial I/R.
Davis Heart and Lung Research Institute, Department of Internal Medicine, Ohio State University College of Medicine, 473 West 12th Ave., Columbus, OH 43210, USA.
M A Hassan
MA
Talukder
Fuchun
F
Yang
Yoshinori
Y
Nishijima
Chun-An
CA
Chen
Lin
L
Xie
Shouvik D
SD
Mahamud
Anuradha
A
Kalyanasundaram
John D
JD
Bonagura
Muthu
M
Periasamy
Jay L
JL
Zweier
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology; D003627:Data Interpretation, Statistical; D004104:Diiodothyronines / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000401:mortality*; D011422:Propionates / Q000633:toxicity*; D013566:Sympathomimetics / Q000494:pharmacology; D013974:Thyroxine / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D002316:Cardiotonic Agents; D004104:Diiodothyronines; D011422:Propionates; D013566:Sympathomimetics; D014284:Triiodothyronine; C082182:3,5-diiodothyropropionic acid; D013974:Thyroxine