Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion

作者：Talukder M A Hassan; Yang Fuchun; Nishijima Yoshinori; Chen Chun An; Xie Lin; Mahamud Shouvik D; Kalyanasundaram Anuradha; Bonagura John D; Periasamy Muthu; Zweier Jay L^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2011, 300(2): H702-H711.

DOI：10.1152/ajpheart.00514.2010

• cardiac function
• postischemic recovery
• fatal cardiac rhythm

Talukder MA, Yang F, Nishijima Y, Chen CA, Xie L, Mahamud SD, Kalyanasundaram A, Bonagura JD, Periasamy M, Zweier JL. Detrimental effects of thyroid hormone analog DITPA in the mouse heart: increased mortality with in vivo acute myocardial ischemia-reperfusion. Am J Physiol Heart Circ Physiol 300: H702-H711, 2011. First published December 3, 2010; doi:10.1152/ajpheart.00514.2010.-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 Ca(2+)-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.

• 出版日期2011-2