Davis Heart and Lung Research Institute, Department of Internal Medicine, Ohio State University College of Medicine, 473 West 12th Ave., Columbus, OH 43210, USA.
Am J Physiol Heart Circ Physiol. 2011 Feb;300(2):H702-11. doi: 10.1152/ajpheart.00514.2010. Epub 2010 Dec 3.
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.
有证据表明，甲状腺激素（TH）治疗可改善缺血性心脏病患者的心功能。3,5-二碘甲状腺原氨酸（DITPA）作为一种 TH 类似物，因其对心脏代谢和心率几乎没有影响，被认为是一种比 TH 更安全的治疗药物。然而，关于 DITPA 的心脏作用，有相互矛盾的结果报道。重要的是，最近的临床试验表明，尽管一些血流动力学和代谢参数有所改善，但 DITPA 对患者并没有带来症状改善。为了解决这些问题，研究了 DITPA 在小鼠中的剂量依赖性作用，以研究其对基础心血管作用以及缺血后心肌功能和/或挽救的影响。小鼠接受皮下 DITPA 治疗，剂量分别为 0.937、1.875、3.75 或 7.5mg·kg(-1)·day(-1)，连续 7 天，并与未治疗的小鼠进行了离体和/或在体心肌缺血再灌注（I/R）的比较。DITPA 对基础体温、体重或心率没有影响，但轻度升高血压。在分离的心脏中，DITPA 预处理的小鼠基础收缩功能显著受损；然而，未治疗组和 DITPA 治疗组的缺血后恢复情况相当。在体基础心脏参数受 DITPA 显著影响，表现为心室尺寸增加和收缩功能降低。重要的是，DITPA 治疗的小鼠在在体缺血和/或再灌注过程中出现致命性心律失常的发生率很高。DITPA 治疗并未改善心肌梗死和缺血后缩短分数。DITPA 治疗后肌浆网（内质网）Ca2+-ATP 酶（SERCA）、磷酸化肌球蛋白结合蛋白（PLB）和热休克蛋白（HSP）水平保持不变。因此，DITPA 给药可损害小鼠的基础心脏参数，并且在在体急性心肌 I/R 中可能是致命的。
