Safe Oral Triiodo-L-Thyronine Therapy Protects from Post-Infarct Cardiac Dysfunction and Arrhythmias without Cardiovascular Adverse Effects.
Safe Oral Triiodo-L-Thyronine Therapy Protects from Post-Infarct Cardiac Dysfunction and Arrhythmias without Cardiovascular Adverse Effects.
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DOI：
10.1371/journal.pone.0151413
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gerdes AM
中科院分区：
文献类型：
--
作者：
Rajagopalan V;Zhang Y;Ojamaa K;Chen YF;Pingitore A;Pol CJ;Saunders D;Balasubramanian K;Towner RA;Gerdes AM
大量证据表明，甲状腺激素对心血管疾病的治疗是有益的。用三碘-L-甲状腺原氨酸(T3)治疗心肌梗死(MI)大鼠3天后，可增加左心室(LV)收缩功能，减少心肌细胞凋亡。然而，目前还没有建立T3治疗缺血性心脏病的临床可翻译方案。我们假设小剂量口服T3将为心肌梗塞提供安全的治疗益处。成年雌性大鼠接受左冠状动脉结扎或假手术。心肌梗死后即刻和持续2个月(S)，饮用水中随机性摄取T3(~6μg/kg/d)。与赋形剂治疗的MI相比，口服T3治疗的MI组在2个月时显著改善了基于磁共振成像的麻醉左室射血分数和容量，而对心率、血清TH水平或心脏重量没有明显的负面影响，表明治疗是安全的。值得注意的是，T3降低了88%的诱发性房性快速性心律失常的发生率，并改善了重构。伴随而来的是基因表达的恢复，涉及几个关键途径，包括甲状腺、离子通道、纤维化、交感神经、线粒体和自噬。小剂量口服T3显著改善了心肌梗死后的心功能，减少了房性心律失常和心脏重构，并逆转了许多基因表达的不利变化，但没有明显的负面影响。这项研究还提供了一种安全有效的治疗/监测方案，应该很容易转化为人类。
A large body of evidence suggests that thyroid hormones (THs) are beneficial for the treatment of cardiovascular disorders. We have shown that 3 days of triiodo-L-thyronine (T3) treatment in myocardial infarction (MI) rats increased left ventricular (LV) contractility and decreased myocyte apoptosis. However, no clinically translatable protocol is established for T3 treatment of ischemic heart disease. We hypothesized that low-dose oral T3 will offer safe therapeutic benefits in MI. Adult female rats underwent left coronary artery ligation or sham surgeries. T3 (~6 μg/kg/day) was available in drinking water ad libitum immediately following MI and continuing for 2 month(s) (mo). Compared to vehicle-treated MI, the oral T3-treated MI group at 2 mo had markedly improved anesthetized Magnetic Resonance Imaging-based LV ejection fraction and volumes without significant negative changes in heart rate, serum TH levels or heart weight, indicating safe therapy. Remarkably, T3 decreased the incidence of inducible atrial tachyarrhythmias by 88% and improved remodeling. These were accompanied by restoration of gene expression involving several key pathways including thyroid, ion channels, fibrosis, sympathetic, mitochondria and autophagy. Low-dose oral T3 dramatically improved post-MI cardiac performance, decreased atrial arrhythmias and cardiac remodeling, and reversed many adverse changes in gene expression with no observable negative effects. This study also provides a safe and effective treatment/monitoring protocol that should readily translate to humans.