Low Thyroid function and myocardial infarction

描述（由申请人提供）：使用2-肾上腺素能阻滞剂（BB）和血管紧张素转换酶抑制剂（ACEi）改善了心肌梗死（MI）的长期生存率。近年来，由于早期干预的进展，心肌梗死（MI）的急性生存率也有所提高。尽管如此，目前的治疗方法仍不充分，许多患者最终发展为扩张性心力衰竭。心肌梗死后，患者甲状腺激素（TH）水平较低，越来越多的证据表明，他们可能受益于TH治疗。心肌梗死后，TH功能迅速降低，这似乎是由于心肌D3脱碘酶表达增加所致。D3将T4转化为无活性的rT3， T3转化为无活性的T2。心肌梗死相关死亡率随着THs的下降和rT3水平的增加而增加。此外，甲状腺功能减退可导致扩张性心力衰竭，同时促进心肌细胞形状的不适应改变和间质胶原蛋白的增加。有趣的是，这两种不适应机制在心肌梗死后非梗死心肌的重构和向扩张性衰竭的进展中都起着重要作用。来自大鼠的新数据显示，TH治疗心肌梗死可改善左心室功能，但心率不升高，心肌细胞形态发生显著改变，心室直径/后壁厚度比降低。这些改变应能预防或减轻扩张型心力衰竭的进展。这一建议将验证以下假设：心肌梗死导致的甲状腺功能低下是不适应的，而TH治疗将通过诱导心肌细胞形状的有益改变、减少间质纤维化和刺激非梗死心肌的微血管生长来阻止房室扩张和衰竭的进展。这些细胞变化背后的信号网络也将被研究。每个目标都旨在提供关键的、临床相关的信息，这些信息涉及心肌梗死后甲状腺激素治疗对细胞和组织重塑、左室功能和长期预后的影响，目前尚不清楚。由于伦理原因，许多需要获得的信息不能从人体试验中收集。例如，将检查单独甲状腺激素治疗和标准治疗（ACE抑制剂，2-阻滞剂）背景下的效果。这些动物数据应该为临床结果的解释提供重要的见解，也应该在计划未来的长期治疗研究中具有预测价值。

DESCRIPTION (provided by applicant): Long-term survival from myocardial infarction (MI) has improved with the use of 2-adrenergic blockers (BB) and angiotensin converting enzyme inhibitors (ACEi). Acute survival from myocardial infarction (MI) has also improved in recent years due to advances in early intervention. Nonetheless, current therapy is inadequate with many patients eventually progressing to dilated heart failure. After MI, patients develop low thyroid hormone (TH) levels and growing evidence suggests they may benefit from TH treatment. After MI, there is a rapid reduction in TH function which appears to be due to increased myocardial expression of the D3 deiodinase. D3 converts T4 to inactive rT3 and T3 to inactive T2. MI-related mortality increases as THs decline and rT3 levels increase. Additionally, hypothyroidism alone can lead to dilated heart failure while promoting a maladaptive change in myocyte shape and increased interstitial collagen. Interestingly, both of these maladaptive mechanisms play an important role in post-MI remodeling of the non-infarcted myocardium and progression to dilated failure. New data from rats shows that TH treatment of MI improved left ventricular function without elevating heart rate and led to a remarkable change in myocyte shape and reduced chamber diameter/posterior wall thickness ratio. These changes should prevent or attenuate progression to dilated heart failure. This proposal will test the hypothesis that low thyroid function resulting from MI is maladaptive and TH treatment will arrest progression of chamber dilatation and failure by induction of a beneficial change in myocyte shape, reduction of interstitial fibrosis, and stimulation of microvascular growth in the non-infarcted myocardium.Signaling networks underlying these cellular changes will also be investigated. Each aim is designed to provide critical, clinically- relevant information about post-MI thyroid hormone treatment effects on cell and tissue remodeling, LV function, and long-term outcome that is not currently available. Much of the information to be obtained cannot be collected from human trials for ethical reasons. For instance, the effects of thyroid hormone treatment alone and in the background of standard therapy (ACE inhibitors, 2-blockers) will be examined. These animal data should provide important insight for interpretation of their clinical results and should also be of predictive value in planning future long-term treatment studies.