Low Thyroid function and myocardial infarction

描述（由申请方提供）：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）可改善心肌梗死（MI）的长期生存率。近年来，由于早期干预的进步，心肌梗死（MI）的急性存活率也有所提高。尽管如此，目前的治疗是不够的，许多患者最终进展为扩张性心力衰竭。MI后，患者甲状腺激素（TH）水平降低，越来越多的证据表明他们可能受益于TH治疗。MI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转化为非活性rT 3，将T3转化为非活性T2。MI相关死亡率随着TH下降和rT 3水平升高而升高。此外，甲状腺功能减退单独可导致扩张性心力衰竭，同时促进肌细胞形状的适应不良变化和间质胶原蛋白的增加。有趣的是，这两种适应不良机制在MI后非梗死心肌重塑和扩张性心力衰竭进展中起重要作用。来自大鼠的新数据表明，TH治疗MI改善了左心室功能，而不升高心率，并导致心肌细胞形状的显着变化和室直径/后壁厚度比的降低。这些变化应防止或减缓扩张性心力衰竭的进展。本研究将验证以下假设：MI引起的甲状腺功能低下是适应不良的，TH治疗可通过诱导心肌细胞形状的有益变化、减少间质纤维化和刺激非梗死心肌微血管生长来阻止心室扩张和衰竭的进展，还将研究这些细胞变化背后的信号网络。每个目的均旨在提供关于MI后甲状腺激素治疗对细胞和组织重塑、LV功能和长期结局影响的关键临床相关信息，这些信息目前不可用。由于伦理方面的原因，许多信息无法从人体试验中收集。例如，将检查甲状腺激素单独治疗和标准治疗（ACE抑制剂，β 2受体阻滞剂）背景下的效果。这些动物数据应该为解释其临床结果提供重要的见解，并且在计划未来的长期治疗研究中也应该具有预测价值。 公共卫生相关性：新的证据表明，心肌梗死触发心脏组织中的甲状腺功能低下，恢复正常的甲状腺功能可能有益于改善重塑和预后。在甲状腺激素治疗的心肌梗死大鼠中进行的拟议实验将提供关键的细胞信息和见解，这些信息和见解有助于推进该领域临床试验的最佳设计和实施。

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. PUBLIC HEALTH RELEVANCE: New evidence indicates that myocardial infarction triggers low thyroid function in cardiac tissue and restoration of normal thyroid function may beneficially improve remodeling and outcome. The proposed experiments in thyroid hormone treated rats with myocardial infarction will provide key cellular information and insight needed to move forward with optimal design and implementation of clinical trials in this area.