Low Thyroid function and myocardial infarction

说明(申请人提供)：2-肾上腺素能阻滞剂(BB)和血管紧张素转换酶抑制剂(ACEI)的使用改善了心肌梗塞(MI)的长期存活率。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改善。尽管如此，目前的治疗方法是不够的，许多患者最终发展为扩张性心力衰竭。心肌梗死后，患者会出现甲状腺激素(TH)水平降低，越来越多的证据表明，他们可能会从TH治疗中受益。心肌梗死后，TH功能迅速下降，这似乎是由于心肌D3脱碘酶表达增加所致。D3将T4转换为无效RT3，将T3转换为无效T2。心肌梗死相关死亡率随着TH的下降和rT3水平的升高而增加。此外，甲状腺功能减退症本身可导致扩张性心力衰竭，同时促进心肌细胞形态的不适应变化和间质胶原蛋白增加。有趣的是，这两种适应不良机制在非梗死性心肌梗死后重塑和发展为扩张性衰竭中都起着重要的作用。来自大鼠的新数据显示，心肌梗死治疗在不提高心率的情况下改善了左心功能，并导致了心肌细胞形态的显着变化和内径/后壁厚度比的降低。这些变化应可防止或延缓扩张性心力衰竭的进展。这项提案将检验这一假设，即心肌梗死导致的甲状腺功能低下是不适应的，TH治疗将通过诱导有益的心肌细胞形态变化、减少间质纤维化和刺激非梗死心肌中的微血管生长来阻止腔扩张和衰竭的进展。还将调查这些细胞变化背后的信号网络。每个目标都旨在提供有关心肌梗死后甲状腺激素治疗对细胞和组织重塑的影响、左心功能以及目前尚不能获得的长期结果的关键的、临床相关的信息。由于伦理原因，许多可以获得的信息不能从人体试验中收集。例如，甲状腺激素单独治疗和标准治疗(血管紧张素转换酶抑制剂、2-受体阻滞剂)的效果将被检验。这些动物数据应该为解释他们的临床结果提供重要的洞察力，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，心肌梗死会导致心脏组织中甲状腺功能低下，恢复正常的甲状腺功能可能有益于改善重构和预后。拟议中的甲状腺激素治疗心肌梗死大鼠的实验将提供关键的细胞信息和洞察力，以推动这一领域临床试验的优化设计和实施。

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.