Low Thyroid function and myocardial infarction

甲状腺功能低下和心肌梗塞

• 批准号: 8266300
• 负责人: ANTHONY Martin GERDES
• 金额: $ 35.61万
• 依托单位: NEW YORK INST OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8266300
• 关键词: Acute; Address; Adrenergic Antagonists; Angiogenic Factor; Angiotensin-Converting Enzyme Inhibitors; Apoptosis; Area; Arteries; Attenuated; Biological Markers; Caliber; Cardiac; Cardiology; Cardiomyopathies; Cell physiology; Cells; Cities; Clinical; Clinical Research; Clinical Trials; Collaborations; Collagen; Data; Data Analyses; Depressed mood; Development; Development Plans; Diagnosis; Dilatation - action; Early treatment; Ethics; Extracellular Matrix; Failure; Fibrosis; Functional disorder; Future; Genes; Goals; Growth; Heart; Heart Diseases; Heart Rate; Heart failure; Human; Hypothyroidism; Impairment; Infarction; Iodide Peroxidase; Italy; Lead; Left Ventricular Function; Left Ventricular Remodeling; Link; Low T3 Syndromes; Magnetic Resonance Imaging; Mediating; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Oklahoma; Outcome; Pathologic; Patients; Pattern; Play; Predictive Value; Rattus; Reperfusion Therapy; Reporting; Research; Resistance; Role; Sarcomeres; Series; Serum; Shapes; Signal Transduction; Stress; Systems Biology; Testing; Thick; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Tissues; angiogenesis; animal data; arteriole; cardiovascular risk factor; clinically relevant; design; improved; insight; interstitial; midkine; mortality; prevent; research study; restoration; treatment effect

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.

描述（由申请人提供）：通过使用 2-肾上腺素能阻滞剂（BB）和血管紧张素转换酶抑制剂（ACEi），心肌梗塞（MI）的长期生存得到改善。近年来，由于早期干预的进步，心肌梗死（MI）的急性生存率也有所改善。尽管如此，目前的治疗还不够，许多患者最终进展为扩张性心力衰竭。心肌梗死后，患者的甲状腺激素 (TH) 水平较低，越来越多的证据表明他们可能会从 TH 治疗中受益。 MI 后，TH 功能迅速下降，这似乎是由于 D3 脱碘酶的心肌表达增加所致。 D3 将 T4 转换为非活动 rT3，并将 T3 转换为非活动 T2。随着 TH 下降和 rT3 水平升高，与 MI 相关的死亡率增加。此外，甲状腺功能减退症本身就可能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心肌梗死后非梗塞心肌重塑和扩张性衰竭进展中发挥着重要作用。来自大鼠的新数据表明，TH 治疗 MI 可以改善左心室功能，而不会提高心率，并导致心肌细胞形状发生显着变化，并降低心室直径/后壁厚度比。这些变化应该可以预防或减轻扩张性心力衰竭的进展。该提案将检验以下假设：MI 导致的甲状腺功能低下是适应不良，而 TH 治疗将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甲状腺中的微血管生长来阻止心室扩张和衰竭的进展。梗死的心肌。这些细胞变化背后的信号网络也将被研究。每个目标均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、左心室功能以及目前无法获得的长期结果的影响的关键临床相关信息。由于伦理原因，许多要获得的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、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，并且对于规划未来的长期治疗研究也应该具有预测价值。