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）：使用2-肾上腺素能阻断剂（BB）和血管紧张素转化酶抑制剂（ACEI）随着使用心肌梗塞（MI）的长期生存率得到了改善。由于早期干预的进步，近年来，心肌梗塞（MI）的急性生存率也有所改善。尽管如此，目前的疗法是不足的，许多患者最终会发展为扩张的心力衰竭。 MI之后，患者患甲状腺激素（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之后，TH功能迅速降低，这似乎是由于D3去二十二酶的心肌表达增加所致。 D3将T4转换为无效的RT3和T3转换为无效T2。随着TH的下降，MI相关的死亡率增加，RT3水平增加。此外，仅甲状腺功能减退症会导致心力衰竭，同时促进肌细胞形状不良的不良变化并增加间质胶原蛋白。有趣的是，这两种不良适应机制在非刻张的心肌的MI重塑中都起着重要作用，并进展为扩张衰竭。来自大鼠的新数据表明，对MI的治疗改善了左心室功能，而不会提高心率，并导致肌细胞形状发生了显着变化，并且腔室直径/后壁厚度比降低。这些变化应防止或减弱心力衰竭的进展。该提议将检验以下假设：MI导致的甲状腺功能低是适应不良的，而治疗将阻止腔室扩张和通过诱导肌细胞形状的有益变化，间质纤维化的有益变化，刺激层状心肌的微血管生长的刺激。每个目标旨在提供有关甲状腺后激素后治疗对细胞和组织重塑，LV功能以及当前尚不可用的长期结局的关键，相关的信息。出于道德原因，无法从人类试验中收集许多要获得的信息。例如，将检查甲状腺激素治疗和在标准疗法（ACE抑制剂，两个阻滞剂）的背景下的影响。这些动物数据应为解释其临床结果的解释提供重要的见解，并且在计划未来的长期治疗研究中也应具有预测价值。