Developing Oral LT3 Therapy for Heart Failure

项目摘要 心力衰竭是发达国家成人住院治疗的最常见原因。治疗目标 心肌和外周器官功能障碍的可逆性原因可能为心脏提供额外的益处 射血分数降低（HFrEF）。此外，目前还没有有效的药理学 射血分数保留的心力衰竭（HFpEF）治疗，占心脏的≥50% 故障负担三碘甲状腺原氨酸（T3）是一种内源性甲状腺激素，对甲状腺功能有多种影响。 心血管系统，通过心肌和血管系统中的T3受体介导，并直接作用于离子 通道和线粒体。T3的过度效应包括心肌收缩力的增加和心肌收缩力的增加。 降低全身血管阻力。尽管心脏低T3综合征的患病率很高（~20-30%） 失败后，外源性给予碘甲状腺原氨酸（LT 3），T3的合成形式，仍然是一个探索不足 治疗选择低T3综合征与HFrEF患者的死亡率增加相关， HFpEF的疾病严重程度，但它是否是健康状况不佳的标志物还是临床相关的介导因素 心力衰竭的异常是未知的。我们的总体目标是确定安全性、可行性和初步 口服LT 3治疗HF和低T3患者的疗效。使用短期的概念验证临床研究 静脉输注LT 3已证明对患有以下疾病的患者的生物标志物和安全性具有有益作用： 缺血性HFrEF。然而，关于口服LT 3治疗HFrEF的安全性仍存在知识缺口。 此外，没有研究检查LT 3在HFpEF中的安全性。我们打算通过两个平行的渠道来填补这些空白， 在低T3综合征患者中进行的LT 3给药的随机、双盲、安慰剂对照研究： 一个在HFrEF患者中，另一个在HFpEF患者中。我们的安全性结果将是T3水平， 节律监测我们的初步疗效结果将是峰值耗氧率（VO 2），质量 生活，心脏生物标志物，通过活动记录仪进行家庭活动，以及LV功能，血管 功能和心室-动脉耦合。拟议的研究将评估安全性和初步疗效 在两个独立的研究人群中进行口服LT 3治疗。我们的团队包括一位甲状腺学家 临床研究者与经验丰富的HFrEF和HFpEF研究者密切合作， 审判经验。拟议试验的优势包括对照设计，选择最有可能 为了获益（T3水平低的患者），仔细滴定LT 3，并使用临床相关结果。行为 这两项平行研究将提高招募和安全性比较的效率。的结果予以 研究将提供必要的数据，以确定是否应该在中国进行更大规模的T3治疗临床试验。 每种情况下的患者。

PROJECT SUMMARY Heart failure is the most common reason for adult hospitalization in the developed world. Therapies that target reversible causes of myocardial and peripheral organ dysfunction are likely to provide added benefit in heart failure with reduced ejection fraction (HFrEF). In addition, there are no proven effective pharmacologic therapies for heart failure with preserved ejection fraction (HFpEF), which accounts for ≥50% of the heart failure burden. Triiodothyronine (T3), an endogenous thyroid hormone, exerts multiple effects on the cardiovascular system, mediated through T3 receptors in the myocardium and vasculature and directly on ion channels and mitochondria. Overarching effects of T3 include an increase in myocardial contractility and a decrease in systemic vascular resistance. Despite the high prevalence (~20-30%) of low T3 syndrome in heart failure, the exogenous administration of liothyronine (LT3), the synthetic form of T3, remains an underexplored therapeutic option. Low T3 syndrome has been associated with increased mortality in patients with HFrEF and disease severity in HFpEF, but whether it is a marker of poor health or a mediator of clinically relevant abnormalities in heart failure is unknown. Our overall goal is to determine the safety, feasibility, and preliminary efficacy of oral LT3 therapy in patients with HF and low T3. Proof of concept clinical studies using short-term intravenous LT3 infusions have demonstrated beneficial effects on biomarkers and safety in patients with ischemic HFrEF. However, knowledge gaps remain regarding the safety of oral LT3 therapy in HFrEF. Furthermore, no studies have examined LT3 safety in HFpEF. We intend to fill those gaps through two parallel, randomized, double-blind, placebo-controlled studies of LT3 administration in patients with low T3 syndrome: one in patients with HFrEF and the other in patients with HFpEF. Our safety outcomes will be T3 levels and rhythm monitoring. Our preliminary efficacy outcomes will be peak rate of oxygen consumption (VO2), quality of life, cardiac biomarkers, home activity via actigraphy, and noninvasive assessments of LV function, vascular function, and ventricular-arterial coupling. The proposed studies will assess the safety and preliminary efficacy of administering oral LT3 therapy in two independent study populations. Our team includes a thyroidologist clinical investigator working closely with seasoned HFrEF and HFpEF investigators with extensive early phase trial experience. Strengths of the proposed trials include the controlled design, selection of patients most likely to benefit (those with low T3 levels), careful titration of LT3, and use of clinically relevant outcomes. Conduct of both studies in parallel will enable efficiencies in recruitment and comparisons of safety. The results of these studies will provide essential data to determine if larger scale clinical trials of T3 therapy should be pursued in patients with each condition.