Developing Oral LT3 Therapy for Heart Failure

项目总结 在发达国家，心力衰竭是成人住院的最常见原因。针对目标的疗法 心肌和外周器官功能障碍的可逆原因可能会为心脏带来额外的好处 衰竭伴射血分数降低(HFrEF)。此外，目前还没有被证实有效的药物。 保留射血分数的心力衰竭的治疗，它占心脏≥的50% 失败的负担。三碘甲腺原氨酸(T3)是一种内源性甲状腺激素，可通过多种途径影响甲状腺功能。 心血管系统，由心肌和血管中的T3受体介导，并直接在离子上 通道和线粒体。T3的主要作用包括增加心肌的收缩能力和 体循环血管阻力降低。尽管心脏低T3综合征的患病率很高(~20%-30%) 失败，作为T3的合成形式的利硫罗宁(LT3)的外源性给药仍然是一个未被探索的问题 治疗选择。低T3综合征与HFrEF和HFrEF患者死亡率增加有关 HFpEF的疾病严重程度，但它是健康状况不佳的标志还是临床相关的中介 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LT3治疗心力衰竭和低T3患者的疗效。使用短期临床研究的概念验证 静脉输注LT3对慢性粒细胞白血病患者的生物标记物和安全性有有利影响 缺血型HFrEF。然而，在HFrEF中口服LT3治疗的安全性仍然存在知识空白。 此外，还没有研究检查LT3在HFpEF中的安全性。我们打算通过两个平行的， 低T3综合征患者服用LT3的随机、双盲、安慰剂对照研究： 一例为HFrEF患者，另一例为HFpEF患者。我们的安全结果将是T3水平和 节律监测。我们的初步疗效结果将是最大氧耗率(VO2)、质量 生命、心脏生物标志物、活动描记的家庭活动，以及左心功能、血管的非侵入性评估 功能和心室-动脉偶联。拟议的研究将评估其安全性和初步疗效。 在两个独立的研究人群中进行口服LT3治疗。我们的团队包括一名甲状腺病学家 临床调查员与经验丰富的HFrEF和HFpEF调查员密切合作，具有广泛的早期阶段 审判经验。拟议试验的优点包括对照设计、最有可能选择的患者 有益于(那些T3水平低的人)，仔细滴定LT3，并使用临床相关结果。进行的行为 这两项研究同时进行，将有助于提高招聘和安全比较的效率。这些研究的结果 研究将提供必要的数据，以确定是否应该在#年进行更大规模的T3疗法临床试验。 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.