Treatment of Veterans with Heart Failure with Reduced Ejection Fraction with Probenecid

心力衰竭伴射血分数降低(HFrEF)是入院的常见原因 在退伍军人事务部(VA)医疗保健系统内。它与严重的脑损伤有关 身体和精神健康状况，并带有高达75%的5年死亡率。即使 对其病理生理学的了解已取得重大进展，目前，其 管理和治疗的基础是对有限数量的受体进行靶向治疗 和小路。 我们的团队和其他人在过去几年里取得了很大的进步，通过了解 并利用瞬时电位受体超家族作为心血管调节因子 功能。具体地说，我们的实验室探索了香草素2(TRPV2)亚型所起的作用 在调节钙的处理和收缩方面。这项工作使我们了解到TRPV2 在节拍的基础上，通过增加心肌细胞中的钙循环来调节收缩能力。 我们已经使用了丙磺舒，一种全球可用的仿制药，具有极其安全的 作为TRPV2激动剂，几十年来一直用于治疗痛风的Profile。我们的工作 这种药物已经证明了它是一种强大的肌力调节作用，没有细胞凋亡，变时性或 心肌细胞在体外以及在体鼠和猪模型中的致心律失常作用。 这些发现与最近发表的一项小型第二阶段研究一起被带到了床边 20名患有HFrEF(Reprosper HF先导研究)的成人患者，我们在那里展示了平均 左心收缩和舒张期功能改善，仅用药1周后无不良反应 一周的治疗。丙磺舒在HFrEF中的使用也得到了最近一项研究的间接支持 对联邦医疗保险数据库中约40,000名患者的回顾研究发现 使用丙磺舒(不是专门针对心脏病)的治疗与9%的下降有关 心衰住院的风险。这些研究有力地证明了阿司匹林的安全性和潜在疗效。 丙磺舒可改善心脏收缩功能，需要更大规模和更长时间的研究 除了收缩功能外，它还评估功能和健康状况结果。 这项研究的总体目标是治疗患有NYHA II-III的门诊退伍军人 应用丙磺舒降低射血分数(HFrEF)以改善收缩功能和健康的心力衰竭 功能。具体地说，我们提出了一种三点双盲随机安慰剂- 三点对照试验，将评估口服丙磺舒是否在1gr.口服 NYHA II-III HFrEF患者每天两次，连续180天改善心脏收缩功能 通过超声心动图测量射血分数(目标1)；改善功能状态，如 通过运动负荷测试(目标2)进行测量；并改善自我报告心力衰竭特定的健康状况 堪萨斯城心肌病问卷(KCCQ)和总体健康状况 由EQ5D衡量的状态(目标3)。 这项试验与退伍军人症人群高度相关，因为HFrEF一直是头号原因 在退伍军人保健系统的患者中入院，这是非常创新的，因为它将 寻求将先前建立的安全药物重新用于新的适应症，基于广泛的 基于动物、临床前和种群的研究。如果成功，这项研究不仅将提供 新的治疗方法也将为未来更大规模的研究提供必要的事件发生率 它在改善住院和死亡率方面的作用。

Heart failure with reduced ejection fraction (HFrEF) is a common cause for admission within the Veterans Affairs (VA) Health Care System. It is associated with severe impairment of physical and mental health status, and carries a high 5-yr mortality rate of ~75%. Even though significant progress has been made in understanding its pathophysiology, currently, its management and treatment is based on therapeutic targeting of a limited number of receptors and pathways. Our team and others have made great progress in the last few years by understanding and harnessing the Transient Potential Receptor superfamily as regulators of cardiovascular function. Specifically, our laboratory has explored the role the vanilloid 2 (TRPV2) subtype plays in regulating calcium handling and contractility. This work has led us to understand that TRPV2 modulates contractility via increasing calcium cycling in myocytes on a beat-to-beat basis. We have used probenecid, a generic, globally available drug with an extremely safe profile that has been used for decades as a treatment for gout, as a TRPV2 agonist. Our work with this drug has demonstrated it to be a potent inotrope without apoptotic, chronotropic or arrhythmogenic effects in cardiomyocytes in vitro as well as in vivo murine and porcine models. These findings have been taken to the bedside with a recently published small phase 2 study of 20 adult patients with HFrEF (the ReProsper HF pilot study) where we demonstrated a mean improvement in left ventricular systolic and diastolic function with no adverse effects after only 1 week of treatment. The use of probenecid in HFrEF was also indirectly supported by a recent retrospective study of approximately 40,000 patients in the Medicare database that found treatment with probenecid (not specifically for heart disease) was associated with a 9% decreased risk of HF hospitalization. These studies strongly argue for the safety and potential efficacy of probenecid to improve systolic function and the need for a larger study, and of longer duration that also evaluates functional and health status outcomes in addition to systolic function. The overall objective of this study is the treatment of outpatient veterans with NYHA II-III heart failure with reduced ejection fraction (HFrEF) with probenecid to improve systolic and health function. Specifically, we are proposing a three-site double-blinded, randomized, placebo- controlled, three-site trial that will assess whether oral probenecid administered at 1 gr. orally twice per day for 180 days in patients with NYHA II-III HFrEF improves systolic function as measured via ejection fraction with echocardiography (aim 1); improves functional status as measured by exercise stress testing (aim 2); and improves self-report heart failure specific health status as measured by Kansas City Cardiomyopathy Questionnaire (KCCQ) and overall health status measured by EQ5D (aim 3). This trial is highly relevant to the VA population as HFrEF has been the number one reason for admission among patients in the VA Health Care System and it is highly innovative as it will seek to repurpose a previously established safe drug for a novel indication based on extensive animal, preclinical and population based studies. If successful, this study will not only provide a novel therapy it will also provide the necessary event rates for a future larger study to establish its role in improving hospitalization and mortality.