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

射血分数降低的心力衰竭（HFrEF）是入院的常见原因 在退伍军人事务部（VA）的医疗保健系统。它与严重的损害有关， 身体和精神健康状况，5年死亡率高达75%。即使 在了解其病理生理学方面取得了重大进展，目前， 管理和治疗是基于有限数量的受体的治疗靶向 和路径。 我们的团队和其他人在过去的几年里取得了很大的进步， 并利用瞬时电位受体超家族作为心血管疾病的调节因子， 功能具体来说，我们的实验室已经探索了香草素2（TRPV 2）亚型在 调节钙的处理和收缩性。这项工作使我们了解到TRPV 2 通过增加肌细胞中的钙循环来调节收缩性。 我们使用丙磺舒，一种全球通用的药物， 作为一种TRPV 2激动剂，它已被用于治疗痛风数十年。我们的工作 已经证明它是一种有效的正性肌力药，没有凋亡，变时性或 体外以及体内小鼠和猪模型中心肌细胞的促凋亡作用。 最近发表的一项小型2期研究将这些发现带到了床边， 20例成人HFrEF患者（ReProximate HF初探性研究），我们证明了平均 左心室收缩和舒张功能改善，仅1小时后无不良反应 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。 一项对医疗保险数据库中约40，000名患者的回顾性研究发现， 丙磺舒治疗（不是专门针对心脏病）与9%的下降有关， HF住院风险。这些研究有力地证明了 丙磺舒改善收缩功能需要更大规模的研究，且持续时间更长 除了心脏收缩功能外，还评估功能和健康状况结果。 本研究的总体目标是治疗NYHA II-III级的门诊退伍军人 丙磺舒治疗射血分数降低的心力衰竭（HFrEF），以改善收缩压和健康 功能具体来说，我们提出了一个三个中心的双盲，随机，安慰剂- 对照，三个地点的试验，将评估是否口服丙磺舒给予1克口服 NYHA II-III级HFrEF患者每天两次持续180天，可改善收缩功能， 通过超声心动图测量射血分数（目的1）;改善功能状态， 通过运动压力测试（目标2）测量;并改善自我报告的心力衰竭特定健康状况 通过堪萨斯城心肌病问卷（KCCQ）测量的状态和总体健康状况 通过EQ 5D（目标3）测量的状态。 本试验与VA人群高度相关，因为HFrEF是导致VA的首要原因 在VA医疗保健系统的患者之间入院，它是高度创新的，因为它将 寻求将先前确定的安全药物重新用于新适应症， 动物、临床前和基于人群的研究。如果成功，这项研究将不仅提供一个 新的治疗方法，它也将提供必要的事件发生率，为未来更大的研究，以建立 它在改善住院率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.