Congestion Phenotypes and Splanchnic Nerve Modulation in Chronic Heart Failure

项目摘要/摘要 仅在美国，心力衰竭(HF)就影响了600多万成年人，而且患病率正在上升。心血管病 充血和由此导致的体力活动受限是慢性失代偿心衰的标志。海流 心衰生理模型表明充血是容量滞留的结果，因此，治疗(如 利尿剂)通常针对的是容量超负荷。然而，缓解拥堵的治疗方法已经 未能显示出对临床结果的显著益处，可能是由于无针对性的去充血方法 治疗。我的初步工作表明，体积再分配对 心脏失代偿。我确定内脏神经是一个潜在的治疗靶点，并显示出短- 长期阻断内脏神经信号可对心血管血流动力学产生有利影响 和症状。 我寻求导师研究职业发展奖的目标是获得必要的培训和 心力衰竭患者个体化治疗和自主神经调节的经验 作为治疗充血，改善功能状态，防止心衰失代偿的治疗干预。 作为我建议的一部分，我将：(1)在随机、 受控开放标签研究；以及(2)使用多水平诊断测试确定心力衰竭的充血表型。这个 新的治疗方法可能会带来心力衰竭治疗的范式转变。利用独特的资源 提出的目标不仅将检验这一范式，还将帮助我们了解哪种表型是 更有可能是由数量重新分配造成的，而不是数量过载。导师团队由Dr。 禤浩焯·埃尔南德斯，临床研究副院长、心力衰竭专家，包括国际知名的 心衰、临床试验设计/操作(Manesh Patel博士)、充血测试(Michael Felker博士)、运动 生理学(威廉·克劳斯和巴里·博劳格博士)、自主神经测试(布尔茨-马克思和本杰明·莱文博士)和 量化培训(Kevin Anstrom，博士)。与正式的教学相结合，他们将提供必要的支持 实现我的培训目标是在以下方面发展技能：(1)HF表型，包括运动生理学、充血和 自主测试；(2)试验设计和操作；(3)数据归约和分析。 提出的科学目标的结果将有助于检验体积再分配的范式转换假说，如 心血管充血和功能限制的驱动因素，并为内脏神经阻断铺平道路 心衰的新治疗方法。随着培训目标的完成，我将成为一名独特的临床医生 经过严格研究方法培训的心力衰竭专家，评估心力衰竭生理学的多个关键组成部分， 开展临床试验，测试新的介入疗法。职业发展补助金提案将提供 我需要必要的技能来成功地实现我的目标，即建立一个独立的研究计划，以 向心力衰竭患者的个性化治疗迈进。

PROJECT SUMMARY/ABSTRACT Heart failure (HF) affects more than 6 million adults in the U.S. alone, with increasing prevalence. Cardiovascular congestion with resultant limitation in physical activity is the hallmark of chronic and decompensated HF. The current HF physiologic model suggests that congestion is the result of volume retention and, therefore, therapies (such as diuretics) have generally been targeted at volume overload. Yet therapeutic approaches to reduce congestion have failed to show significant benefit on clinical outcomes, potentially due to an untargeted approach of decongestive therapies. My preliminary work suggested a complimentary contribution of volume redistribution to the mechanism of cardiac decompensation. I identified the splanchnic nerves as a potential therapeutic target and showed that short- term interruption of the splanchnic nerve signaling could have favorable effects on cardiovascular hemodynamics and symptoms. My goal in seeking a Mentored Research Career Development Award is to acquire the necessary training and experience to develop personalized treatment approaches to patients with HF and advance autonomic modulation as a therapeutic intervention to treat cardiac congestion, improve functional status, and prevent HF decompensation. As part of my proposal I will: (1) test the safety and efficacy of prolonged splanchnic nerve block in a randomized, controlled, open-label study; and (2) define congestion phenotypes in HF using multi-level diagnostic testing. The novel therapeutic approach could present a paradigm shift in the treatment of HF. Leveraging resources unique to Duke University, the proposed aims will not only test this paradigm, but also help us understand which phenotype is more likely to be caused by volume redistribution rather than volume overload. The mentorship team, led by Dr. Adrian Hernandez, Vice Dean of Clinical Research and HF specialist, includes internationally-renowned experts in the fields of HF, clinical trial design/operations (Dr. Manesh Patel), congestion testing (Dr. Michael Felker), exercise physiology (Drs. William Kraus and Barry Borlaug), autonomic testing (Drs. Boortz-Marx and Benjamin Levine) and quantitative training (Kevin Anstrom, PhD). Combined with formal didactics, they will provide the support needed to achieve my training aims to develop skills in: (1) HF phenotyping including exercise physiology, congestion and autonomic testing; (2) trial design and operations; (3) data reduction and analysis. The results of the proposed scientific aims will help test the paradigm-shifting hypothesis of volume redistribution as a driver of cardiovascular congestion and functional limitations and pave the way for splanchnic nerve blockade as a novel therapeutic approach to HF. With the completion of the training aims, I will be uniquely-positioned as a clinical HF specialist, trained in rigorous research methodology, to assess multiple critical components of HF physiology, execute clinical trials, and test novel interventional therapies. The Career Development Grant proposal will provide me the necessary skills to successfully pursue my goal of establishing an independent research program geared towards personalizing treatments for patients with HF.