Congestion Phenotypes and Splanchnic Nerve Modulation in Chronic Heart Failure

项目总结/摘要 心力衰竭（HF）仅在美国就影响了600多万成年人，患病率不断增加。心血管 充血导致身体活动受限是慢性和失代偿性HF的标志。当前 HF生理模型表明，充血是容量保留的结果，因此，治疗（如 利尿剂）通常针对容量超负荷。然而，减少充血的治疗方法 未能显示出对临床结局的显著获益，可能是由于非靶向的缓解充血方法 治疗我的初步工作表明，体积再分配对 心脏代偿失调我发现内脏神经是一个潜在的治疗目标，并表明短- 内脏神经信号的长期中断可能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， 为HF患者开发个性化治疗方法和推进自主神经调节的经验 作为治疗心脏充血、改善功能状态和预防HF失代偿的治疗性干预。 作为我建议的一部分，我将：（1）在一个随机的， 对照、开放标签研究;和（2）使用多水平诊断测试定义HF中的充血表型。的 一种新的治疗方法可以在HF的治疗中呈现范式转变。利用独特的资源， 杜克大学，提出的目标不仅将测试这种范式，而且还有助于我们了解哪种表型是 更有可能是由体积重新分配而不是体积过载引起的。导师团队由Dr. Adrian埃尔南德斯，临床研究副院长和HF专家，包括国际知名的专家， HF、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（William Kraus和巴里博洛格博士）、自主神经测试（Boortz-Marx和Benjamin Levine博士）和 定量培训（Kevin Anstrom，PhD）。与正式教学法相结合，它们将提供所需的支持， 实现我的培训目标，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）数据简化和分析。 拟议的科学目标的结果将有助于检验体积再分配的范式转移假设， 心血管充血和功能限制的驱动因素，并为内脏神经阻滞作为一种 HF的新治疗方法。随着培养目标的完成，我将被定位为一名临床医生。 HF专家，接受过严格的研究方法培训，可评估HF生理学的多个关键组成部分， 执行临床试验并测试新型介入疗法。职业发展补助金提案将提供 我的必要技能，成功地追求我的目标，建立一个独立的研究计划， 为HF患者提供个性化治疗。

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.