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.
Although cardiovascular congestion is the hallmark of heart failure our understanding of mechanisms that lead to cardiovascular congestion and potential treatment options remain limited. Supported by my recent work, cardiac congestion and decompensation could be the result of internal volume redistribution from the splanchnic vascular compartment but validation of this innovative concept and novel therapeutic intervention requires detailed physiological testing. During this project, I will test the safety and efficacy of a prolonged splanchnic nerve blockade on exercise performance in patients with chronic heart failure and will learn relevant methodology in phenotyping patients with chronic heart failure.