This proposal describes a five year intensive mentored training program with the goal of developing the Principal Investigator (PI) into an independent and high impact, patient-oriented researcher. The PI is a fully trained adult cardiologist, has obtained formal research training in the Masters in Translational Research program, and is currently completing an advanced heart failure (HF) and cardiac transplantation clinical fellowship at the University of Pennsylvania. His clinical research mentorship to date has been lead by Dr. Stephen Kimmel (Primary Mentor of this proposal) and as evidenced by the PI's 11 first author publications under Dr. Kimmel's supervision, this is a highly effective mentoring relationship. However, successful transition of the PI to research independence will require substantial additional training and intense mentored career development. A comprehensive training proposal is thus proposed to facilitate the above, which will include: 1) Intensive mentoring from a team lead by Dr. Kimmel 2) Advanced didactic coursework 3) Hands on experience in prospective patient-oriented research 4) Scientific advisory by eminent cardio-renal scholars such as Drs. John Burnett and Robert Schrier 5) Structured career development and establishment of a body of scientific work with which the transition to independence will be based. The overall objective of the scientific aspect of this proposal is to better define cardio-renal phenotypes and their prognostic importance in HF. Renal dysfunction (RD) is a common complication of HF and one of the strongest risk factors for death in these patients. Severe HF and its treatment (i.e., loop diuretics) are known to result in progressive neurohormonal activation and peripheral organ dysfunction (i.e., RD). The risk attributable to RD appears to be isolated to patients with an elevated blood urea nitrogen to creatinine ratio (BUN/Cr), which is a surrogate for renal neurohormonal activation. If neurohormonal activation is indeed underlying the above observations, the direct treatment implications are substantial. However, BUN/Cr is influenced by factors external to neurohormonal activation, and these non-neurohormonal factors may also be important in RD- associated mortality.
The aims of this proposal are to quantify the degree to which neurohormones are elevated in HF patients with RD and elevated BUN/Cr, investigate the influence of loop diuretics in the genesis of these neurohormonal abnormalities, and establish whether it is the neurohormonally dependent aspects of BUN/Cr that are driving these mortality observations. We will achieve these aims by: 1) Direct characterization of neurohormonal parameters in HF patients with RD and either a high or low BUN/Cr in the Clinical and Translational Research Center, before and after loop diuretic exposure. 2) Determination in a large prospective HF cohort, the Penn Heart Failure Study, if the fractional excretion of urea (which captures the neurohormonally mediated aspect of BUN/Cr) is responsible for the ability of BUN/Cr to differentiate high and low risk forms of RD. The results of this line of investigation will form the basis upon which future interventional trias in these high risk patients can be based. The combination of formal advanced research training and mentored patient-oriented research experience will ensure the PI emerges as a highly successful independent patient-oriented researcher in HF and cardio- renal interactions.

Public Health Relevance

Heart failure is a common condition and can cause dysfunction of other organs such as the kidneys. Recent studies have shown that people with kidney dysfunction from heart failure have a very high risk of death. An improved understanding of how heart failure causes kidney dysfunction could lead to important therapies for these patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1)
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Scott, Jane
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Testani, Jeffrey M; Hanberg, Jennifer S; Cheng, Susan et al. (2016) Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure. Circ Heart Fail 9:e002370
Brisco, Meredith A; Zile, Michael R; Ter Maaten, Jozine M et al. (2016) The risk of death associated with proteinuria in heart failure is restricted to patients with an elevated blood urea nitrogen to creatinine ratio. Int J Cardiol 215:521-6
Hanberg, Jennifer S; Sury, Krishna; Wilson, F Perry et al. (2016) Reduced Cardiac Index Is Not the Dominant Driver of Renal Dysfunction in Heart Failure. J Am Coll Cardiol 67:2199-208
Brisco, Meredith A; Testani, Jeffrey M; Cook, Jennifer L (2016) Renal dysfunction and chronic mechanical circulatory support: from patient selection to long-term management and prognosis. Curr Opin Cardiol 31:277-86
Oh, Janice; Bia, Joshua R; Ubaid-Ullah, Muhamad et al. (2016) Provider acceptance of an automated electronic alert for acute kidney injury. Clin Kidney J 9:567-71
Laur, Olga; Brisco, Meredith A; Kula, Alexander J et al. (2016) The Impact of Donor and Recipient Renal Dysfunction on Cardiac Allograft Survival: Insights Into Reno-Cardiac Interactions. J Card Fail 22:368-75
Hanberg, Jennifer S; Rao, Veena; Ter Maaten, Jozine M et al. (2016) Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights. Circ Heart Fail 9:
Kula, Alexander J; Hanberg, Jennifer S; Wilson, F Perry et al. (2016) Influence of Titration of Neurohormonal Antagonists and Blood Pressure Reduction on Renal Function and Decongestion in Decompensated Heart Failure. Circ Heart Fail 9:e002333
Grodin, Justin L; Verbrugge, Frederik H; Ellis, Stephen G et al. (2016) Importance of Abnormal Chloride Homeostasis in Stable Chronic Heart Failure. Circ Heart Fail 9:e002453
Testani, Jeffrey M; Hanberg, Jennifer S; Arroyo, Juan Pablo et al. (2016) Hypochloraemia is strongly and independently associated with mortality in patients with chronic heart failure. Eur J Heart Fail 18:660-8

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