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)
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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Brisco, Meredith A; Kimmel, Stephen E; Coca, Steven G et al. (2014) Prevalence and prognostic importance of changes in renal function after mechanical circulatory support. Circ Heart Fail 7:68-75
Testani, Jeffrey M; Brisco, Meredith A; Turner, Jeffrey M et al. (2014) Loop diuretic efficiency: a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure. Circ Heart Fail 7:261-70
Testani, Jeffrey M; Brisco, Meredith A; Han, Gang et al. (2014) Influence of age-related versus non-age-related renal dysfunction on survival in patients with left ventricular dysfunction. Am J Cardiol 113:127-31
Brisco, Meredith A; Testani, Jeffrey M (2014) Novel renal biomarkers to assess cardiorenal syndrome. Curr Heart Fail Rep 11:485-99
Singh, Dhssraj; Shrestha, Kevin; Testani, Jeffrey M et al. (2014) Insufficient natriuretic response to continuous intravenous furosemide is associated with poor long-term outcomes in acute decompensated heart failure. J Card Fail 20:392-9
Testani, Jeffrey M; Damman, Kevin; Brisco, Meredith A et al. (2014) A combined-biomarker approach to clinical phenotyping renal dysfunction in heart failure. J Card Fail 20:912-9
Testani, Jeffrey M (2014) Renal subanalysis of the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF): the end of nesiritide as a cardiorenal therapeutic? Circulation 130:936-8
Testani, Jeffrey M; Brisco, Meredith A; Tang, W H Wilson et al. (2013) Potential effects of digoxin on long-term renal and clinical outcomes in chronic heart failure. J Card Fail 19:295-302
Brisco, Meredith A; McCauley, Brian D; Chen, Jennifer et al. (2013) Biochemical evidence of mild hepatic dysfunction identifies decompensated heart failure patients with reversible renal dysfunction. J Card Fail 19:739-45
Testani, Jeffrey M; Brisco, Meredith A; Chen, Jennifer et al. (2013) Timing of hemoconcentration during treatment of acute decompensated heart failure and subsequent survival: importance of sustained decongestion. J Am Coll Cardiol 62:516-24