This proposal outlines a five-year mentored training program to develop Meredith A. Brisco, MD, MSCE, an Assistant Professor of Medicine at the Medical University of South Carolina, into an independent clinical investigator. She is a trained advanced heart failure and transplant cardiologist who obtained dedicated clinical research expertise during her Masters of Science in Clinical Epidemiology, emphasizing her dedication to an academic medical career. During those two years, she developed focused research interests in cardiorenal interactions and mechanical circulatory support that led to multiple first-author manuscripts in high- impact cardiology journals. The career development plan and mentorship team outlined in this application are specifically designed to meet Dr. Brisco's unique educational, experimental and clinical research goals, ensuring her maturation into an independent physician scientist focusing on cardiorenal interactions in patients with left ventricular assist devices (LVADs). These career goals include: 1) to develop expertise in kidney injury biomarker analysis, 2) to develop practical skills in gold-standard methodologic assessment of renal physiology and neurohormonal activation in LVAD patients, 3) to develop expertise in longitudinal and repeated measures data analysis, and 4) to develop practical skills in conducting human subjects research. The comprehensive training plan, which includes formal coursework, mentored activities, and scientific conferences, will be performed under the close supervision and guidance of a senior team of mentors comprised of thought-leaders in nephrology (John Arthur, MD, PhD), heart failure (Michael Zile, MD) and the cardiorenal syndrome (Jeffrey Testani, MD, MTR). The outstanding training environment of the Medical University of South Carolina and the clinical research support of the South Carolina Clinical and Translational Research Institute, coupled with the Department of Medicine's complete commitment, will ensure her future success. The overall objective of the scientific aspect of this proposal is to better understand the mechanistic and physiologic basis of LVAD-induced changes in renal function. The dramatic survival benefit with LVADs compared to medical therapy has led to a shift in the goals of LVAD care from simply surviving device implantation to decreasing long-term morbidity by improving and maintaining end-organ function. Notably, dramatic early improvements in renal function are common after LVAD placement, but renal dysfunction (RD) recurs at an alarming rate and is associated with markedly increased mortality. LVAD-induced kidney damage is likely responsible for the declining glomerular filtration rate (GFR); in animal models current LVADs lead to dramatic upregulation of the intrarenal renin angiotensin aldosterone system (RAAS). Our central hypothesis is that despite early improvements in renal function, progressive ongoing injury secondary to continued RAAS activation may be involved in the ensuing deterioration in renal function. In a prospective cohort study of LVAD patients, the specific aims are to: 1) Determine changes in renal physiology following LVAD support using gold standard methodology, 2) Determine whether kidney injury is involved in changes in renal function following LVAD placement, and 3) Define if intrarenal and systemic RAAS activation are associated with changes in renal physiology and kidney injury during LVAD support and if RAAS antagonism can mitigate this injury. We will achieve these aims by longitudinally measuring renal physiology (glomerular filtration rate, renal blood flow, filtration fraction), biomarkers of kidney injury, and neurohormones following LVAD implantation. Furthermore, we will conduct a small, randomized controlled pilot trial of losartan versus placebo to compare the effects of treatment on kidney injury biomarker levels. This proposal represents the first effort to characterize the renal and neurohormonal physiology of prognostically important changes in renal function after LVAD. The research outlined in this application is innovative because it employs a combination of gold-standard techniques, novel injury biomarkers, intrarenal RAAS assessment, and a clinical intervention in a multi-tiered and comprehensive approach to define the physiology and upstream mechanisms of changes in renal function on LVAD support. The results of this study will provide the groundwork to improve diagnosis and develop prevention and treatment strategies for post-LVAD RD.

Public Health Relevance

Left ventricular assist devices (LVADs) are mechanical heart pumps that when surgically attached to the heart improve quality of life and survival in patients with advanced heart failure. Renal dysfunction is present in more than 50% of LVAD recipients and is one of the strongest predictors of poor survival. An improved understanding of the mechanism of renal dysfunction in LVAD patients is expected to lead to important treatments ultimately improving morbidity and mortality.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
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Scott, Jane
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Temple University
Internal Medicine/Medicine
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United States
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Testani, Jeffrey M; Brisco-Bacik, Meredith A (2017) Worsening Renal Function and Mortality in Heart Failure: Causality or Confounding? Circ Heart Fail 10:
Rao, Veena S; Planavsky, Noah; Hanberg, Jennifer S et al. (2017) Compensatory Distal Reabsorption Drives Diuretic Resistance in Human Heart Failure. J Am Soc Nephrol 28:3414-3424
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; Rao, Veena; Ter Maaten, Jozine M et al. (2016) Hypochloremia and Diuretic Resistance in Heart Failure: Mechanistic Insights. Circ Heart Fail 9:
Testani, Jeffrey M; Brisco, Meredith A (2016) Plasma NGAL: So, it Really Is Just Expensive Creatinine! J Am Coll Cardiol 68:1432-1434
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
Brisco-Bacik, Meredith A (2016) ""Usual"" Yet Not Uniform Care Limits Our Understanding of Trials of Self-Management Interventions in Heart Failure. J Card Fail 22:872-874
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
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
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

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