This is a K08 application for Dr Amil Shah, a cardiology faculty member and early stage investigator at the Brigham and Women's Hospital in Boston, MA. His goal is to become a leading clinical investigator using noninvasive assessments of cardiac structure and function to better understand heart failure risk and progression, and to inform new therapeutic interventions. His near-term goal is to employ novel echocardiographic measures of cardiac function to define the role of previously under-recognized systolic dysfunction in heart failure with preserved ejection fraction (HFpEF). This application presents a comprehensive training plan, including structured mentorship, a well-developed advisory committee, and a tailored didactic curriculum in advanced statistical and imaging methods, which together will provide Dr Shah with the skills necessary to achieve this goal and transition into a successful independent investigator. HFpEF is a well-recognized public health burden. The inability of noninvasive measures of diastolic function to distinguish HFpEF patients from their symptom-free counterparts and to predict adverse events among HFpEF patients, along with the under-appreciation of co-existing systolic dysfunction (detected using novel myocardial deformation imaging) are critical barriers to progress in effectively phenotyping and developing treatments for this heterogeneous syndrome. The main hypothesis of this proposal is that concomitant impairments in systolic and diastolic function occur in parallel with accumulating cardiovascular risk factors and that these impairments are central to the development of HFpEF and subsequent morbidity and mortality. Dr Shah will use state-of-the-art echocardiographic data from two unique, complementary, and well-phenotyped populations with prospectively adjudicated clinical outcomes - the NHLBI TOPCAT clinical trial in HFpEF and the community based NHLBI ARIC cohort - to address the following specific aims: (1) To determine the relationship of novel measures of systolic deformation with clinical and echocardiographic risk markers for incident HF in approximately 8,000 elderly community-dwelling ARIC participants;(2) To determine the extent to which these novel measures of systolic dysfunction associate with risk of developing HFpEF, and risk of CV death or HF hospitalization in prevalent HFpEF;and (3) To improve prognostication by combining novel measures of systolic dysfunction with soluble biomarkers of myocardial stress (NT-pro-BNP) and injury (high sensitivity troponin T) to develop parsimonious risk prediction models for incident HFpEF and for adverse outcomes in patients with prevalent HFpEF. The results of the proposed early career development award will (1) provide key benchmarks for defining pathologic diastolic and systolic dysfunction, (2) clarify the role of these abnormalities in HFpEF to help inform tailored interventions, (3) improve risk assessment to inform future preventative and therapeutic studies, and (4) serve as an ideal vehicle for Dr Shah to transition to an independent investigator.

Public Health Relevance

The proposed research is relevant to public health because heart failure with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and causes substantial morbidity, mortality, and resource utilization, particularly among the elderly. The results of this proposal will clarify the role of systolic and diastolic dysfunction in HFpEF ad improve risk assessment, providing crucial insight to inform future preventative and therapeutic investigations.

National Institute of Health (NIH)
Clinical Investigator Award (CIA) (K08)
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Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Wright, Jacqueline
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Brigham and Women's Hospital
United States
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Santos, Angela B S; Gupta, Deepak K; Bello, Natalie A et al. (2016) Prehypertension is Associated With Abnormalities of Cardiac Structure and Function in the Atherosclerosis Risk in Communities Study. Am J Hypertens 29:568-74
Gonçalves, Alexandra; Hung, Chung-Lieh; Claggett, Brian et al. (2016) Left Atrial Structure and Function Across the Spectrum of Cardiovascular Risk in the Elderly: The Atherosclerosis Risk in Communities Study. Circ Cardiovasc Imaging 9:e004010
Shah, Amil M; Solomon, Scott D (2016) Mechanical Dyssynchrony: A Risk Factor but not a Target. Eur Heart J 37:60-2
Nadruz Jr, Wilson; West, Erin; Santos, Mário et al. (2016) Heart Failure and Midrange Ejection Fraction: Implications of Recovered Ejection Fraction for Exercise Tolerance and Outcomes. Circ Heart Fail 9:e002826
Gori, Mauro; Gupta, Deepak K; Claggett, Brian et al. (2016) Natriuretic Peptide and High-Sensitivity Troponin for Cardiovascular Risk Prediction in Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care 39:677-85
Nadruz Jr, Wilson; Gonçalves, Alexandra; Claggett, Brian et al. (2016) Influence of cigarette smoking on cardiac biomarkers: the Atherosclerosis Risk in Communities (ARIC) Study. Eur J Heart Fail 18:629-37
Santos, Angela B S; Roca, Gabriela Querejeta; Claggett, Brian et al. (2016) Prognostic Relevance of Left Atrial Dysfunction in Heart Failure With Preserved Ejection Fraction. Circ Heart Fail 9:e002763
Shah, Amil M; Claggett, Brian; Loehr, Laura R et al. (2016) Heart Failure Stages Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study. Circulation :
Shah, Amil M; Claggett, Brian; Kitzman, Dalane et al. (2016) Contemporary Assessment of Left Ventricular Diastolic Function in Older Adults: The Atherosclerosis Risk in Communities Study. Circulation :
Folsom, Aaron R; Shah, Amil M; Lutsey, Pamela L et al. (2015) American Heart Association's Life's Simple 7: Avoiding Heart Failure and Preserving Cardiac Structure and Function. Am J Med 128:970-6.e2

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