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.
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.
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