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Proteomic Profiling of Precise Exercise Pathophenotypes Across the HFpEF Spectrum

Award Number: R01HL131029
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Proteomic Profiling of Precise Exercise Pathophenotypes Across the HFpEF Spectrum - PROJECT SUMMARY/ABSTRACT Heart failure (HF) with preserved ejection fraction (HFpEF) represents ≈50% of HF, with limited methods for prevention and treatment. Current approaches to detect/treat HFpEF rely on cardiac phenotypes obtained at rest, missing reserve capacity impairments in multiple organ systems central to HFpEF that are uniquely revealed through exercise. In the first R01 period, we performed 3117 cardiopulmonary exercise tests (CPETs) in the Framingham Heart Study (FHS) to quantify cardiorespiratory fitness, individual exercise responses, and their metabolomic signatures. We defined a “normal” metabolic response to exercise and reported novel measures of impaired fitness and HF risk. Strikingly, ≈1 in 4 asymptomatic community-dwelling FHS participants displayed fitness impairment that overlapped with individuals with hemodynamically confirmed HFpEF studied in our clinical referral lab. Metabolites related to HFpEF physiology were also associated with exercise responses in FHS. These results underscore a critical molecular and phenotypic overlap between clinical HFpEF and the early stages of its development, providing a unique opportunity to define the origins of HFpEF and reveal new targets for its screening/prevention. Proteins are potentially targetable biomarkers that provide a readout of specific pathways relevant to multiple organs, have direct correlation with genetics, and have a well-defined process for assay development. The hypothesis of this renewal is that molecular pathways related to precise HFpEF phenotypes captured during exercise will specify mechanisms underlying HFpEF susceptibility long before its usual clinical detection. We leverage 2 unique samples developed in the first period: (1) deeply-phenotyped HFpEF patients with hemodynamic measures during CPET (MGH-ExS, N=500) and (2) FHS participants with CPET and plasma samples at rest/peak exercise (N=1500). We will study a broad circulating proteome (>3000 proteins at rest/peak exercise) in relation to precise exercise phenotypes, in silico bioinformatics, and human genetics to specify proteomic signatures of exercise response in 3 aims. In Aim 1, we identify pathways of organ- specific responses to exercise in HFpEF (using the rest proteome) and their relation to subclinical phenotypes central to HFpEF susceptibility in the community. In Aim 2, we will quantify changes in the circulating proteome with acute exercise and evaluate how exercise-induced changes differ in the presence of HFpEF (MGH-ExS vs. FHS) and HFpEF risk factors. In Aim 3, we measure association of proteomic signatures of HFpEF phenotypes with incident HF and cardiovascular disease (CVD) in racially diverse primary prevention cohorts. We also construct genetic instruments of implicated proteins (pQTLs) for association with HF/CVD in large biobanks using Mendelian randomization. This application unites profiling of broad pathways with relevance to HFpEF with unique, precise exercise phenotypes collected during the first grant period to resolve clinical heterogeneity in HFpEF and to prioritize novel targets for earlier and more precise prevention. This project will provide a unique resource for the scientific community, with all data made publicly available immediately upon completion.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,416,634 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	7	6/12/2025	NON-COMPETING CONTINUATION	$1,416,634
														Subtotal = $1,416,634

Issue Date FY: 2024 ( Subtotal = $1,396,877 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	001	6	6/21/2024	NON-COMPETING CONTINUATION	$114,030
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	6	2/23/2024	NON-COMPETING CONTINUATION	$1,282,847
														Subtotal = $1,396,877

Issue Date FY: 2023 ( Subtotal = $1,463,930 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Cardiovascular Diseases Research	000	5	4/5/2023	COMPETING CONTINUATION	$1,463,930
														Subtotal = $1,463,930

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	6/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $468,685 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	12/28/2018	NON-COMPETING CONTINUATION	$468,685
														Subtotal = $468,685

Issue Date FY: 2018 ( Subtotal = $529,660 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	3	12/22/2017	NON-COMPETING CONTINUATION	$519,066
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	001	3	7/6/2018	NON-COMPETING CONTINUATION	$10,594
														Subtotal = $529,660

Issue Date FY: 2017 ( Subtotal = $557,645 )
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	2	12/23/2016	NON-COMPETING CONTINUATION	$557,645
														Subtotal = $557,645

Issue Date FY: 2016 ( Subtotal = $490,774 )
2016	2016	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	12/17/2015	NEW	$490,774
														Subtotal = $490,774

Grand Total All Awards = $6,324,205

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Proteomic Profiling of Precise Exercise Pathophenotypes Across the HFpEF Spectrum

Award Number: R01HL131029

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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