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Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Precision Therapy Based on Patient Specific Pathophysiology

Award Number: P01HL137630
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Precision Therapy Based on Patient Specific Pathophysiology - Project Summary/Abstract Heart failure with preserved ejection fraction (HFpEF) is perhaps the most common “untreatable” disease in the world. It makes up more than 50% of all heart failure cases and in contrast to other cardiovascular diseases, its prevalence is increasing resulting in substantial morbidity, mortality, and cost. HFpEF has been resistant to “one-size-fits-all” therapies that have become standard treatment of heart failure with a reduced ejection fraction (HFrEF); therefore there has been increasing pressure to better phenotype this complex and multifactorial disease in order to direct “personalized” pathophysiology based therapy. The dominant symptom of patients with HFpEF is exercise intolerance and dyspnea on exertion (DOE). Such dyspnea can be pro- found, occur at very low levels of external work, and thereby limits physical activity leading to a downward spiral of inactivity and deconditioning which compounds the underlying cardiac and vascular disease. In 2012 The National Heart, Lung, and Blood Institute convened a working group to identify the key knowledge gaps in this field and to suggest strategies for future research on exercise intolerance, and exercise training as a treat- ment for heart failure.(Fleg 2015) We propose to address each of the working group recommendations through a unique PPG that links 4 projects and 3 cores to address the global objective of determining the mechanisms of exercise intolerance and dyspnea in patients with HFpEF and based on this pathophysiology, designing cre- ative exercise interventions that improve quality of life. Although virtually all Program Project Grants are linked together by a common theme, this PPG will be unique in that the individual projects will be linked even more closely by working together on common patients. All patients will be recruited into the Program by a specializ- ed Recruitment Core; each patient will then undergo high resolution physiological phenotyping by all 4 projects followed by a tailored intervention designed to test the clinical relevance of the phenotyping strategy. This approach will allow us to accomplish the following specific aims: Specific Aim 1: To determine the mechan- ism(s) of exercise intolerance and DOE in patients with HFpEF using invasive and non-invasive cardio- pulmonary exercise testing. Patients will be divided into those with a primarily “central” limitation and those with a primarily “peripheral limitation” based on this initial assessment. Specific Aim #2: to determine whether a “precision” exercise intervention based on the high resolution phenotyping will lead to clinically meaningful improvements in functional capacity and reduction in dyspnea. All patients will be randomized to undergo one of two tailored exercise interventions for 16 weeks: a) small muscle mass, single leg kicking exercise to allow high intensity muscle exercise without challenging cardiovascular reserve; b) reduce cardiac filling pressure during exercise with acute ingestion of TNG to allow higher systemic workloads and improved training. By combining efforts into a PPG integrated by studying the same patients across multiple platforms, our team has the potential to make highly novel advances towards improving the quality of life for patients with HFpEF.


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 = $0 )
2025	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	5	1/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $2,271,524 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	5	1/28/2023	NON-COMPETING CONTINUATION	$2,271,524
														Subtotal = $2,271,524

Issue Date FY: 2022 ( Subtotal = $2,268,997 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	002	4	5/31/2022	NON-COMPETING CONTINUATION	$226,900
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	4	1/14/2022	NON-COMPETING CONTINUATION	$2,042,097
2022	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	3	11/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,268,997

Issue Date FY: 2021 ( Subtotal = $2,268,508 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$226,852
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	3	1/29/2021	NON-COMPETING CONTINUATION	$2,041,656
														Subtotal = $2,268,508

Issue Date FY: 2020 ( Subtotal = $2,269,684 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	2	2/6/2020	NON-COMPETING CONTINUATION	$2,269,684
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	002	2	7/16/2020	NON-COMPETING CONTINUATION	$0
2020	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	1	7/15/2020	NEW	$0
														Subtotal = $2,269,684

Issue Date FY: 2019 ( Subtotal = $2,322,430 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	1	2/11/2019	NEW	$2,322,430
														Subtotal = $2,322,430

Grand Total All Awards = $11,401,143

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Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Precision Therapy Based on Patient Specific Pathophysiology

Award Number: P01HL137630

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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