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

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $2,269,684

## Abstract

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 w...

## Key facts

- **NIH application ID:** 9869931
- **Project number:** 5P01HL137630-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** BENJAMIN D LEVINE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,269,684
- **Award type:** 5
- **Project period:** 2019-02-09 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869931

## Citation

> US National Institutes of Health, RePORTER application 9869931, Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Precision Therapy Based on Patient Specific Pathophysiology (5P01HL137630-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869931. Licensed CC0.

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