# Targeting skeletal muscle to improve exercise capacity in heart failure with preserved ejection fraction.

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $336,905

## Abstract

PROJECT SUMMARY 
Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure, is almost 
exclusively found in older persons and is associated with a high morbidity and mortality rate. The primary 
chronic symptom in HFpEF patients is severe exercise intolerance measured objectively as decreased peak 
exercise oxygen uptake (peak VO2). By convention, the majority of work to date has focused on central 
limitations, however drug therapies targeting cardiac function do not improve peak VO2 or survival in HFpEF. 
Emerging evidence from our group suggests that peripheral `non-cardiac' factors (e.g. decreased lean mass, 
impaired oxidative capacity and muscle blood flow) contribute significantly to the reduced peak VO2 in HFpEF. 
Exercise training is the only proven therapy to increase peak VO2 in older HFpEF patients, however the 
peripheral mechanisms (skeletal muscle O2 delivery/extraction, oxidative capacity) responsible for this 
improvement are unknown. A limitation of prior exercise training studies was the primary focus on whole body 
exercise which in the setting of marked increases in cardiac filling pressures and impaired cardiac output 
reserve—as occurs in HFpEF—may not be an optimal form of training for these patients. Exercise training 
modalities focused on removing the central limitation to exercise (as occurs with dynamic single-leg knee 
extension [KE] exercise) may prove more effective. Accordingly, the current project is dedicated to defining: a) 
the specific “peripheral mechanism(s)” contributing to exercise intolerance in HFpEF, and b) specific 
“peripheral” adaptations to exercise training. To achieve this objective, we will perform the first ever-direct 
 ≥ 
measure of leg VO2, leg O2 (convective and diffusive) transport and extraction, using invasive intravascular 
measures and Dopper ultrasound, during maximal dynamic single-leg KE exercise in older ( 60 years) HFpEF 
patients with a “primary central” phenotypye (Type A, n=40), “primary peripheral” phenotype (Type B, 
n=40) and controls (n=20). Our program grant Imaging Core we will also perform the most comprehensive in 
vivo assessment of skeletal muscle metabolism (1H and 31P NMR spectroscopy) at rest and in response to 
dynamic exercise. After baseline testing, Type “A” and “B” HFpEF patients will be randomly assigned to two 
different forms of training, each which are uniquely focused on removing the central limitation to exercise 
(Group 1: dynamic single-leg KE exercise; or Group 2: sublingual nitroglycerin given prior to and during cycle 
exercise training to lower cardiac filling pressures). Given the pathophysiology of exercise intolerance and 
mechanisms for improvement with physical training is poorly understood, and no medications have been 
proven effective, our results have the potential to shift paradigms, and have a major impact on the 
management of older patients with HFpEF in a short-time period.

## Key facts

- **NIH application ID:** 9869937
- **Project number:** 5P01HL137630-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** PAUL J FADEL
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,905
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869937

## Citation

> US National Institutes of Health, RePORTER application 9869937, Targeting skeletal muscle to improve exercise capacity in heart failure with preserved ejection fraction. (5P01HL137630-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9869937. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*