Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients

February 29, 2020 updated by: Mark Haykowsky, The University of Texas at Arlington

Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is the fastest growing form of heart failure with a high morbidity and mortality rate, and is associated with severe exercise intolerance. The mechanisms responsible for the reduced exercise tolerance remain poorly understood. The investigators propose a novel paradigm shift, focusing on peripheral limitations to exercise. In particular, the investigators will test the hypothesis that muscle sympathetic nerve activity (MSNA) is elevated in older HFpEF patients compared to healthy controls, and is associated with reduced exercise tolerance. The investigators will also test whether 16-weeks of exercise training will lower MSNA compared to attention control, and correlate with improved exercise tolerance in older HFpEF patients.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Heart failure with preserved ejection fraction is the fastest growing form of heart failure, is almost exclusively found in older persons, particularly older women, 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). A consequence of the reduced exercise tolerance is that activities of daily living require near maximal effort, resulting in further deconditioning and reduced quality of life. The majority of work to date has focused on cardiac limitations, showing impaired cardiac output and marked diastolic dysfunction. Although these findings have provided important insight into the pathophysiology of HFpEF, drug therapies targeting cardiac function do not improve peak VO2, quality of life, or survival in HFpEF patients.

Older HFpEF patients have multiple skeletal muscle abnormalities including reduced skeletal muscle oxidative capacity and capillary-to-fiber ratio resulting in increased anaerobic metabolism during low-level exercise. Importantly, accumulation of anaerobic metabolites within the exercising muscles are known to activate skeletal muscle afferent fibers (called metaboreceptors), that elicit a reflex-mediated increase in efferent muscle sympathetic (vasoconstrictor) nerve activity (MSNA). The investigators here propose a novel paradigm of exercise intolerance in older HFpEF patients whereby skeletal muscle abnormalities lead to overactivation of the muscle metaboreflex and MSNA mediated vasoconstriction that limits delivery of oxygenated blood to the active muscles. Further, exercise training mediated improvements in skeletal muscle function will alleviate the metaboreflex, thereby reducing MSNA and improve oxygen delivery to the contracting muscles.

To test this novel paradigm, the investigators will first perform an initial cross-sectional comparison of older (≥60 years) HFpEF patients (N=24) with age and sex-matched healthy controls (N=24), and then enter the HFpEF patients into a randomized, controlled, single blind, trial of exercise training to test the following hypothesis: (i) that MSNA is elevated in older HFpEF patients compared to healthy controls, and is associated with reduced peak VO2, physical functional performance, aerobic endurance, muscle blood flow, and quality of life; and (ii) Exercise training will attenuate MSNA compared to attention control, and will correlate with improved peak VO2, physical functional performance, aerobic endurance, muscle blood flow, and quality of life in older HFpEF patients.

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Arlington, Texas, United States, 76019
        • University of Texas at Arlington

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

60 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria for Heart Failure Preserved Ejection Fraction Patients:

  • ≥60 years of age, male or female.
  • Documented heart failure diagnosis.
  • Left ventricular ejection fraction ≥50%.
  • Clinically stable (no heart failure hospitalization within prior month).

Inclusion Criteria for Healthy Controls:

  • ≥60 years of age, male or female (matched to the age and sex of HFpEF patients).
  • No cardiac medications except for statins.
  • Sedentary (exercise three days per week or less).

Exclusion Criteria for Heart Failure Preserved Ejection Fraction Patients:

  • Greater than moderate valvular disease or congenital heart disease.
  • New York Heart Association class IV.
  • Any orthopedic or medical condition that would limit exercise testing or training.
  • Development of signs and symptoms of myocardial ischemia (1 mm ST segment depression on EKG), or unstable hemodynamics/rhythm, or systolic/diastolic blood pressure >240/110 mmHg during baseline cardiopulmonary (peak VO2) testing.

Exclusion Criteria for Healthy Controls:

  • Chronic medical condition (e.g. self reported hypertension, or diabetes, or chronic obstructive pulmonary disease or heart disease)
  • Abnormal history or cardiovascular physical exam.
  • Segmental wall motion abnormalities or structural valvular abnormalities.
  • Left ventricular ejection fraction <50%.
  • Any orthopedic or medical condition that would limit exercise testing.
  • Development of signs and symptoms of myocardial ischemia (1 mm ST segment depression on EKG), or unstable hemodynamics/rhythm, or systolic/diastolic blood pressure >240/110 mmHg during baseline cardiopulmonary (peak VO2) testing.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Exercise Training
Subjects will perform continuous endurance exercise (arm and leg cycle on Schwinn AD6 Airdyne ergometer, treadmill walking) 3 days per week. During the first 4-weeks, the exercise intensity will be set at 60%-70% of heart rate reserve and will increase by 5% per month. The initial exercise duration be 30 minutes and will gradually increase by 10 minutes every month. A 5-minute warm up and cool-down will precede and follow the aerobic conditioning phase. After the aerobic training phase is completed, patients will also perform unilateral handgrip exercise at an initial intensity of 50% maximal voluntary contraction for 1 set of 10 repetitions, and the intensity and sets will increase by 5% and 1 set, respectively each month.
Other: Exercise Training
HFpEF patients randomized to either 16 weeks of exercise training or attention control group.
No Intervention: Attention Control
These subjects will be asked to continue with normal activity and will not be given any exercise training. The subjects will be contacted by the study coordinator at pre-arranged times and dates once a month and involve inquiry regarding overall well-being of the subject.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Muscle sympathetic nerve activity (MSNA) assessed by direct microneurography
Time Frame: Change from Baseline MSNA at 16 weeks
Standard microneurographic procedures will be used to directly measure MSNA, at rest and during handgrip exercise and post-exercise cuff occlusion, using the peroneal nerve.
Change from Baseline MSNA at 16 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Peak Oxygen Uptake (Peak VO2) assessed by gas exchange indirect calorimetry
Time Frame: Change from Baseline Peak VO2 at 16 weeks.
Peak VO2 will be measured as the highest oxygen uptake during a peak cycle exercise test on an upright cycle ergometer.
Change from Baseline Peak VO2 at 16 weeks.
Physical functional performance assessed by Short Physical Performance Battery (SPPB) Test
Time Frame: Change from Baseline physical functional performance at 16 weeks.
The Short Physical Performance Battery consists of 3 subtasks: standing balance, walking speed, and time to raise from a chair 5 times.
Change from Baseline physical functional performance at 16 weeks.
Aerobic endurance assessed by six-minute walk distance
Time Frame: Change from Baseline aerobic endurance at 16 weeks.
The six-minute walk test is a validated measure of aerobic endurance in patients with heart failure that measures the distance covered in a 6 min period.
Change from Baseline aerobic endurance at 16 weeks.
Muscle blood flow assessed by brachial artery Doppler Ultrasound
Time Frame: Change from Baseline muscle blood flow at 16 weeks.
Measurement of brachial artery diameter and blood velocity via Doppler Ultrasound to calculate blood flow.
Change from Baseline muscle blood flow at 16 weeks.
Quality of life assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ)
Time Frame: Change from Baseline quality of life at 16 weeks.
The KCCQ is a valid, reliable and responsive health status measure for patients with heart failure.
Change from Baseline quality of life at 16 weeks.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The University of Texas at Arlington

Investigators

  • Principal Investigator: Mark Haykowsky, PhD, University of Texas at Arlington

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 17, 2017

Primary Completion (Actual)

December 12, 2019

Study Completion (Actual)

December 12, 2019

Study Registration Dates

First Submitted

March 25, 2017

First Submitted That Met QC Criteria

April 5, 2017

First Posted (Actual)

April 12, 2017

Study Record Updates

Last Update Posted (Actual)

March 3, 2020

Last Update Submitted That Met QC Criteria

February 29, 2020

Last Verified

February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 1R15NR016826-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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