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Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients

Primary Purpose

Heart Failure, Diastolic

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Exercise Training
Sponsored by
The University of Texas at Arlington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Heart Failure, Diastolic focused on measuring muscle sympathetic nerve activity, exercise tolerance, exercise training, peak oxygen uptake

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • University of Texas at Arlington

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

Exercise Training

Attention Control

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Muscle sympathetic nerve activity (MSNA) assessed by direct microneurography
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.

Secondary Outcome Measures

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

Full Information

First Posted
March 25, 2017
Last Updated
February 29, 2020
Sponsor
The University of Texas at Arlington
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1. Study Identification

Unique Protocol Identification Number
NCT03111017
Brief Title
Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients
Official Title
Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients With Preserved Ejection Fraction
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
April 17, 2017 (Actual)
Primary Completion Date
December 12, 2019 (Actual)
Study Completion Date
December 12, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The University of Texas at Arlington

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Failure, Diastolic
Keywords
muscle sympathetic nerve activity, exercise tolerance, exercise training, peak oxygen uptake

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Exercise Training
Arm Type
Experimental
Arm Description
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.
Arm Title
Attention Control
Arm Type
No Intervention
Arm Description
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.
Intervention Type
Other
Intervention Name(s)
Exercise Training
Intervention Description
HFpEF patients randomized to either 16 weeks of exercise training or attention control group.
Primary Outcome Measure Information:
Title
Muscle sympathetic nerve activity (MSNA) assessed by direct microneurography
Description
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.
Time Frame
Change from Baseline MSNA at 16 weeks
Secondary Outcome Measure Information:
Title
Peak Oxygen Uptake (Peak VO2) assessed by gas exchange indirect calorimetry
Description
Peak VO2 will be measured as the highest oxygen uptake during a peak cycle exercise test on an upright cycle ergometer.
Time Frame
Change from Baseline Peak VO2 at 16 weeks.
Title
Physical functional performance assessed by Short Physical Performance Battery (SPPB) Test
Description
The Short Physical Performance Battery consists of 3 subtasks: standing balance, walking speed, and time to raise from a chair 5 times.
Time Frame
Change from Baseline physical functional performance at 16 weeks.
Title
Aerobic endurance assessed by six-minute walk distance
Description
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.
Time Frame
Change from Baseline aerobic endurance at 16 weeks.
Title
Muscle blood flow assessed by brachial artery Doppler Ultrasound
Description
Measurement of brachial artery diameter and blood velocity via Doppler Ultrasound to calculate blood flow.
Time Frame
Change from Baseline muscle blood flow at 16 weeks.
Title
Quality of life assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ)
Description
The KCCQ is a valid, reliable and responsive health status measure for patients with heart failure.
Time Frame
Change from Baseline quality of life at 16 weeks.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Mark Haykowsky, PhD
Organizational Affiliation
University of Texas at Arlington
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Texas at Arlington
City
Arlington
State/Province
Texas
ZIP/Postal Code
76019
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
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Mechanisms and Management of Exercise Intolerance in Older Heart Failure Patients

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