Exercise Therapy to Reduce Heart Failure Symptoms; Sorting Mechanisms of Benefit

Not Applicable

Completed

Conditions: Heart Failure

Interventions: Behavioral: Combined Aerobic and Strength Exercise Intervention
Behavioral: Inspiratory Muscle Training Exercise Intervention
Behavioral: Aerobic Exercise Intervention

Registration Number: NCT03648762

Lead Sponsor: VA Office of Research and Development

Brief Summary: The purpose of this research study is to better understand how exercise training in older adults (≥65 years) with heart failure (HF) affects skeletal muscle both intrinsically and in respect to its impact on functional capacity. While many conceptualize HF as a pathophysiology that exclusively affects the heart, skeletal muscle atrophy and weakening are also elemental to the disease. While reduced exercise capacity is typically associated with HF, this may be related more to disease effects in skeletal muscle than the heart. This is a clinical study that focuses on exercise training which compares functional endpoints before and after training. Patients are randomized to one of three exercise training interventions (aerobic vs. aerobic and strength vs. inspiratory muscle training) for 12 weeks and are assessed pre- and post-training to determine if any differences occur in their skeletal muscle and functional capacity. Skeletal muscle biopsies before and after the exercise training intervention in order to study changes in skeletal muscle histology and biology.

Functional endpoints in this study include ventilatory gas indices from cardiopulmonary exercise testing, lower body strength testing, grip strength, sit-to-stand, six-minute-walk distance, gait speed, inspiratory muscle strength, and quality of life and physical activity-oriented questionnaires, including the Kansas City Cardiomyopathy Questionnaire, Duke Activity Status Index, and CHAMPS Physical Activity Questionnaire for Older Adults. Body composition is measured with Dual Energy X-ray (DXA) scanning. Skeletal muscle biopsies are completed in the vastus lateralis of the non-dominant leg to assess histology and biologic endpoints.

Detailed Description: Despite decades of research, HF remains a common disease that continues to rise in prevalence, particularly among the expanding population of older adults. By virtue of age, older adults are prone to higher incidence of HF and worse clinical consequences. Exercise intolerance and dyspnea are common symptoms that portend poor prognosis, and which erode functional independence and quality of life. Mortality and morbidity also increase significantly as functional capacity declines.

Growing evidence suggests that pathophysiology of central cardiac dysfunction is linked to skeletal muscle pathophysiology. While HF therapeutic guidelines primarily emphasize steps that improve cardiac parameters, and/or volume status, goals to modify HF skeletal muscle myopathy may constitute a vital complementary treatment target.

Ongoing analyses from our pilot VA Merit investigation provide pertinent insights and substantiation. The investigators demonstrated reduced functional capacity (both aerobic and strength) in 31 HF patients (mean age 66 years) compared to 39 age-matched healthy controls (mean age 67). The investigators also showed increased expression of genes signaling ubiquitin-mediated proteolysis in skeletal muscle in relation to decreasing aerobic and strength performance. Consistently, reduced lean muscle mass, as measured by DXA, correlated to the reduced strength indices.

This proposal constitutes a logical progression of this pilot analysis and follows the analytic path the investigators anticipated. Whereas the initial work characterized key skeletal muscle gene expression patterns in association to disease, exercise capacity, and body composition, this study compares the effects of three exercise training regimens (i.e., aerobic vs. combined aerobic and strength vs. inspiratory muscle training \[IMT\]) each with a unique physiological rationale. The investigators will explore differences in how each training regimen modifies clinical attributes (function/symptoms) as well as skeletal muscle biology that likely underlie these differences. These insights will help identify therapeutic strategies that better suppress injurious disease mechanisms and thereby facilitate improved clinical outcomes and quality of life.

Specific Aims:

a. To assess differences in functional outcomes (peak oxygen utilization \[VO2\]) and one-repetition max \[1RM\]) relative to different training regimens: a. Aerobic vs. Aerobic-Strength vs. inspiratory Muscle Training (IMT).

i. Analyses will include assessments of training differences in respect to broader functional parameters (aerobic, strength, inspiration), symptoms, and quality of life.

b. To assess gene expression in relation to the different training regimens.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 65

Inclusion Criteria

Diagnosis of Heart failure
Echo in two years
NYHA class II or III
Optimal therapy according to AHA/ACC and HFSA HF guidelines; unless documented by a provider for variation.

Exclusion Criteria

Major cardiovascular event or procedure within the prior 6 weeks.
Dementia
Severe COPD (FEV1<50%),
End-stage malignancy
Severe valvular heart disease that would make exercise un safe
Orthopedic limitation preventing exercise
Any bleeding disorder that would contraindicate safe exercise
Women who are pregnant, breastfeeding, or likely to become pregnant within the next 6 months
Psychiatric hospitalization within the last 3 months
ICD device with heart rate limits that prohibit exercise assessments or exercise training.
- Referring physicians will be provided with an opportunity to reprogram devices so that patients can participate.
Chronic use of oral corticosteroids or medications that affect muscle function.
- Notably, patients using statins will be eligible, and this will be factored into the randomization and analysis.
Chronic ETOH or drug dependency shown within the last year

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Combined Aerobic and Strength Exercise Intervention	Combined Aerobic and Strength Exercise Intervention	12 weeks of a minimum of 3 days a week for 60 minutes of Combined Aerobic and Strength Exercise
Inspiratory Muscle Training Exercise Intervention	Inspiratory Muscle Training Exercise Intervention	12 weeks of a minimum of 3 days a week for 60 minutes of Inspiratory Muscle Training Exercise
Aerobic Exercise Intervention	Aerobic Exercise Intervention	12 weeks of a minimum of 3 days a week for 60 minutes of aerobic exercise

Primary Outcome Measures

Name	Time	Method
One Repetition Maximum- Leg Press	baseline and through study completion an average of 14 weeks	Leg press will be performed on the Keiser Leg press and measured in kilograms (kg)
Oxygen Uptake (VO2) Peak	baseline and through study completion an average of 14 weeks	a cardiopulmonary exercise test will be performed to determined peak VO2 in ML/KG/Min

Secondary Outcome Measures

Name	Time	Method
Skeletal Muscle Gene Expression	baseline and through study completion an average of 14 weeks	Skeletal muscle gene expression will be measured in RNA isolated from skeletal muscle biopsy samples via Illumina platform. The measure "Number" indicates the number of differentially expressed genes, and units are fold change over baseline. To investigate how the lifestyle interventions impacted gene expression at the mRNA level in skeletal muscles of our research participants we performed high-throughput RNA-Sequencing (Illumina HiSeq paired-end 150 base pairs). Differential gene expression analysis was performed on the RNA-seq. data using DeSEQ2 to determine differentially expressed genes (DEGs) between groups. All DEG analyses were performed using the Wald test (p \< 0.05) corrected for multiple comparisons using the Benjamini and Hochberg method.
Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults - Duration Component	baseline and through study completion an average of 12 weeks	Participants completed the Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults as part of the Quality of Life and Daily Function study outcome. The CHAMPS questionnaire assesses duration and frequency of self-reported weekly physical activities of varying intensities in older adults. One component of the CHAMPS score is the self-reported duration in hours per week of all exercise-related activities, and duration in hours per week of moderate-vigorous exercise-related activities. The mean duration of all exercise-related activities and moderate-vigorous activities in hours per week are reported here for participants in each study arm who completed both the baseline and 12 week follow-up assessments. A higher mean indicates that a longer duration of exercise-related activities in hours per week were reported.
Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults - Frequency Component	baseline and through study completion an average of 12 weeks	Participants completed the Community Healthy Activities Model Program for Seniors (CHAMPS) Physical Activity Questionnaire for Older Adults as part of the Quality of Life and Daily Function study outcome. The CHAMPS questionnaire assesses duration and frequency of self-reported weekly physical activities of varying intensities in older adults. One component of the CHAMPS score is the frequency per week (i.e. number or count of events per week) that the participant reported that they engaged in all exercise related activities, and the frequency per week that the participant engaged in moderate-vigorous activities. The mean frequency of activities per week at baseline and follow-up for each study arm are reported here for the participants who completed both a baseline and follow-up assessment. A higher mean indicates a higher number of exercise-related activities were reported per week.
Metabolomics	baseline and through study completion an average of 14 weeks	Nitric Oxide Bioavailability (uM) Metabolomics The scientific direction of our analyses for this measure has shifted over time. The investigators will pursue RNA seq and metabolomics to provide an unbiased path forward on viable targets in the muscle.
Quality of Life and Daily Function Questionnaires	baseline and through study completion an average of 12 weeks	Participants completed the Kansas City Cardiomyopathy questionnaire (KCCQ) and Duke Activity Status (DASI) Index standardized questionnaires. The KCCQ is scored on a scale of 0 to 100 with a higher score representing better health status. DASI is a 12-item questionnaire that is scored on a scale of 0 to 58.2, with a higher score representing a higher functional status.

Trial Locations

Locations (2): VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
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Boston, Massachusetts, United States
VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
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Pittsburgh, Pennsylvania, United States