Exercise Therapy to Reduce Heart Failure Symptoms; Sorting Mechanisms of Benefit
| Status: | Recruiting |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 50 - Any |
| Updated: | 3/9/2019 |
| Start Date: | May 8, 2017 |
| End Date: | September 30, 2019 |
| Contact: | Daniel E Forman, MD |
| Email: | Daniel.Forman@va.gov |
| Phone: | (412) 360-2917 |
The purpose of this research study is to better understand how skeletal muscle is affected by
heart failure, and to determine how exercise interventions impact skeletal muscle and
functional capacity. While many think of heart failure as a disease that only affects the
heart, doctors now believe that it actually affects the whole body, including skeletal
muscle, such as the muscles of your arms and legs. Therefore, while many people with heart
failure develop weakness and reduced exercise capacity, this may be related more to their
skeletal muscle than their weakened hearts. This study looks directly at how exercise might
change skeletal muscle and possibly improve quality of life in heart failure patients.
As part of the study participants will take part in a cardiopulmonary exercise test, lower
body strength testing, breathing assessment, a muscle biopsy (optional), blood draw, and DXA
scanning (to assess lean body mass). Participants with heart failure will complete 1 of 3
exercise training interventions (aerobic vs. aerobic and strength vs. inspiratory) for 12
weeks and will be assessed pre and post to determine if any differences occur in their
skeletal muscle and functional capacity as part of the exercise intervention.
heart failure, and to determine how exercise interventions impact skeletal muscle and
functional capacity. While many think of heart failure as a disease that only affects the
heart, doctors now believe that it actually affects the whole body, including skeletal
muscle, such as the muscles of your arms and legs. Therefore, while many people with heart
failure develop weakness and reduced exercise capacity, this may be related more to their
skeletal muscle than their weakened hearts. This study looks directly at how exercise might
change skeletal muscle and possibly improve quality of life in heart failure patients.
As part of the study participants will take part in a cardiopulmonary exercise test, lower
body strength testing, breathing assessment, a muscle biopsy (optional), blood draw, and DXA
scanning (to assess lean body mass). Participants with heart failure will complete 1 of 3
exercise training interventions (aerobic vs. aerobic and strength vs. inspiratory) for 12
weeks and will be assessed pre and post to determine if any differences occur in their
skeletal muscle and functional capacity as part of the exercise intervention.
Despite decades of research, heart failure (HF) remains a common disease that continues to
rise in prevalence, particularly among an expanding senior population. 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 also
insidiously detract from 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 associated
with peripheral pathophysiology (particularly skeletal muscle and vascular perfusion
abnormalities) such that symptoms, exercise intolerance, and poor clinical outcomes
correspond to a complex aggregate pathophysiological process. While HF therapeutic guidelines
primarily emphasize steps that improve cardiac parameters, and/or volume status, goals to
modify what some describe as "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) 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 Dual Energy
X-ray Absorptiometry (DXA) scanning, correlated to the reduced strength indices.
This proposal constitutes a logical progression of this pilot analysis, and follows the
analytic path the investigators anticipated 3 years ago. The pilot (cross-sectional) study
enabled us to characterize key skeletal muscle gene expression patterns in association to
disease, exercise capacity, and body composition. The investigators now propose an exercise
intervention trial to compare the effects of 3 regimens (i.e., aerobic vs. aerobic and
strength vs. inspiratory) each with a unique physiological rationale. The investigators will
explore differences in how each modifies clinical attributes (function/symptoms) as well as
peripheral mechanisms of disease that likely underlie these differences, i.e., skeletal
muscle biology (histology, gene expression) and effects of body composition. These insights
will help identify therapeutic strategies that better suppress injurious disease mechanisms
and thereby facilitate improved clinical outcomes and quality of life.
The investigators propose to study 100 total male and female HF patients aged 50 years. At
the outset, a comprehensive battery of function and symptoms will be assessed (aerobic,
strength, and integrated performance indices/questionnaires) as well as pertinent peripheral
components that include skeletal muscle (histology, gene expression); and body composition
(DXA); serum measurements of inflammation, cytokines, and adipokines. Subjects will then be
randomized into one of 3 training regimens. After 12 weeks of thrice weekly 60 minute
sessions, all subjects will be reassessed using the same clinical and mechanistic assessments
to ascertain differences. Confounding effects of body habitus, age, medications, sleep, and
nutrition will also be assessed and controlled for.
Specific Aims:
1. To assess differences in functional outcomes (peak VO2, 1RM) relative to the training
therapy. a. Aerobic vs. Aerobic-Strength regimens will be compared to one another. The
investigators hypothesize that Aerobic-Strength will be superior to Aerobic alone.
2. Inspiratory Training will be compared to Aerobic-Strength. The investigators hypothesize
that Inspiratory Training will match the effects of traditional Aerobic-Strength
training as it imparts similar aerobic and strengthening physiology in orientation to
the diaphragm.
Secondary analyses will include assessments of training differences in respect to broader
functional parameters (aerobic, strength, inspiration), symptoms, and quality of life.
2. To assess gene expression in relation to the different training regimens. The
investigators hypothesize that proteolytic genes (including Foxo and Ubiquitin) will be
over-expressed in relation to diminished function and that genes that counteract skeletal
muscle proteolysis (IGF-1, PGC-1 ) will increase in relation to functional gains.
The investigators hypothesize that exercise modes with direct skeletal muscle stimulus
(strength training) will induce greater changes in gene expression (diminished proteolytic
and increased anabolic genes).
The investigators hypothesize that exercise modes that stimulate central cardiac performance
and vascular relaxation (aerobic and inspiratory training) will induce greater changes in
skeletal muscle perfusion.
Secondary analyses will include assessment of the relative impact of skeletal gene expression
vs. perfusion dynamics on function, symptoms, and quality of life. Consequences of serum
inflammation, cytokines, adipokines, and effects of muscle histology will be factored in
these analyses.
rise in prevalence, particularly among an expanding senior population. 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 also
insidiously detract from 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 associated
with peripheral pathophysiology (particularly skeletal muscle and vascular perfusion
abnormalities) such that symptoms, exercise intolerance, and poor clinical outcomes
correspond to a complex aggregate pathophysiological process. While HF therapeutic guidelines
primarily emphasize steps that improve cardiac parameters, and/or volume status, goals to
modify what some describe as "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) 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 Dual Energy
X-ray Absorptiometry (DXA) scanning, correlated to the reduced strength indices.
This proposal constitutes a logical progression of this pilot analysis, and follows the
analytic path the investigators anticipated 3 years ago. The pilot (cross-sectional) study
enabled us to characterize key skeletal muscle gene expression patterns in association to
disease, exercise capacity, and body composition. The investigators now propose an exercise
intervention trial to compare the effects of 3 regimens (i.e., aerobic vs. aerobic and
strength vs. inspiratory) each with a unique physiological rationale. The investigators will
explore differences in how each modifies clinical attributes (function/symptoms) as well as
peripheral mechanisms of disease that likely underlie these differences, i.e., skeletal
muscle biology (histology, gene expression) and effects of body composition. These insights
will help identify therapeutic strategies that better suppress injurious disease mechanisms
and thereby facilitate improved clinical outcomes and quality of life.
The investigators propose to study 100 total male and female HF patients aged 50 years. At
the outset, a comprehensive battery of function and symptoms will be assessed (aerobic,
strength, and integrated performance indices/questionnaires) as well as pertinent peripheral
components that include skeletal muscle (histology, gene expression); and body composition
(DXA); serum measurements of inflammation, cytokines, and adipokines. Subjects will then be
randomized into one of 3 training regimens. After 12 weeks of thrice weekly 60 minute
sessions, all subjects will be reassessed using the same clinical and mechanistic assessments
to ascertain differences. Confounding effects of body habitus, age, medications, sleep, and
nutrition will also be assessed and controlled for.
Specific Aims:
1. To assess differences in functional outcomes (peak VO2, 1RM) relative to the training
therapy. a. Aerobic vs. Aerobic-Strength regimens will be compared to one another. The
investigators hypothesize that Aerobic-Strength will be superior to Aerobic alone.
2. Inspiratory Training will be compared to Aerobic-Strength. The investigators hypothesize
that Inspiratory Training will match the effects of traditional Aerobic-Strength
training as it imparts similar aerobic and strengthening physiology in orientation to
the diaphragm.
Secondary analyses will include assessments of training differences in respect to broader
functional parameters (aerobic, strength, inspiration), symptoms, and quality of life.
2. To assess gene expression in relation to the different training regimens. The
investigators hypothesize that proteolytic genes (including Foxo and Ubiquitin) will be
over-expressed in relation to diminished function and that genes that counteract skeletal
muscle proteolysis (IGF-1, PGC-1 ) will increase in relation to functional gains.
The investigators hypothesize that exercise modes with direct skeletal muscle stimulus
(strength training) will induce greater changes in gene expression (diminished proteolytic
and increased anabolic genes).
The investigators hypothesize that exercise modes that stimulate central cardiac performance
and vascular relaxation (aerobic and inspiratory training) will induce greater changes in
skeletal muscle perfusion.
Secondary analyses will include assessment of the relative impact of skeletal gene expression
vs. perfusion dynamics on function, symptoms, and quality of life. Consequences of serum
inflammation, cytokines, adipokines, and effects of muscle histology will be factored in
these analyses.
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
We found this trial at
2
sites
Boston, Massachusetts 02130
Phone: 857-203-6478
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Pittsburgh, Pennsylvania 15240
Principal Investigator: Daniel E. Forman, MD
Phone: 412-360-2917
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