Exercise Therapy to Reduce Heart Failure Symptoms; Sorting Mechanisms of Benefit (EXT-HF)

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.

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: 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. 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.

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.

Aerobic Exercise Intervention - 12 weeks of a minimum of 3 days a week for 60 minutes of aerobic exercise

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- 12 weeks of a minimum of 3 days a week for 60 minutes of Inspiratory Muscle Training Exercise

Assessment of proteolytic genes (Forkhead box O3 [Foxo3] and Ubiquitin) through assessment real-time -polymerase chain reaction of skeletal muscle biopsy measured in relative expression.

Gene Expression anabolic genes Peroxisome proliferator-activated receptor gamma coactivator 1-alpha and Insulin-like growth factor 1

Gene Expression anabolic genes Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 ) and Insulin-like growth factor 1 (IGF-1) through assessment real-time -polymerase chain reaction of skeletal muscle biopsy measured in relative expression.

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