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

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.

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.

Eligibility Criteria:
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