Older adults exhibit poor recovery and are at high risk for rehospitalization after acute heart failure. Current rehabilitation and clinical management strategies have shown only modest benefits because the mechanisms underlying poor outcomes remain under recognized and therefore unmitigated. The proposed study will address this critical knowledge gap by examining the role of systemic mitochondrial bioenergetic capacity as a fundamental factor underlying poor physical function in hospitalized acute decompensated heart failure, the success of rehabilitation, and the prognosis of patients following hospitalization. This will be accomplished in a highly translational and cost-effective manner as an ancillary study to REHAB-HF (R01AG045551; PI: Kitzman), a multi-center clinical trial funded by the NIA that tests the hypothesis that impaired physical function underlies adverse outcomes in older hospitalized ADHF patients and employs a novel rehabilitation program that targets multiple domains of physical function for 12 weeks beginning during hospitalization. The results of REHAB-HF can impact clinical practice; however, its outcomes do not directly address potential mechanisms of action. Mitochondrial function is likely candidate for mediating physiological decline in REHAB-HF participants, because these organelles are sensitive to a myriad of intrinsic and extrinsic factors related to aging, physical function, heart failure, and hospitalization. Mitochondrial dysfunction across multiple tissues has been implicated in physiological decline associated with heart failure and is thought to be mediated by circulating factors that affect systemic bioenergetic capacity. Therefore, we propose that respirometric profiling of circulating cells can be used to report on systemic bioenergetic decline in heart failure patients and will be associated with physical function and long term outcomes - including rehospitalization rate. We will determine whether the REHAB-HF rehabilitation program increases bioenergetic capacity, compared to control, thereby improving functional outcomes. Bioenergetic profiling of multiple blood cell populations will enable us to identify the specific cell types and bioenergetic parameters, or patterns comprised of multiple variables, that are most closely associated with REHAB-HF outcomes such as physical function and quality of life. We will also determine the ability of blood cells to report on systemic bioenergetic decline y examining relationships with mitochondrial function measured in skeletal muscle. Successful strategies for mitigating poor physical function and improving long-term outcomes rely on the identification of mechanisms that contribute to the vulnerability of patients after discharge. Bioenergetic profiling may enable the identification of patients in need of more intensive management and targeted rehabilitation. The advancement of blood-based bioenergetic profiling will enhance the use of this promising test in future trials, and potentially, in the cliical care of older patients with the wide range of chronic medical conditions associated with physical disability and poor clinical outcomes.

Public Health Relevance

The proposed project will examine the role of mitochondrial bioenergetics in the physical function of older adults hospitalized for acute heart failure, and th long term rehabilitation outcomes of these patients. Understanding the mechanisms that underlie the success of recovery will lead to improved treatment strategies that can be personalized in order to maximize benefits for individual patients. The results of this study can improve the management of older adults hospitalized with acute heart failure and will be generalizable to the broader issues of age-related bioenergetic decline and post-hospitalization syndrome.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Aging Systems and Geriatrics Study Section (ASG)
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Zieman, Susan
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Wake Forest University Health Sciences
Internal Medicine/Medicine
Schools of Medicine
United States
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Tyrrell, Daniel J; Bharadwaj, Manish S; Jorgensen, Matthew J et al. (2016) Blood cell respirometry is associated with skeletal and cardiac muscle bioenergetics: Implications for a minimally invasive biomarker of mitochondrial health. Redox Biol 10:65-77
Molina, Anthony J A; Shirihai, Orian S (2009) Monitoring mitochondrial dynamics with photoactivatable [corrected] green fluorescent protein. Methods Enzymol 457:289-304