The proposed study will examine the effects of aerobic exercise (AEX) on changes in methylation of ASC (apoptosis-associated spec-like protein containing a caspase recruitment domain) and whether these changes influence downstream pro-inflammatory cytokine production in persons with heart failure (HF). HF imposes enormous physical, psychological and economic consequences. Identification of novel therapeutic targets that may attenuate disease progression, reduce symptom severity and enhance quality of life in this population is urgently needed. In HF, inflammation occurs via the inflammasome, a complex of intracellular interaction proteins that trigger maturation of pro-inflammatory cytokines interleukin-1beta (IL-1) and interleukin-18 (IL- 18) to initiate the inflammatory response; this response is amplified through production of tumor necrosis factor alpha (TNFa) and inducible nitric oxide synthase (iNOS). Inflammatory cytokines, such as IL-1 and TNFa, are positively influenced by AEX in HF, while increased inflammatory cytokines, such as IL-1, are associated with poor aerobic capacity in HF. Inflammasome modification has been proposed as a therapeutic target for inflammation in HF. This study proposes that AEX-mediated ASC methylation decreases circulating IL-1, IL- 18, TNFa, and iNOS, and thus represents a non-pharmacological, modifiable molecular pathway as an intervention target for persons with HF. The population for the study will be derived from a parent randomized controlled trial testing an aerobic exercise intervention as compared to usual care in 60 stable New York Heart Association Class II and III participants with HF. Participants will be 40 to 75 years of age, sedentary and able to undergo treadmill testing and able to safely perform a moderate intensity, home-based AEX regimen. This proposed secondary study will compare whether the AEX intervention is associated with a greater increase in measures of ASC methylation at 3 and 6 months compared to usual care. In addition, this study will examine the relationship between ASC methylation, inflammatory cytokines and iNOS at 3 and 6 months. A repeated measures multivariate analysis of variance (ANOVA) will be conducted to determine any significant differences between groups on the major outcome variables. Correlation analyses using Pearson's r correlation coefficient will be used to analyze relationships between variables. This biobehavioral study links molecular and behavioral science by examining epigenetic changes after an aerobic exercise program in persons with HF. This study will yield data that will bridge the gap between the current understanding of the roles of exercise on the immune response and potential underlying mechanisms that will ultimately lead to exercise and other non- pharmacological interventions for persons with HF. Findings will be used to support the development of future studies and possible postdoctoral work on identifying and translating the underlying physiological mechanisms associated with worsening HF and non-pharmacological interventions to attenuate these deleterious changes.

Public Health Relevance

Heart failure is the leading cause of illness and death in the United States and the discovery of new therapeutic targets that can slow its debilitating progression are urgently needed. Long-term changes in cardiac load are characteristic of heart failure and lead to changes in cardiac tissue and function, a strong prognostic indicator of worsening disease severity and poor clinical outcomes. The purpose of this study is to examine the effects of aerobic exercise on changes in ASC methylation and the inflammatory cytokines, interleukin-1, interleukin- 18 and tumor necrosis factor-a.

National Institute of Health (NIH)
National Institute of Nursing Research (NINR)
Predoctoral Individual National Research Service Award (F31)
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National Institute of Nursing Research Initial Review Group (NRRC)
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Banks, David
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Emory University
Schools of Nursing
United States
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Butts, Brittany; Butler, Javed; Dunbar, Sandra B et al. (2018) Effects of Exercise on ASC Methylation and IL-1 Cytokines in Heart Failure. Med Sci Sports Exerc 50:1757-1766
Butts, Brittany; Higgins, Melinda; Dunbar, Sandra et al. (2018) The Third Time's a Charm: Psychometric Testing and Update of the Atlanta Heart Failure Knowledge Test. J Cardiovasc Nurs 33:13-21
Butts, Brittany; Butler, Javed; Dunbar, Sandra B et al. (2017) ASC Methylation and Interleukin-1? Are Associated with Aerobic Capacity in Heart Failure. Med Sci Sports Exerc 49:1072-1078
Butts, Brittany; Gary, Rebecca A; Dunbar, Sandra B et al. (2016) Methylation of Apoptosis-Associated Speck-Like Protein With a Caspase Recruitment Domain and Outcomes in Heart Failure. J Card Fail 22:340-6
Butts, Brittany; Gary, Rebecca A; Dunbar, Sandra B et al. (2015) The Importance of NLRP3 Inflammasome in Heart Failure. J Card Fail 21:586-93