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Effects of Exercise on ASC Methylation and IL-1 Cytokines in Heart Failure.

ABSTRACT: INTRODUCTION/PURPOSE:Inflammation contributes to heart failure (HF) progression and the interleukin (IL)-1 cytokine IL-1? is implicated in this process. The adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is necessary for inflammasome activation of IL-1?. Lower ASC methylation is associated with worse outcomes in HF. The purpose of this study was to examine the effects of exercise on changes in ASC methylation and activation of the IL-1 family cytokine IL-1? in persons with HF. METHODS:Participants (N = 54) were randomized to receive exercise intervention (n = 38) or attention control (n = 16) for 3 months. Percent methylation of the ASC gene, plasma IL-1?, and ASC mRNA and were obtained at baseline, 3 months, and 6 months. RESULTS:ASC methylation was higher in the exercise group as compared to control at 3 months (6.10% ± 0.5% vs 5.80% ± 0.4%; P = 0.04) and 6 months (6.07 ± 0.4 vs 5.82 ± 0.4; P = 0.04). Plasma IL-1? was lower in the exercise group at 3 months (1.43 ± 0.5 pg·mL vs 2.09 ± 1.3 pg·mL; P = 0.02) and 6 months (1.49 ± 0.5 pg·mL vs 2.13 ± 1.4 pg·mL; P = 0.004). ASC mRNA expression was negatively associated with ASC methylation at baseline (r = -0.97, P = 0.001), 3 months (r = -0.90, P = 0.001), and 6 months (r = -0.81, P = 0.001). ASC mRNA was lower than baseline at 3 months (P = 0.004) and 6 months (P = 0.002) among those in the exercise group. ASC methylation was positively associated with 6-min walk test at baseline (r = 0.517, P < 0.001), 3 months (r = 0.464, P = 0.004), and 6 months (r = 497, P = 0.05). CONCLUSIONS:Exercise was related to increased mean percent ASC methylation and decreased IL-1? and ASC mRNA gene expression in HF. Epigenetic regulation of ASC can be a biological mechanism by which exercise can promote better outcomes in HF.

SUBMITTER: Butts B

PROVIDER: S-EPMC6095733 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Effects of Exercise on ASC Methylation and IL-1 Cytokines in Heart Failure.

Butts Brittany B Butler Javed J Dunbar Sandra B SB Corwin Elizabeth E Gary Rebecca A RA

Medicine and science in sports and exercise 20180901 9

<h4>Introduction/purpose</h4>Inflammation contributes to heart failure (HF) progression and the interleukin (IL)-1 cytokine IL-1β is implicated in this process. The adaptor protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is necessary for inflammasome activation of IL-1β. Lower ASC methylation is associated with worse outcomes in HF. The purpose of this study was to examine the effects of exercise on changes in ASC methylation and activation of the IL ...[more]

PMID: 29683921

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Project description:BackgroundExercise training is recommended for chronic heart failure (HF) patients to improve functional status and reduce risk of adverse outcomes. Elevated plasma levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and cardiac troponin T (cTnT) are associated with increased risk of adverse outcomes in this patient population. Whether exercise training leads to improvements in biomarkers and how such improvements relate to clinical outcomes are unclear.Methods and resultsAmino-terminal pro-brain natriuretic peptide, hs-CRP, and cTnT levels were assessed at baseline and 3 months in a cohort of 928 subjects from the HF-ACTION study, a randomized clinical trial of exercise training versus usual care in chronic HF patients with reduced left ventricular ejection fraction (<35%). Linear and logistic regressions were used to assess 3-month biomarker levels as a function of baseline value, treatment assignment (exercise training vs usual care), and volume of exercise. Linear regression and Cox proportional hazard modeling were used to evaluate the relations between changes in biomarker levels and clinical outcomes of interest that included change in peak oxygen consumption (peak VO2), hospitalizations, and mortality. Exercise training was not associated with significant changes in levels of NT-proBNP (P = .10), hs-CRP (P = .80), or detectable cTnT levels (P = .83) at 3 months. Controlling for baseline biomarker levels or volume of exercise did not alter these findings. Decreases in plasma concentrations of NT-proBNP, but not hs-CRP or cTnT, were associated with increases in peak VO2 (P < .001) at 3 months and decreased risk of hospitalizations or mortality (P ≤ .04), even after adjustment for a comprehensive set of known predictors.ConclusionsExercise training did not lead to meaningful changes in biomarkers of myocardial stress, inflammation, or necrosis in patients with chronic HF. Only improvements in NT-proBNP translated to reductions in peak VO2 and reduced risk of clinical events.

Dataset Information

Effects of Exercise on ASC Methylation and IL-1 Cytokines in Heart Failure.

Publications

Effects of Exercise on ASC Methylation and IL-1 Cytokines in Heart Failure.

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