Hypermethylation of ACADVL is involved in high-intensity interval training-associated reduction of cardiac fibrosis in heart failure patients

Abstract

Abstract Background Emerging evidence suggests that DNA methylation can be affected by physical activities and is associated with cardiac fibrosis. The translational research examined the implications of DNA methylation presentations behind high-intensity interval training (HIIT) effects on cardiac fibrosis in patients with heart failure (HF). Methods Twelve HF patients were included and received cardiovascular magnetic resonance imaging with late gadolinium enhancement for cardiac fibrosis severity and cardiopulmonary exercise test for peak oxygen consumption (⩒O2peak). Afterwards, they underwent 36 sessions of HIIT at alternating 80% and 40% of ⩒O2peak for 30 min per session in 3–4 months. Human serum from 11 participants, linking cell biology to clinical presentations, was used to investigate exercise effects on cardiac fibrosis. Primary human cardiac fibroblasts (HCFs) incubated in patient serum for cell behaviors, proteomics (n = 6) and DNA methylation profiling (n = 3) were performed. All measurements were followed after completing HIIT. Results An increase of ⩒O2peak along with decreased b-type natriuretic peptide was observed after HIIT. Significantly decreased left ventricle (LV) myocardium fibrosis by 8–12% at middle and apical myocardial segments, decreased LV volume, and increased LV ejection fraction were identified after HIIT. 49 in 1222 identified proteins were significantly involved in the HIIT-induced altered HCF activities. A significant hypermethylation on acyl-CoA dehydrogenase very long chain (ACADVL) gene was identified. Downstream caspases-mediated actin disassembly and cell death pathway were activated after HIIT. Conclusions HIIT is associated with hypermethylation of ACADVL to impede HCF activities. This exercise-associated epigenetic reprogramming may contribute to reduce cardiac fibrosis and furthermore, promotes cardiorespiratory fitness in HF patients. Trial registration : NCT04038723. Registered 31 July 2019, https://clinicaltrials.gov/ct2/show/NCT04038723.