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

Abstract

Background Emerging evidence suggests that DNA methylation can be affected by physical activities and is associated with cardiac fibrosis. This translational research examined the implications of DNA methylation associated with the 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 a cardiopulmonary exercise test for peak oxygen consumption ($$\normalsize \tt V$$ V O2peak). Afterwards, they underwent 36 sessions of HIIT at alternating 80% and 40% of $$\normalsize \tt V$$ V O2peak for 30 min per session in 3–4 months. Human serum from 11 participants, as a means to link cell biology to clinical presentations, was used to investigate the exercise effects on cardiac fibrosis. Primary human cardiac fibroblasts (HCFs) were incubated in patient serum, and analyses of cell behaviour, proteomics (n = 6) and DNA methylation profiling (n = 3) were performed. All measurements were conducted after completing HIIT. Results A significant increase (p = 0.009) in $$\normalsize \tt V$$ V O2peak (pre- vs. post-HIIT = 19.0 ± 1.1 O2 ml/kg/min vs. 21.8 ± 1.1 O2 ml/kg/min) was observed after HIIT. The exercise strategy resulted in a significant decrease in left ventricle (LV) volume by 15% to 40% (p < 0.05) and a significant increase in LV ejection fraction by approximately 30% (p = 0.010). LV myocardial fibrosis significantly decreased from 30.9 ± 1.2% to 27.2 ± 0.8% (p = 0.013) and from 33.4 ± 1.6% to 30.1 ± 1.6% (p = 0.021) in the middle and apical LV myocardium after HIIT, respectively. The mean single-cell migration speed was significantly (p = 0.044) greater for HCFs treated with patient serum before (2.15 ± 0.17 μm/min) than after (1.11 ± 0.12 μm/min) HIIT. Forty-three of 1222 identified proteins were significantly involved in HIIT-induced altered HCF activities. There was significant (p = 0.044) hypermethylation of the acyl-CoA dehydrogenase very long chain (ACADVL) gene with a 4.474-fold increase after HIIT, which could activate downstream caspase-mediated actin disassembly and the cell death pathway. Conclusions Human investigation has shown that HIIT is associated with reduced cardiac fibrosis in HF patients. Hypermethylation of ACADVL after HIIT may contribute to impeding HCF activities. This exercise-associated epigenetic reprogramming may contribute to reduce cardiac fibrosis and promote cardiorespiratory fitness in HF patients. Trial registration: NCT04038723. Registered 31 July 2019, https://clinicaltrials.gov/ct2/show/NCT04038723.

High‐Intensity Interval Training Is Associated With Improved 10‐Year Survival by Mediating Left Ventricular Remodeling in Patients With Heart Failure With Reduced and Mid‐Range Ejection Fraction

“…Our work has shown that HIIT provided a robust stimulus of ≈15% to 21% increase of O 2peak in patients with the 3 different HF phenotypes, which was similar to findings found in several previous studies. 4 , 7 , 8 Aerobic capacity was not followed for patients with HF who underwent GDMT because clinicians did not refer them for secondary CPET examination in the study. However, the decrease of O 2peak in GDMT participants could be expected, because a significant decrease of O 2peak has been reported in patients with HFrEF without HIIT.…”

“…Baseline demographic information and differences in LV geometric changes between the HIIT and GDMT participants with different HF phenotypes were compared using Student t test for continuous variables, and χ 2 test was conducted to assess categorical variables. In addition, clinical information assessed in the study, including cardiorespiratory fitness, LV geometry, and questionnaire for quality of life, were considered as possible confounders according to our serial works 4 , 5 , 6 , 7 , 8 , 15 and other prior publications 16 , 17 for related HF studies.…”

“…The primary outcome measure was the change in O 2peak measured after the HIIT in patients with different HF phenotypes. 8 With a mean SD value of the main criterion of 0.2, statistical power (1‐β) of 80%, and α value of 0.05 in a bilateral hypothesis, we estimated that to obtain a 20% change in O 2peak with HIIT versus GDMT with G*Power software, 18 we needed ≥10 participants in each group.…”

“…High‐intensity interval training (HIIT) is characterized by exercising at ≥80% of one's peak oxygen consumption ( O 2peak ) interspersed with 40% to 50% of O 2peak to allow for recovery. 4 HIIT‐induced alternating aerobic and anaerobic metabolic responses 5 have been shown to increase aerobic capacity, 4 improve red blood cell deformability, 6 decrease cardiac chamber dimensions, 4 , 7 reduce cardiac fibrosis, 8 and increase 8‐month survival 7 in patients with HF. Thus, HIIT has been advocated as a beneficial therapy for patients with HF.…”

Bioactive Compounds and Cardiac Fibrosis: Current Insight and Future Prospect

“…Increased methylation of RASAL1 promoter diminished RASAL1 expression and ultimately led to cardiac fibrosis [62]. Cardiopulmonary exercise in heart failure patients was reported to reduce cardiac fibrosis via hypermethylation of acyl-CoA dehydrogenase very long-chain (ACADVL) gene [63]. Furthermore, studies have shown that the promoter region of the genes encoding matrix metalloproteinases (MMPs), which are enzymes involved in ECM degradation, are targeted by DNA methylation.…”