The Aerobic Exercise-induced Epigenetic Adaptations in Cardiomyocytes

Design: The Institutional Review Board of a tertiary care hospital approved the study (IRB No.: 201902170A3). Patients with heart failure (HF) were sequentially enrolled from August 1, 2019 to January 31, 2022. All enrolled participants received guideline directed medical therapy (GDMT) and provided informed consent after understanding the experimental procedures. They were then allocated to undergo additional 30 min of HIIT or regular medical treatment (GDMT) groups using a computer-generated, concealed allocation schedule. The HIIT participants underwent additional 36 sessions of HIIT in the hospital.

Participants: Patients with HF had stable clinical presentations for greater than 4 weeks and received individualized patient education under optimized GDMT by our HF care team. The HF care team provided individualized education related to HF and methods for self-monitoring, optimized guideline-based HF medication, and further laboratory assessments (Lee et al. Int Heart J. 2012;53:364-369). In the primarily included patients, we excluded individuals aged <20 years and >80 years, or with pregnancy, cardiac transplantation within the next 6 months, moderate to severe chronic obstructive pulmonary disease, decompensated HF, non-cardiac disease prohibiting cycling exercise, or absolute contraindications for exercise suggested by the American College of Sports Medicine (Pescatello et al. ACSM's guidelines for exercise testing and prescription. 9th ed. Philadelphia, PA.: Wolters Kluwer/Lippincott Williams & Wilkins; 2014). HF patients with estimated glomerular filtration rate of < 30 mL/min/1.73 m^2 were also excluded because most of them were under hemodialysis and could not have regular exercise training.

Clinical Assessment: We recorded baseline age, sex, body mass index, co-morbidities, incremental cardiopulmonary exercise test (CPET) findings, 2-D echocardiography measurements and bioimpedance analysis for body compositions. 25 mL of blood was sampled for serum b-type natriuretic peptide (BNP) levels in all participants. After completing the above study, the remaining blood sample was centrifuged at 2500 rpm for 5 min at room temperature for serum preparation. Circulating microRNA (miRNA) and metabolites profiles were also analyzed using the sampled serum. Thereafter, we used the prepared serum to harvest the cardiomyocyte and/or cardiac fibroblast to observe their cell activities.

Exercise Training: Among the included patients with HF, those who underwent additional 36 sessions (2-3 sessions weekly) of a supervised bicycle ergometer training as in the previous protocol (Fu et al. Int J Cardiol. 2013;167:41-50) were classified as HIIT participants. They exercised alternatively at 3-min intervals of 80% VO2peak and 3-min intervals of 40% VO2peak for 30-min in each session. The other participants without supervised HIIT were classified as GDMT participants.

Echocardiography: Baseline 2-D echocardiography images of all participants were acquired at end-expiration using a 2-5 MHz tightly curved-array ultrasound transducer to measure the left ventricular end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV ejection fraction (LVEF), LV mass (LVM), LVM index (LVMI), and early diastolic mitral inflow velocity/early diastolic mitral annular velocity (E/e') for all participants (Lang et al. J Am Soc Echocardiogr. 2005;18:1440-1463).