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Necroptosis is required for atrial fibrillation and involved in aerobic exercise-conferred cardioprotection.

ABSTRACT: Necroptosis, a novel programmed cell death, plays a critical role in the development of fibrosis, yet its role in atrial fibrillation (AF) remains elusive. Mounting evidence demonstrates that aerobic exercise improves AF-related symptoms and quality of life. Therefore, we explored the role of necroptosis in AF pathogenesis and exercise-conferred cardioprotection. A mouse AF model was established either by calcium chloride and acetylcholine (CaCl₂ -Ach) administration for 3 weeks or high-fat diet (HFD) feeding for 12 weeks, whereas swim training was conducted 60 min/day, for 3-week duration. AF susceptibility, heart morphology and function and atrial fibrosis were assessed by electrophysiological examinations, echocardiography and Masson's trichrome staining, respectively. Both CaCl₂ -Ach administration and HFD feeding significantly enhanced AF susceptibility (including frequency and duration of episodes), left atrial enlargement and fibrosis. Moreover, protein levels of necroptotic signaling (receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, mixed lineage kinase domain-like protein and calcium/calmodulin-dependent protein kinase II or their phosphorylated forms) were markedly elevated in the atria of AF mice. However, inhibiting necroptosis with necrostatin-1 partly attenuated CaCl₂ -Ach (or HFD)-induced fibrosis and AF susceptibility, implicating necroptosis as contributing to AF pathogenesis. Finally, we found 3-week swim training inhibited necroptotic signaling, consequently decreasing CaCl₂ -Ach-induced AF susceptibility and atrial structural remodeling. Our findings identify necroptosis as a novel mechanism in AF pathogenesis and highlight that aerobic exercise may confer benefits on AF via inhibiting cardiac necroptosis.

SUBMITTER: Fu Y

PROVIDER: S-EPMC8419184 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Necroptosis is required for atrial fibrillation and involved in aerobic exercise-conferred cardioprotection.

Fu Yuping Y Jiang Tiannan T Sun Hongke H Li Tong T Gao Feng F Fan Boyuan B Li Xiaoli X Qin Xinghua X Zheng Qiangsun Q

Journal of cellular and molecular medicine 20210720 17

Necroptosis, a novel programmed cell death, plays a critical role in the development of fibrosis, yet its role in atrial fibrillation (AF) remains elusive. Mounting evidence demonstrates that aerobic exercise improves AF-related symptoms and quality of life. Therefore, we explored the role of necroptosis in AF pathogenesis and exercise-conferred cardioprotection. A mouse AF model was established either by calcium chloride and acetylcholine (CaCl<sub>2</sub> -Ach) administration for 3 weeks or hi ...[more]

PMID: 34288408

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Project description:BackgroundThe safety and efficacy of aerobic exercise in heart failure (HF) patients with atrial fibrillation (AF) has not been well evaluated.ObjectivesThis study examined whether outcomes with exercise training in HF vary according to AF status.MethodsHF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) randomized 2,331 ambulatory HF patients with ejection fraction ≤35% to exercise training or usual care. We examined clinical characteristics and outcomes (mortality/hospitalization) by baseline AF status (past history of AF or AF on baseline electrocardiogram vs. no AF) using adjusted Cox models and explored an interaction with exercise training. We assessed post-randomization AF events diagnosed via hospitalizations for AF and reports of serious arrhythmia caused by AF.ResultsOf 2,292 patients with baseline rhythm data, 382 (17%) had AF, 1,602 (70%) had sinus rhythm, and 308 (13%) had "other" rhythm. Patients with AF were older and had lower peak Vo2. Over a median follow-up of 2.6 years, AF was associated with a 24% per year higher rate of mortality/hospitalization (hazard ratio [HR]: 1.53; 95% confidence interval [CI]: 1.34 to 1.74; p < 0.001) in unadjusted analysis; this did not remain significant after adjustment (HR: 1.15; 95% CI: 0.98 to 1.35; p = 0.09). There was no significant difference in AF event rates by randomized treatment assignment in the overall population or by baseline AF status (all p > 0.10). There was no interaction between AF and exercise training on measures of functional status or clinical outcomes (all p > 0.10).ConclusionsAF in patients with chronic HF was associated with older age, reduced exercise capacity at baseline, and a higher overall rate of clinical events, but not a differential response to exercise training for clinical outcomes or changes in exercise capacity. (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training [HF-ACTION]; NCT00047437).

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Necroptosis is required for atrial fibrillation and involved in aerobic exercise-conferred cardioprotection.

Publications

Necroptosis is required for atrial fibrillation and involved in aerobic exercise-conferred cardioprotection.

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