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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 |

REPOSITORIES: biostudies-literature

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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).

Project description:BACKGROUND:Both cortical and cortical-subcortical (cortex-involved) lesions are typically associated with embolic stroke, of which atrial fibrillation (AF) is the common cause. The aim of this study was to find out the associations between cortex-involved stroke, vascular risk factors, and the subtypes (discovery time and duration) of AF. METHODS:This was an imaging study of the China Atrial Fibrillation Screening in Acute Ischemic Stroke Patients (CRIST) trial. Between October 2013 and June 2015, 1511 acute ischemic stroke or transient ischemic attack (TIA) patients within 7 days after stroke onset at 20 Chinese hospitals were enrolled in this prospective, multicenter cohort, cross-sectional study. The final analysis of this sub-study included 243 patients with AF with required magnetic resonance imaging (MRI) sequences. AF was diagnosed by 6-day Holter monitoring and classified by duration of 24 h. Two stroke specialists blinded to the clinical information reviewed MRI (diffusion-weighted MRI). The third stroke specialists, also blinded to the clinical information, assessed the conflicts. Adjusted large artery atherosclerosis as confounding factor, the associations between cortex-involved lesions, vascular risk factors, and the subtype of AF were evaluated by univariate and multivariate regression analyses. RESULTS:Of 243 acute ischemic stroke patients with AF, 190 were known AF and 53 were newly detected AF. There were 28 patients with AF persistent >24 h and 25 persistent ?24 h in newly detected AF. Patients with newly detected AF were likely to have a fewer history of stroke or TIA (16.98% vs. 36.31%, P = 0.008) and lower fasting blood glucose (5.91?±?1.83?mmol/L vs. 6.75?±?3.83?mmol/L, P = 0.030) than patients with known AF. Among these 243 patients, 102 (41.98%) patients were with cortex-involved lesions. Cortex-involved lesions were significantly related to newly detected AF persistent >24 h (odds ratio [OR]: 4.517, 95% confidence interval [CI]: 1.490-13.696, P = 0.008), proteinuria (OR: 3.431, 95% CI: 1.530-7.692, P = 0.021), and glycosylated hemoglobin (OR: 0.632, 95% CI: 0.464-0.861, P = 0.004). CONCLUSIONS:Compared to previously known AF, newly detected AF persistent >24 h was associated with cortex-involved ischemic stroke. CLINICAL TRIAL REGISTRATION:NCT02156765, https://clinicaltrials.gov/ct2/show/record/NCT02156765.

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

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