No abstract

The exact mechanism of atrial fibrillation (AF) has been not well elucidated. Ferroptosis is an iron-dependent cell death due to excessive accumulation of peroxidized polyunsaturated fatty acids. However, the molecular mechanism underlying AF and ferroptosis has never been reported. Here, we established the rapid pacing model in vivo and vitro to investigate the relationship between AF and ferroptosis. In canine model of rapid atrial pacing, the content of malondialdehyde and total ions in the atrial tissue of the Pacing group was significantly increased and the exosome inhibitor GW4869 reduced ferroptosis, fibrosis, and inflammation and improved histological and electrophysiological remodeling. In rapid pacing h9c2 cells, the expression of antioxidative stress genes associated with ferroptosis presented sequential changes and proteins involved in ferroptosis such as FTH1, SLC7A11, and GPX4 were gradually depleted. Furthermore, pacing cardiac fibroblast-derived exosomes (CF-exos) exacerbated ferroptosis in h9c2 cells and pretreated pacing-CF-exos with GW4869 alleviated injury to h9c2 cells. In mechanism, our results demonstrated that pacing-CF-exos highly expressed miR-23a-3p by informatics analysis and experimental verification. Inhibitor-miR-23a-3p protected h9c2 cells from ferroptosis accompanying with upregulation of SLC7A11. In addition, SLC7A11 was shown to be the target gene of miR-23a-3p. In conclusion, our results suggest that CF-exos-miR-23a-3p may promote ferroptosis. The development of AF in a persistent direction could be prevented by intervening with exosomal miRNAs to reduce oxidative stress injury and ferroptosis.

Atrial fibrillation (AF) is a highly prevalent arrhythmia that causes high morbidity and mortality. However, the underlying mechanism of AF has not been fully elucidated. Recent research has suggested that, during AF, the immune system changes considerably and interacts with the environment and cells involved in the initiation and maintenance of AF. This may provide a new direction for research and therapeutic strategies for AF. In this review, we elaborate the concept of immune remodeling based on available data in AF. Then, we highlight the complex relationships between immune remodeling and atrial electrical, structural and neural remodeling while also pointing out some research gaps in these field. Finally, we discuss several potential immunomodulatory treatments for AF. Although the heterogeneity of existing evidence makes it ambiguous to extrapolate immunomodulatory treatments for AF into the clinical practice, immune remodeling is still an evolving concept in AF pathophysiology and further studies within this field are likely to provide effective therapies for AF.

Background: Clinical studies have shown that exosomes are associated with atrial fibrillation (AF). However, the roles and underlying mechanisms remain unclear. Hence, this study aimed to investigate the function of exosomes in AF development.Methods: Twenty beagles were randomly divided into the sham group (n = 6), the pacing group (n = 7), and the pacing + GW4869 group (n = 7). The pacing and GW4869 groups underwent rapid atrial pacing (450 beats/min) for 7 days. The GW4869 group received intravenous GW4869 injection (an inhibitor of exosome biogenesis/release, 0.3 mg/kg, once a day) during pacing. Electrophysiological measurements, transmission electron microscopy, nanoparticle tracking analysis, western blotting, RT-PCR, Masson's staining, and immunohistochemistry were performed in this study.Results: Rapid atrial pacing increased the release of plasma and atrial exosomes. GW4869 treatment markedly suppressed AF inducibility and reduced the release of exosomes. After 7 days of pacing, the expression of transforming growth factor-β1 (TGF-β1), collagen I/III, and matrix metalloproteinases was enhanced in the atrium, and the levels of microRNA-21-5p (miR-21-5p) were upregulated in both plasma exosomes and the atrium, while the tissue inhibitor of metalloproteinase 3 (TIMP3), a target of miR-21-5p, showed a lower expression in the atrium. The administration of GW4869 abolished these effects.Conclusions: The blockade of exosome release with GW4869 suppressed AF by alleviating atrial fibrosis in a canine model, which was probably related to profibrotic miR-21-5p enriched in exosomes and its downstream TIMP3/TGF-β1 pathway.

ObjectivesTo investigate the characteristics of new-onset atrial fibrillation (AF) and its impact on prognosis in acute pulmonary embolism (aPE).DesignA retrospective cohort studySettingThe study cohort included patients diagnosed with aPE who were admitted to the Renmin Hospital of Wuhan University from January 2017 to January 2019.ParticipantsPatients were ≥18 years of age and hospitalised for aPE.Outcome measuresAF was diagnosed based on an ECG recording or a Holter monitor during hospitalisation. aPE was diagnosed by CT pulmonary angiography. The prescription was determined from the discharge medication list. All-cause mortality was observed after 6-month follow-up. The logistic regression model and Cox proportional hazards model were used to study the risk factor of the new-onset AF and the predictor of all-cause mortality, respectively.ResultsA total of 590 patients with aPE were enrolled, 23 (3.9%) in the new-onset paroxysmal AF group, 31 (5.3%) in the new-onset persistent AF group and 536 (90.8%) in the sinus rhythm (SR) group. The incidence of the new-onset AF was 9.2% (54/590). A significant difference in age, heart rate, cardiac troponin I ultra, amino-terminal pro-brain natriuretic peptide, D-dimer, left atrial diameter, left ventricular ejection fraction, pulmonary infection, venous thromboembolism, congestive heart failure, chronic cor pulmonale and ischaemic heart disease was found among the three groups (p<0.05). Risk factors for the new-onset AF were massive PE, ischaemic heart disease and congestive heart failure. The survival rate of the paroxysmal and persistent AF group was significantly lower than that of the SR group within 6 months (60.9% and 51.6% vs 88.8%, p<0.001). New-onset persistent AF (OR 2.73; 95% CI 1.28 to 5.81; p=0.009) was an independent predictor affecting the 6-month survival in aPE patients.ConclusionsMassive PE, ischaemic heart disease and congestive heart failure are high-risk factors which were related to new-onset AF in aPE. New-onset persistent AF was an independent predictor for 6-month all-cause mortality in PE patients.

Previous studies have indicated that ganglionated plexi (GP) function influences atrial fibrillation (AF) vulnerability, and intermediate-conductance calcium-activated potassium channels (SK4) have a close relationship with cardiomyocyte automaticity and the induction of AF. However, the effects of the SK4 inhibitor on GP function and AF vulnerability are unknown. Eighteen beagles were randomly divided into a control group (n = 6), rapid atrial pacing (RAP) group (n = 6), and triarylmethane-34 (TRAM-34, an SK4 inhibitor) group (n = 6). TRAM-34 (0.3 ml, 15 mmol/L) and saline were locally injected into GPs in the TRAM-34 group dogs and dogs from the other groups, respectively. After that, dogs in the RAP and TRAM-34 groups were subjected to RAP, and the neural activity of anterior right GP (ARGP) and atrial electrophysiology were measured. The levels of inflammatory cytokines and function of macrophages in the ARGP were measured in the three groups. At 10 min after TRAM-34 injection, ARGP activity and atrial electrophysiology did not significantly change. The atrial pacing shortened effective refractory period (ERP) values at all sites and increased the AF vulnerability and ARGP neural activity, while TRAM-34 reversed these changes. The levels of CD68 + cells, induced nitric oxide synthase (iNOS), interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the ARGP tissues were higher in the RAP group and TRAM-34 group than they were in the control group. Furthermore, the levels of the CD68 + cells, iNOS, and inflammatory cytokines in the ARGP tissues were higher in the pacing group than those in the TRAM-34 group. Based on these results, administration of TRAM-34 into the atrial GP can suppress GP activity and AF vulnerability during atrial pacing. The effects of TRAM-34 might be related to macrophage polarization and the inflammatory response of GP.

Background: Methamphetamine (METH)-induced cardiovascular toxicity has been attributed to its destructive effect on mitochondrial function at least to some extent. Previous studies highlighted the benefits of dapagliflozin (DAPA) on the cardiovascular system, but the response of METH-induced cardiomyopathy to DAPA is never addressed before. The present study aimed to investigate the potential ability of DAPA in preventing METH-induced cardiomyopathy.Materials and Methods: C57BL/6 mice were randomly divided into control group (n = 24), METH group (n = 24), and METH + DAPA group (n = 24). The METH-induced cardiomyopathy group received intraperitoneal METH injections at gradually increasing doses thrice weekly for 14 weeks. Mice in the METH + DAPA group were simultaneously treated with DAPA 1 mg/kg/day by intragastric administration. Echocardiography was performed to assess cardiac function. Reactive oxygen species (ROS), JC-1, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were performed to evaluate oxidative stress, mitochondrial damage, and apoptosis, respectively. Mitochondrial and apoptosis-related protein expression was measured by western blotting.Results: Mice exposed to METH exhibited reduced cardiac function (left ventricular ejection fraction [LVEF]: 56.51 ± 6.49 vs. 73.62 ± 1.42, p &lt; 0.01), fibrotic remodeling, and mitochondrial dysfunction, leading to apoptosis (apoptotic cells%: 7.4 ± 1.3 vs. 1.3 ± 0.5, p &lt; 0.01). DAPA significantly reduced mitochondrial dynamics and function, ROS, apoptosis (apoptotic cells%: 2.4 ± 0.8 vs. 7.4 ± 1.3, p &lt; 0.01), cardiac function decline (LVEF: 70.99 ± 4.936 vs. 56.51 ± 6.49, p &lt; 0.01), and fibrotic remodeling. These results indicated that DAPA could be considered as an effective therapeutic agent in the protection against METH-associated cardiomyopathy.Conclusion: DAPA protects against METH-induced cardiomyopathy in mice by decreasing mitochondrial damage and apoptosis.

Atrial fibrillation (AF) poses a serious healthcare burden on society due to its high morbidity and the resulting serious complications such as thrombosis and heart failure. The principle of catheter ablation is to achieve electrical isolation by linear destruction of cardiac tissue, which makes AF a curable disease. Currently, catheter ablation does not have a high long-term success rate. The current academic consensus is that inflammation and fibrosis are central mechanisms in the progression of AF. However, artificially caused inflammatory cell death by catheter ablation may have a significant impact on structural and electrical remodeling, which may affect the long-term prognosis. This review first focused on the inflammatory response induced by apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis and their interaction with arrhythmia. Then, we compared the differences in cell death induced by radiofrequency ablation, cryoballoon ablation and pulsed-field ablation. Finally, we discussed the structural and electrical remodeling caused by inflammation and the association between inflammation and the recurrence of AF after catheter ablation. Collectively, pulsed-field ablation will be a revolutionary innovation with faster, safer, better tissue selectivity and less inflammatory response induced by apoptosis-dominated cell death.