Mechanisms Of Atrial Fibrillation Research Articles

Elevation of circulating FGF23 in chronic kidney disease promotes atrial fibrosis through the AKT pathway

Abstract Background The relationship between chronic kidney disease (CKD) and atrial fibrillation (AF) remains unclear. Elevated level of fibroblast growth factor 23 (FGF23) is highly associated with increased cardiovascular disease and mortality in patients suffering from CKD. In recent years, studies have shown that FGF23 promotes cardiac hypertrophy through FGFR4, suggesting that FGF23 may be an important bridge between the heart and kidney. Purpose In this study, we sought to use a well-established rat model of CKD to further characterize the effects of CKD on AF and to identify potential drivers of CKD-induced AF. Methods 14 SD rats were randomly selected to undergo 5/6 nephrectomy and fed for 15 weeks to establish a CKD model, while the SHAM group (8 rats) underwent the same surgery without removing kidney tissue. Body weight, blood pressure, renal function, cardiac ultrasound, epicardial electrocardiography, and pathological indices were monitored in both groups. Gene sequencing was performed on the left atria to search for differentially expressed genes. Rat atrial fibroblasts were selected for further mechanism exploration. We chose TGF-β to stimulate fibroblasts to mimic the process of fibrosis in vivo, and then administered FGFR inhibitors to explore the downstream molecular mechanisms. Results Systolic blood pressure and creatinine were elevated in the CKD group. Compared with the SHAM group, the incidence of AF was significantly higher, left atrial diameter was significantly larger, and epicardial electrical markers showed that left atrial electrical conduction velocity was significantly slower and conduction heterogeneity was significantly increased in the CKD group. Pathologic staining of the left atrium showed significant fibrosis in the CKD group. Consistent with previous findings, FGF23 was significantly elevated in CKD rats. Transcriptomic sequencing revealed that FGFR4 expression was significantly upregulated in the left atrium of CKD rats, The results in rat atrial fibroblasts showed that blocking FGFR4 expression inhibited TGF-β-induced fibrosis and was mediated by the AKT pathway. Conclusions The mechanism of CKD-induced AF is that CKD promotes both structural and electrical remodeling of the atria. Further investigation of its possible downstream molecules revealed that elevated FGF23 in the CKD circulation promotes the development of atrial fibrosis by binding to FGFR4 through the AKT pathway.

Temporal relationship between high-intensity training sessions and episodes of atrial fibrillation among previously inactive patients with paroxysmal or persistent AF

Abstract Background Exercise is considered beneficial for managing comorbidities in atrial fibrillation (AF) patients in the long term, and emerging evidence also indicate that high-intensity interval training (HIIT) may reduce AF burden and symptoms. However, more data on the impact of individual training sessions on recurrence of AF is needed to understand mechanisms and tailor exercise recommendations. Purpose To assess the temporal relationship between training sessions and recurrent AF episodes among previously inactive patients with paroxysmal or persistent AF being introduced to HIIT. Methods The Norwegian Exercise in Atrial Fibrillation Trial is a multi centre randomized controlled trial including inactive patients with paroxysmal or persistent AF, who are randomly assigned to either a structured exercise intervention or control for 12 months. We analysed AF episodes and training data from the initial weeks with introduction to structured exercise in the intervention group (8 supervised sessions of HIIT at 85-95% of maximal heart rate). AF episodes lasting ≥30 seconds were registered using implantable cardiac monitors (ICM). Training sessions were registered using sports watches and manual logs. We report event rates and rate ratios for recurrent AF episodes during HIIT compared to episodes occurring outside HIIT. Due to non-normal data distribution statistical comparisons were performed using the Wilcoxon sign-ranked test. Results 81 patients (24 female, 57 male), mean age of 64.2 years (range 35-78), were included. 57 patients had paroxysmal and 24 had persistent AF. The combined duration of monitoring was 5272 days (median 53, range 30 – 163). The participants performed a total of 418 hours of HIIT (median 5.3 hours, range 0.67 – 6.58) during 615 training sessions (median 8, range 1 – 8). In total 4528 AF episodes (median 4, range 0 – 1693) were registered, of which 18 occurred during HIIT. The mean AF rate per 24 hours was 0.69 outside HIIT, 1.20 during HIIT, 0.92 for the periods 1 – 3 hours and 4-6 hours after HIIT (Figure 1). The rate ratio for AF during HIIT compared to outside HIIT was 1.73 (p=0.002). In the 52 participants with at least one episode of AF during follow-up, the rate ratio for AF during HIIT compared to outside HIIT was 10.4 (bootstrapped 95% CI 0.2 to 30.3). Conclusion Among previously inactive patients with paroxysmal or persistent AF, the rate of recurrent AF episodes was significantly higher during high-intensity exercise than outside exercise. Given the few AF episodes, this mechanism of trigging AF by high-intensity exercise needs further investigation.Mean AF per 24 hours

Ibrutinib Promotes Atrial Fibrillation by Disrupting A-Kinase Anchoring Protein 1-Mediated Mitochondrial Quality Surveillance in Cardiomyocytes.

Background: Ibrutinib, a potent Bruton's tyrosine kinase inhibitor with marked efficacy against hematological malignancies, is associated with the heightened risk of atrial fibrillation (AF). Although ibrutinib-induced AF is linked to enhanced oxidative stress, the underlying mechanisms remain unclear. Objective: This research aimed to explore the molecular mechanism and regulatory target in ibrutinib-induced AF. Methods: We performed invivo electrophysiology studies using ibrutinib-treated mice, and then employed proteomic and single-cell transcriptomic analyses to identify the underlying targets and mechanisms. The effects of A-kinase anchoring protein 1 (AKAP1) depletion on mitochondrial quality surveillance (MQS) were evaluated using both invivo and exvivo AKAP1 overexpression models. Results: Atrial AKAP1 expression was significantly reduced in ibrutinib-treated mice, leading to inducible AF, atrial fibrosis, and mitochondrial fragmentation. These pathological changes were effectively mitigated in an overexpression model of ibrutinib-treated mice injected with an adeno-associated virus carrying Akap1. In ibrutinib-treated atrial myocytes, AKAP1 down-regulation promoted dynamin-related protein 1 (DRP1) translocation into mitochondria by facilitating DRP1 dephosphorylation at Ser637, thereby mediating excessive mitochondrial fission. Impaired MQS was also suggested by defective mitochondrial respiration, mitochondrial metabolic reprogramming, and suppressed mitochondrial biogenesis, accompanied by excessive oxidative stress and inflammatory activation. The ibrutinib-mediated MQS disturbance can be markedly improved with the inducible expression of the AKAP1 lentiviral system. Conclusions: Our findings emphasize the key role of AKAP1-mediated MQS disruption in ibrutinib-induced AF, which explains the previously observed reactive oxygen species overproduction. Hence, AKAP1 activation can be employed to prevent and treat ibrutinib-induced AF.

Pathophysiological Mechanisms of Psychosis-Induced Atrial Fibrillation: The Links between Mental Disorder and Arrhythmia.

Atrial fibrillation (AF) is a common phenomenon of sustained arrhythmia leading to heart failure or stroke. Patients with mental disorders (MD), particularly schizophrenia and bipolar disorder, are at a high risk of AF triggered by the dysregulation of the autonomic nervous system, atrial stretch, oxidative stress, inflammation, and electrical or structural remodeling. Moreover, pathophysiological mechanisms underlying MD may also contribute to the genesis of AF. An overactivated hypothalamic-pituitary-adrenal axis, aberrant renin-angiotensin-aldosterone system, abnormal serotonin signaling, disturbed sleep, and genetic/epigenetic factors can adversely alter atrial electrophysiology and structural substrates, leading to the development of AF. In this review, we provide an update of our collective knowledge of the pathophysiological and molecular mechanisms that link MD and AF. Targeting the pathogenic mechanisms of MD-specific AF may facilitate the development of therapeutics that mitigate AF and cardiovascular mortality in this patient population.

Calcium-mediated DAD in membrane potentials and triggered activity in atrial myocytes of ETV1f / fMyHCCre /+ mice.

The E-twenty-six variant 1 (ETV1)-dependent transcriptome plays an important role in atrial electrical and structural remodelling and the occurrence of atrial fibrillation (AF), but the underlying mechanism of ETV1 in AF is unclear. In this study, cardiomyocyte-specific ETV1 knockout (ETV1f/fMyHCCre/+, ETV1-CKO) mice were constructed to observe the susceptibility to AF and the underlying mechanism in AF associated with ETV1-CKO mice. AF susceptibility was examined by intraesophageal burst pacing, induction of AF was increased obviously in ETV1-CKO mice than WT mice. Electrophysiology experiments indicated shortened APD50 and APD90, increased incidence of DADs, decreased density of ICa,L in ETV1-CKO mice. There was no difference in VINACT,1/2 and VACT,1/2, but a significantly longer duration of the recovery time after inactivation in the ETV1-CKO mice. The recording of intracellular Ca2+ showed that there was significantly increased in the frequency of calcium spark, Ca2+ transient amplitude, and proportion of SCaEs in ETV1-CKO mice. Reduction of Cav1.2 rather than NCX1 and SERCA2a, increase RyR2, p-RyR2 and CaMKII was reflected in ETV1-CKO group. This study demonstrates that the increase in calcium spark and SCaEs corresponding to Ca2+ transient amplitude may trigger DAD in membrane potential in ETV1-CKO mice, thereby increasing the risk of AF.

Mechanistic Insights From Trials of Atrial Fibrillation Ablation: Charting a Course for the Future.

Success rates for catheter ablation of atrial fibrillation (AF), particularly persistent AF, remain suboptimal. Pulmonary vein isolation has been the cornerstone for catheter ablation of AF for over a decade. While successful for most patients, pulmonary vein isolation alone is still insufficient for a substantial minority. Frustratingly, multiple clinical trials testing a diverse array of additional ablation approaches have led to mixed results, with no current strategy that improves AF outcomes beyond pulmonary vein isolation in all patients. Nevertheless, this large collection of data could be used to extract important insights regarding AF mechanisms and the diversity of the AF syndrome. Mechanistically, the general model for arrhythmogenesis prompts the need for tools to individually assess triggers, drivers, and substrates in individual patients. A key goal is to identify those who will not respond to pulmonary vein isolation, with novel approaches to phenotyping that may include mapping to identify alternative drivers or critical substrates. This, in turn, can allow for the implementation of phenotype-based, targeted approaches that may categorize patients into groups who would or would not be likely to respond to catheter ablation, pharmacological therapy, and risk factor modification programs. One major goal is to predict individuals in whom additional empirical ablation, while feasible, may be futile or lead to atrial scarring or proarrhythmia. This work attempts to integrate key lessons from successful and failed trials of catheter ablation, as well as models of AF, to suggest future paradigms for AF treatment.

Telomerase Reverse Transcriptase Regulates Intracellular Ca2+ Homeostasis and Mitochondrial Function via the p53/PGC-1α Pathway in HL-1 Cells.

Telomere shortening is strongly associated with cardiovascular aging and disease, and patients with shorter telomeres in peripheral blood leukocytes are at higher risk of cardiovascular diseases such as heart failure and atrial fibrillation (AF). Telomerase reverse transcriptase (TERT) maintains telomere length, and overexpression of TERT has been shown to reduce cardiomyocyte apoptosis and myocardial infarct size, and extend the lifespan of aged mice. However, the specific impact of TERT on the electrophysiology of cardiomyocytes remains to be elucidated. The aims of this study were to evaluate the role of TERT in Ca2+ homeostasis and mitochondrial function in atrial myocytes as well as the underlying mechanisms. TERT overexpressed and silenced HL-1 cells were constructed with lentiviruses, and the respective empty lentiviral vectors were used as negative controls. Then the patch clamp technique was used to record the electrophysiological characteristics such as cell action potential duration (APD) and L-type Ca2+ currents (ICa,L), flow cytometry was used to detect intracellular Ca2+ concentration and mitochondrial membrane potential (MMP), and the Seahorse assay was used to measure the oxygen consumption rate (OCR). TERT silencing led to intracellular Ca2+ overload, shortened APD, decreased ICa,L current density, altered Ca2+ gating mechanism, decreased MMP and OCR, and increased reactive oxygen species (ROS), whereas TERT overexpression led to the reverse effects. Additionally, TERT silencing resulted in intracellular Ca2+ overload with decreased expression of the SERCA2a, CaV1.2, and NCX1.1, whereas TERT overexpression had opposing effects. Furthermore, we discovered that TERT could regulate the expression of p53 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The expression of PGC-1α was downregulated by the p53 agonist Tenovin-6 but upregulated by the p53 inhibitor PFTα. The effects of the PGC-1α inhibitor SR-18292 on intracellular Ca2+ and cell electrophysiology were similar to those of silencing TERT, whereas the PGC-1α agonist ZLN005 produced comparable outcomes to TERT overexpression. TERT silencing-induced Ca2+ overload and mitochondrial dysfunction may be one mechanism of age-related AF. Overexpression of TERT reduced the basis for arrhythmia formation such as AF, suggesting a favorable safety profile for TERT therapy. TERT regulated intracellular Ca2+ homeostasis and mitochondrial function through the p53/PGC-1α pathway. In addition, PGC-1α might be a novel target for AF, suggesting that intervention for AF should be not limited to abnormal cation handling.

Left Atrial Volume Index Predicts Atrial Fibrillation Recurrence after Catheter Ablation Only in Obese Patients-Brief Report.

It has been shown that obesity and a higher body mass index (BMI) are associated with a higher recurrence rate of atrial fibrillation (AF) after successful catheter ablation (CA). The same has been proven for the left atrial volume index (LAVI). It has also been shown that there is a correlation between LAVI and BMI. However, whether the LAVI's prognostic impact on AF recurrence is BMI-independent remains unclear. We prospectively included 62 patients with paroxysmal AF who were referred to our institution for CA. All patients underwent radiofrequency CA with standard pulmonary veins isolation. Transthoracic 2-D echocardiography was performed one day after CA to obtain standard measures of cardiac function and morphology. Recurrence was defined as documented AF within 6 months of the follow-up period. Patients were also instructed to visit our outpatient clinic earlier in case of symptoms suggesting AF recurrence. We observed AF recurrence in 27% of patients after 6 months. The mean BMI in our cohort was 29.65 ± 5.08 kg/cm2 and the mean LAVI was 38.04 ± 11.38 mL/m2. We further divided patients into two groups according to BMI. Even though the LAVI was similar in both groups, we found it to be a significant predictor of AF recurrence only in obese patients (BMI ≥ 30) and not in the non-obese group (BMI < 30). There was also no significant difference in AF recurrence between both cohorts. The significance of the LAVI as an AF recurrence predictor in the obesity group was also confirmed in a multivariate model. According to our results, the LAVI tends to be a significant predictor of AF recurrence after successful catheter ablation in obese patients, but not in normal-weight or overweight patients. This would suggest different mechanisms of AF in non-obese patients in comparison to obese patients. Further studies are needed in this regard.

When the Clock Strikes A-fib.

Within the broad spectrum of atrial fibrillation (AF) symptomatology, there is a striking subset of patients with predominant or even solitary nocturnal onset of the arrhythmia. This review covers AF with nocturnal onset, with the aim of defining this distinctive subgroup among patients with AF. A periodicity analysis is provided showing a clear increased onset between 10:00 pm and 7:00 am. Multiple interacting mechanisms are discussed, such as circadian modulation of electrophysiological properties, vagal tone, and sleep disorders, as well as the potential interaction and synergism between these factors, to provide a better understanding of this clinical entity. Lastly, potential therapeutic targets for AF with nocturnal onset are addressed such as upstream therapy for underlying comorbidities, type of drug and timing of drug administration and pulmonary vein isolation, ablation of the ganglionated plexus, and autonomic nervous system modulation. Understanding the underlying AF mechanisms in the individual patient with nocturnal onset will contribute to patient-specific therapy.

Pacemaker-induced atrial fibrillation reconsidered-associations with different pacing sites and prevention approaches.

The incidence of atrial fibrillation (AF) is significantly higher in patients with pacemakers than in the general population, which could be due to patient characteristics and the diagnostic tool of the pacemaker in detecting atrial high-rate episodes and subclinical AF, but also to the pacemaker itself providing AF-promoting conditions. It is well known that high ventricular pacemaker burden increases the likelihood of AF occurrence. However, the sites of atrial and ventricular pacing may also influence the risk for AF. The conventional sites for atrial and ventricular pacing are in the right atrial appendage and in the right ventricular apex. However, growing evidence suggests that alternative pacing sites may be superior for the prevention of AF. Bachmann bundle pacing, for example, promotes interatrial excitation conduction, resulting in atrial synchronicity and a shorter total atrial activation time, which may be preventive for the occurrence of AF. Moreover, in recent years, new ventricular pacing sites have come into focus with His bundle and left bundle branch pacing. In addition to the hemodynamic and electrophysiological cardiac benefits, these new options may also offer benefits in the prevention of AF. This review provides an overview of pacing-induced AF mechanisms and the association with different pacing sites, as well as approaches for prevention of pacing-induced AF, highlighting different sites and modes of atrial pacing and the newer sites of ventricular pacing.

Effects of different types of fibrotic remodelling in areas of low voltage on atrial fibrillation dynamics: an in-silico study

Abstract Background Personalized computational models include the effects of personalised anatomy and atrial fibrillation (AF) remodelling in a framework that can be used to investigate patient-specific AF mechanisms and test treatment response, but modelling fibrosis remains an unresolved matter. The interpretation of regions exhibiting low voltage in electroanatomic mapping data at different pacing rates also remain unclear. However, these occurrences are correlated with fibrotic remodelling. We aimed to use patient-specific simulations to investigate the effects of fibrosis type on AF properties by modelling conduction velocity slowing, changes in ionic channels, and replacement fibrosis, incorporated in regions of low voltage identified through omnipolar mapping at different pacing rates. Methods Local activation times (LATs) voltage and geometry data were obtained from patients undergoing ablation for persistent AF. LATs were collected in sinus rhythm with coronary sinus pacing at pacing interval (PIs) of 250ms and 600ms. For a total of 10 cases, personalised anatomical models were constructed for electrophysiology simulations, and analysed using an automated pipeline in python. For conductivity models, areas with peak omnipolar voltage (OV) below 0.5mV were assigned low conduction velocity. To incorporate ionic changes, the ionic properties were altered in fibrotic regions (peak OV &amp;lt; 0.5mV). In the simulations where replacement fibrosis was included through a probabilistic percolation method, percolation was modelled by using random number generator to probabilistically remove elements of low voltage. Pulmonary vein isolation was simulated in each model after 5s of AF, and wavefront propagation patterns were analysed to quantify the number of rotational areas or areas of wavefront break-up in 7 anatomical segments. Results The models with conductivity fibrotic remodelling demonstrated rotational drivers in more than two LA anatomical segments for both CS250ms pacing rate and CS600ms pacing rate across all 10 cases. The anterior wall exhibited the largest degree of rotational activity in 7 out of 10 cases for CS250ms pacing rate and in 9 out of 10 cases for CS600ms pacing rate (Figure A). The combination of percolation and conductivity remodelling also exhibited rotational activity on the anterior wall in 9 out of 10 cases at CS250ms pacing rate, and 7 out of 10 cases for CS600ms pacing rate. For the simulations where replacement fibrosis was included (percolation), both the roof and anterior wall exhibited the largest degree of rotational activity in 5 out of 10 cases at CS250ms pacing rate; while at CS600ms pacing rate, the posterior walled exhibited the majority of rotational activity in 7 cases (Figure B). All fibrosis models containing ionic changes terminated in more than half of the 10 cases for both pacing rates (CS250ms and 600). Conclusion The impact of low voltage on fibrotic remodelling causes complex effects on AF dynamics.

Systematic in-silico evaluation of fibrosis effects on re-entrant wave dynamics in atrial tissue.

Despite the key role of fibrosis in atrial fibrillation (AF), the effects of different spatial distributions and textures of fibrosis on wave propagation mechanisms in AF are not fully understood. To clarify these aspects, we performed a systematic computational study to assess fibrosis effects on the characteristics and stability of re-entrant waves in electrically-remodelled atrial tissues. A stochastic algorithm, which generated fibrotic distributions with controlled overall amount, average size, and orientation of fibrosis elements, was implemented on a monolayer spheric atrial model. 245 simulations were run at changing fibrosis parameters. The emerging propagation patterns were quantified in terms of rate, regularity, and coupling by frequency-domain analysis of correspondent synthetic bipolar electrograms. At the increase of fibrosis amount, the rate of reentrant waves significantly decreased and higher levels of regularity and coupling were observed (p < 0.0001). Higher spatial variability and pattern stochasticity over repetitions was observed for larger amount of fibrosis, especially in the presence of patchy and compact fibrosis. Overall, propagation slowing and organization led to higher stability of re-entrant waves. These results strengthen the evidence that the amount and spatial distribution of fibrosis concur in dictating re-entry dynamics in remodeled tissue and represent key factors in AF maintenance.

Advances in the Study of Thyroid Hormones and Atrial Fibrillation

Atrial fibrillation (AF) is a common cardiac arrhythmia characterized by irregular, rapid and ineffective contractions of the atrial rhythm. The relationship between thyroid hormones and AF has been of interest because past studies have identified that thyroid hormones play an important role in the cardiovascular system and that there is a strong link between abnormal thyroid function and AF. Hyperthyroidism is often accompanied by symptoms of arrhythmia such as increased heart rate and arrhythmia, whereas hypothyroidism patients may exhibit abnormalities such as slowed heart rate and enlarged atria. Thyroid hormones are involved in the onset and development of AF through several pathways. First, thyroid hormone may affect the electrophysiological properties of cardiomyocytes, altering the excitability and repolarization process of atrial cells. Second, thyroid hormones may also affect the structure and function of the atria, leading to atrial enlargement and fibrosis, thereby increasing susceptibility to AF. In addition, thyroid hormones may alter the maintenance and regression of AF by affecting the autonomic regulation of the cardiovascular system. This suggests that thyroid hormones play a key role in the pathophysiologic mechanisms of AF. In recent years, an increasing number of studies have focused on the relationship between thyroid hormones and AF and have attempted to reveal their specific mechanisms of action. Some studies have suggested that modulation of thyroid function may be a new strategy for the treatment of atrial fibrillation. In this article, we present a review of the latest research progress on thyroid hormones and atrial fibrillation.

Artificial-intelligence-based risk prediction and mechanism discovery for atrial fibrillation using heart beat-to-beat intervals

Early diagnosis of atrial fibrillation (AF) is important for preventing stroke and other complications. Predicting AF risk in advance can improve early diagnostic efficiency. Deep learning hasbeen used for disease risk prediction; however, it lacks adherenceto evidence-based medicine standards. Identifying the underlyingmechanisms behind disease risk prediction is important and required. We developed an explainable deep learning model called HBBI-AI to predict AF risk using only heart beat-to-beat intervals (HBBIs) during sinus rhythm. We proposed a possible AF mechanism based on the model's explainability and verified this conjecture using confirmed AF risk factors while also examining new AF risk factors. Finally, we investigated the changes in clinicians' ability to predict AF risk using only HBBIs before and after learning the model's explainability. HBBI-AI consistently performed well across large in-house and external public datasets. HBBIs with large changes or extreme stability were critical predictors for increased AF risk, and the underlying cause was autonomic imbalance. We verified various AF risk factors and discovered that autonomic imbalance was associated with all these factors. Finally, cardiologists effectively understood and learned from these findings to improve their abilities in AF risk prediction. HBBI-AI effectively predicted AF risk using only HBBI information through evaluating autonomic imbalance. Autonomic imbalance may play an important role in many risk factors of AF rather than in a limited number of risk factors. This study was supported in part by the National Key R&D Program and the National Natural Science Foundation of China.

Ion channel dysfunction and fibrosis in atrial fibrillation: Two sides of the same coin.

Atrial fibrillation (AF) is a common heart rhythm disorder that is associated with an increased risk of stroke and heart failure (HF). Initially, an association between AF and ion channel dysfunction was identified, classifying the pathology as a predominantly electrical disease. More recently it has been recognized that fibrosis and structural atrial remodeling play a driving role in the development of this arrhythmia also in these cases. Understanding the role of fibrosis in genetic determined AF could be important to better comprise the pathophysiology of this arrhythmia and to refine its management also in nongenetic forms. In this review we analyze genetic and epigenetic mechanisms responsible for AF and their link with atrial fibrosis, then we will consider analogies with the pathophysiological mechanism in nongenetic AF, and discuss consequent therapeutic options.

Identify novel gene signatures in atrial fibrillation by comprehensive bioinformatics analysis

Background: Atrial fibrillation (AF), one of the most prevalent heart rhythm disorders, may lead to thromboembolism, heart failure, and sudden death. However, the mechanism of AF has not yet been fully explained. Objective: This study aims to identify novel gene signatures and to investigate the potential therapeutic targets of AF with an integrated bioinformatic approach. Methods: The gene expression and methylation datasets of AF were obtained through the Gene Expression Omnibus (GEO) database. Subsequently, a set of differentially expressed genes and differential methylation sites were identified. Gene functional annotation analysis was conducted to explore the potential function of differentially-methylated/expressed genes. Then, we constructed a PPI network and TF–miRNA–mRNA network. Finally, weighted gene co-expression network analysis (WGCNA) was presented to study critical modules of AF. Results: Seven hypomethylated-high expression genes and nine hypermethylated-low expression genes were acquired from AF patients. Functional enrichment results indicated that the differentially-methylated/expressed genes were mainly concentrated in decidualization, maternal placenta development, regulation of nitric-oxide synthase activity, and osteoclast differentiation. Based on the results of the PPI, we defined 4 key genes namely FHL2, STC2, ALPK3, and RAP1GAP2 as the core genes, playing essential roles in the TF-miRNA-mRNA network. In the end, we constructed two co-expression modules that highly correlated with AF-related phenotype. Conclusion: In our study, we found critical genes for AF that might help understand the molecular changes in AF.

Therapeutic advances in atrial fibrillation based on animal models.

Atrial fibrillation (AF) is the most prevalent sustained cardiac arrhythmia among humans, with its incidence increasing significantly with age. Despite the high frequency of AF in clinical practice, its etiology and management remain elusive. To develop effective treatment strategies, it is imperative to comprehend the underlying mechanisms of AF; therefore, the establishment of animal models of AF is vital to explore its pathogenesis. While spontaneous AF is rare in most animal species, several large animal models, particularly those of pigs, dogs, and horses, have proven as invaluable in recent years in advancing our knowledge of AF pathogenesis and developing novel therapeutic options. This review aims to provide a comprehensive discussion of various animal models of AF, with an emphasis on the unique features of each model and its utility in AF research and treatment. The data summarized in this review provide valuable insights into the mechanisms of AF and can be used to evaluate the efficacy and safety of novel therapeutic interventions.

Catheter Ablation of Persistent AF-Where are We Now?

Persistent atrial fibrillation (AF) is a diverse condition that includes various subtypes and underlying causes of arrhythmia. Progress made in catheter ablation technology in recent years has significantly enhanced the durability of ablation. Despite these advances however, the effectiveness of ablation in treating persistent AF is still relatively modest. Studies exploring the mechanisms behind persistent AF have identified substrate-driven focal and re-entrant sources within the atrial body as crucial in sustaining AF among individuals with persistent AF. Furthermore, the widespread adoption of atrial late gadolinium enhancement cardiac magnetic resonance (CMR) imaging and the ongoing refinement of invasive voltage mapping techniques have allowed for detailed assessment of fibrotic remodelling prior to or at the time of procedure. Translation into clinical practice, however, has yielded overall disappointing results. The clinical application of AF mapping in ablation procedures has not shown any substantial advantages beyond the use of pulmonary vein isolation (PVI) alone and adjunct ablation of fibrotic areas has yielded conflicting results in recent randomized trials. The emergence of pulsed field ablation represents a welcome development in the field and several studies have demonstrated an enhanced safety profile and increased procedural efficiency with this non-thermal energy modality. Pulsed field ablation also holds promise for safe and efficient substrate ablation beyond the pulmonary veins, but further trials are needed to assess its impact on longer term success rates. Continued advancements in our comprehension of AF mechanisms, alongside ongoing developments in catheter technology aimed at safe formation of transmural lesions, are essential for achieving better clinical outcomes for patients with persistent AF.

Identification and verification of atrial fibrillation hub genes caused by primary mitral regurgitation.

In the clinic, atrial fibrillation (AF) is a common arrhythmia. Despite constant innovation in treatments for AF, they remain limited by a lack of knowledge of the underlying mechanism responsible for AF. In this study, we examined the molecular mechanisms associated with primary mitral regurgitation (MR) in AF using several bioinformatics techniques. Limma was used to identify differentially expressed genes (DEGs) associated with AF using microarray data from the GSE115574 dataset. WGCNA was used to identify significant module genes. A functional enrichment analysis for overlapping genes between the DEGs and module genes was done and several AF hub genes were identified from a protein-protein interaction (PPI) network. Receiver operating characteristic (ROC) curves were generated to evaluate the validity of the hub genes. We examined 306 DEGs and 147 were upregulated and 159 were downregulated. WGCNA analysis revealed black and ivory modules that contained genes associated with AF. Functional enrichment analysis revealed various biological process terms related to AF. The AUCs for the 8 hub genes screened by the PPI network analysis were > 0.7, indicating satisfactory diagnostic accuracy. The 8 AF-related hub genes included SYT13, VSNL1, GNAO1, RGS4, RALYL, CPLX1, CHGB, and CPLX3. Our findings provide novel insight into the molecular mechanisms of AF and may lead to the development of new treatments.

Integrated epigenomic and network analysis identifies novel DNA methylation signature in atrial fibrillation

Abstract Background CD4+ T cells are associated with atrial fibrillation (AF) pathogenesis but mechanistic insights as well as epigenetic phenomena underlying the onset and progression of AF are not fully understood. Purpose To identify differential methylation signature in circulating CD4+ T lymphocytes isolated from AF patients and HS enrolled in the DIANA clinical trial through epigenome and network medicine approaches. Methods DNA was extracted from CD4+ T lymphocytes obtained from patients diagnosed with AF (n = 10) vs patients with no known arrhythmias (n = 11). DNA was then used for paired-end reduced representation bisulfite sequencing to quantify differentially methylated regions (DMRs). NetworkAnalyst tool was interrogated in order to build a specific protein-protein interaction network and identify hub differentially methylated genes (DMGs) in AF. We considered the centrality degree as main network topological measure and defined hubs those DMGs with a centrality degree &amp;gt; 10. Results The analysis provided 7,846 DMRs (P&amp;lt;0.05), associated with 5,373 annotated genes, among which 7,075 hyper-methylated and 771 hypo-methylated regions were uncovered (Figure 1A). Among the identified DMRs, 3,601 were located within gene promoters of which 3,513 were hypermethylated while 88 hypomethylated. Network analysis including the 50 top hyper- and hypomethylated DMGs, according to the differential methylation values, provided a heart specific subnetwork with 56 nodes and 611 edges and 51 seeds (Figure 1B). Although the DNA methylation trend showed a predominant hypermethylation pattern in CD4+ T cells from AF patients (Figure 1A), network analysis demonstrated that hypomethylation was prevalent in the top 15 hub DMGs. In particular, GSTK1, WWP1, PSMD6, TFRC, CDK5R1, HSPG2, WDFY3, WT1, USP49, ACOT7, LAMB2, ITGB7, SHARPIN, and PLXNB2 emerged as hypomethylated hub DMGs, while AIFM1, PFDN1, LMO3, CDK5RAP2, COL4A1, SEPT8, and CYTH4 resulted hypermethylated hub DMGs. Interestingly, several genes are involved in pathological mechanisms of AF in cardiac tissues such as inflammation, fibrosis and cardiac remodeling. Conclusions Our preliminary data represent the first global methylation analysis in circulating CD4+ T cells in AF. The validation of specific genomic regions and the detection of molecular pathways characterized by aberrant DNA methylation changes may help to clarify pathological mechanisms underlying AF, thus providing an important translational impact for novel diagnostic biomarker discovery and therapeutic target identification.Figure 1