Genesis Of Atrial Fibrillation Research Articles

Phenotypic characterisation of people at risk of atrial fibrillation: Protocol for the FIND-AF longitudinal cohort study.

The Future Innovations in Novel Detection of Atrial Fibrillation (FIND-AF) longitudinal cohort study is a multi-centre prospective cohort study of patients identified at risk of atrial fibrillation (AF). The aim of the FIND-AF longitudinal cohort study is to provide multi-modal phenotypic characterisation of these patients. 1955 participants identified as at risk of AF by the FIND-AF algorithm from primary care electronic health (EHR) data, aged 30 years and above and eligible for oral anticoagulation, will be be recruited between October 2023 and November 2024 to receive home-based intermittent ECG monitoring. About 500 participants without diagnosed AF will then undergo cross-sectional phenotypic characterisation including physical examination, symptoms assessment, serum blood biomarkers and echocardiography, and non-stress cardiac magnetic resonance imaging. Longitudinal information about cardio-renal-metabolic-pulmonary outcomes will be ascertained from linkages to EHR data. The study is funded by the British Heart Foundation (CC/22/250026). The study has ethical approval (North West - Greater Manchester South Research Ethics Committee reference 23/NW/0180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the Funder's open access policy. The FIND-AF multi-centre prospective longitudinal cohort study aims to (i) provide evidence for the impact of comorbidities on AF genesis (ii) uncover actionable targets to prevent AF, and (iii) act as a platform for cohort randomised clinical trials that investigate enhanced detection and prevention of 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.

Abstract Mo065: An Anti-arrhythmic Action and Novel Molecular Mechanisms of Alda-1 in Holiday Heart Syndrome

Introduction: Holiday Heart Syndrome (HHS) is caused by excessive binge alcohol intake. Atrial fibrillation (AF) is the most common arrhythmia in HHS patients. With a worldwide rising trend in heavy alcohol consumption despite significant prevention efforts, effective drugs against alcohol-evoked AF are in urgent need. Methods: We assessed the effect of Alda-1, a cardiac protective agent, on mitigating binge alcohol-evoked AF and alcohol-activated stress kinase JNK2 in 50mM alcohol-exposed (24hr) H9c2 differentiated myocytes and in a well-characterized HHS mouse model (2g/kg ethanol i.p., 4 injections, every other day). Alda-1’s effect on alcohol-evoked RyR2 channel-mediated Ca 2+ waves/sparks & tachycardia/fibrillation (AT/AF) incidence were measured in intact mouse atria. RyR2 channel open probability was assessed in human RyR2 single-channel recordings. Results: We found that Alda-1 significantly reduced atrial arrhythmia inducibility in HHS mouse atria, as evidenced by a decreased incidence of alcohol-evoked AT/AF (0 vs. 0.21 incidences/pacing attempts/animal; n=6, 8). Alda-1 is an agonist of aldehyde dehydrogenase 2 (ALDH2; a key enzyme in alcohol detoxification), which inhibits cellular apoptosis. We found that ALDH2 was increased by 42%±6 in HHS mice compared to controls, and which remained elevated upon Alda-1 treatment (n=6,7,7; p<0.05). HHS hearts showed unchanged apoptotic signaling pathways, suggesting alternative mechanisms in AF genesis. Our lab recently revealed a critical role of activated cardiac stress kinase JNK2 in AF risk. Intriguingly, Alda-1 suppressed alcohol-activated JNK2 by 70%±13 (immunoprecipitated JNK2-specific activity; n=9,9, p<0.001) (but not JNK1, the other cardiac JNK isoform) in cells, while JNK2 inhibition alleviated alcohol-evoked RyR2 channel dysfunction in human RyR2 channels as well as Ca 2+ -triggered atrial arrhythmic activities and AT/AF (0 out of 8; p<0.05) in intact mouse hearts. Conclusion: Alda-1 effectively mitigates binge alcohol-evoked atrial arrhythmogenesis by suppressing JNK2 activity independently of an ALDH2-mediated anti-apoptosis effect. Our findings highlight the potential of Alda-1 as a therapeutic agent for the increasing incidence of alcohol-evoked AF.

Chronic Partial Sleep Deprivation Increased the Incidence of Atrial Fibrillation by Promoting Pulmonary Vein and Atrial Arrhythmogenesis in a Rodent Model.

Sleep deprivation (SD) is a recognized risk factor for atrial fibrillation (AF), yet the precise molecular and electrophysiological mechanisms behind SD-induced AF are unclear. This study explores the electrical and structural changes that contribute to AF in chronic partial SD. We induced chronic partial SD in Wistar rats using a modified multiple-platform method. Echocardiography demonstrated impaired systolic and diastolic function in the left ventricle (LV) of the SD rats. The SD rats exhibited an elevated heart rate and a higher low-frequency to high-frequency ratio in a heart-rate variability analysis. Rapid transesophageal atrial pacing led to a higher incidence of AF and longer mean AF durations in the SD rats. Conventional microelectrode recordings showed accelerated pulmonary vein (PV) spontaneous activity in SD rats, along with a heightened occurrence of delayed after-depolarizations in the PV and left atrium (LA) induced by tachypacing and isoproterenol. A Western blot analysis showed reduced expression of G protein-coupled receptor kinase 2 (GRK2) in the LA of the SD rats. Chronic partial SD impairs LV function, promotes AF genesis, and increases PV and LA arrhythmogenesis, potentially attributed to sympathetic overactivity and reduced GRK2 expression. Targeting GRK2 signaling may offer promising therapeutic avenues for managing chronic partial SD-induced AF. Future investigations are mandatory to investigate the dose-response relationship between SD and AF genesis.

Ablation of Paroxysmal Atrial Fibrillation: between Present and Future.

Pulmonary vein isolation (PVI) is the established cornerstone for atrial fibrillation (AF) ablation, indeed current guidelines recognize PVI as the gold standard for first-time AF ablation, regardless of if it is paroxysmal or persistent. Since 1998 when Haïssaguerre pioneered AF ablation demonstrating a burden reduction after segmental pulmonary vein (PV) ablation, our approach to PVI was superior in terms of methodology and technology. This review aims to describe how paroxysmal atrial fibrillation ablation has evolved over the last twenty years. We will focus on available techniques, a mechanistic understanding of paroxysmal AF genesis and the possibility of a tailored approach for the treatment of AF, before concluding with a future perspective.

Interactions between calcium-induced arrhythmia triggers and the electrophysiological-anatomical substrate underlying the induction of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is sustained by spontaneous focal excitations and re-entry. Spontaneous electrical firing in the pulmonary vein (PV) sleeves is implicated in AF generation. The aim of this simulation study was to identify the mechanisms determining the localisation of AF triggers in the PVs and their contribution to the genesis of AF. A novel biophysical model of the canine atria was used that integrates stochastic, spontaneous subcellular Ca2+ release events (SCRE) with regional electrophysiological heterogeneity in ionic properties and a detailed three-dimensional model of atrial anatomy, microarchitecture and patchy fibrosis. Simulations highlighted the importance of the smaller inward rectifier potassium current (IK1 ) in PV cells compared to the surrounding atria, which enabled SCRE more readily to result in delayed-afterdepolarisations that induced triggered activity. There was a leftward shift in the dependence of the probability of triggered activity on sarcoplasmic reticulum Ca2+ load. This feature was accentuated in 3D tissue compared to single cells (Δ half-maximal [Ca2+ ]SR =58μM vs. 22μM). In 3D atria incorporating electrical heterogeneity, excitations preferentially emerged from the PV region. These triggered focal excitations resulted in transient re-entry in the left atrium. Addition of fibrotic patches promoted localised emergence of focal excitations and wavebreaks that had a more substantial impact on generating AF-like patterns than the PVs. Thus, a reduced IK1 , less negative resting membrane potential, and fibrosis-induced changes of the electrotonic load all contribute to the emergence of complex excitation patterns from spontaneous focal triggers. KEY POINTS: Focal excitations in the atria are most commonly associated with the pulmonary veins, but the mechanisms for this localisation are yet to be elucidated. We applied a multi-scale computational modelling approach to elucidate the mechanisms underlying such localisations. Myocytes in the pulmonary vein region of the atria have a less negative resting membrane potential and reduced time-independent potassium current; we demonstrate that both of these factors promote triggered activity in single cells and tissues. The less negative resting membrane potential also contributes to heterogeneous inactivation of the fast sodium current, which can enable re-entrant-like excitation patterns to emerge without traditional conduction block.

Inhibition of EPAC1 signaling pathway alters atrial electrophysiology and prevents atrial fibrillation.

Introduction: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with increased mortality and morbidity. The Exchange Protein directly Activated by cAMP (EPAC), has been implicated in pro-arrhythmic signaling pathways in the atria, but the underlying mechanisms remain unknown. Methods: In this study, we investigated the involvement of EPAC1 and EPAC2 isoforms in the genesis of AF in wild type (WT) mice and knockout (KO) mice for EPAC1 or EPAC2. We also employed EPAC pharmacological modulators to selectively activate EPAC proteins (8-CPT-AM; 10μM), or inhibit either EPAC1 (AM-001; 20μM) or EPAC2 (ESI-05; 25μM). Transesophageal stimulation was used to characterize the induction of AF in vivo in mice. Optical mapping experiments were performed on isolated mouse atria and cellular electrophysiology was examined by whole-cell patch-clamp technique. Results: In wild type mice, we found 8-CPT-AM slightly increased AF susceptibility and that this was blocked by the EPAC1 inhibitor AM-001 but not the EPAC2 inhibitor ESI-05. Consistent with this, in EPAC1 KO mice, occurrence of AF was observed in 3/12 (vs. 4/10 WT littermates) and 4/10 in EPAC2 KO (vs. 5/10 WT littermates). In wild type animals, optical mapping experiments revealed that 8-CPT-AM perfusion increased action potential duration even in the presence of AM-001 or ESI-05. Interestingly, 8-CPT-AM perfusion decreased conduction velocity, an effect blunted by AM-001 but not ESI-05. Patch-clamp experiments demonstrated action potential prolongation after 8-CPT-AM perfusion in both wild type and EPAC1 KO mice and this effect was partially prevented by AM-001 in WT. Conclusion: Together, these results indicate that EPAC1 and EPAC2 signaling pathways differentially alter atrial electrophysiology but only the EPAC1 isoform is involved in the genesis of AF. Selective blockade of EPAC1 with AM-001 prevents AF in mice.

Regional Differences in Ca2+ Signaling and Transverse-Tubules across Left Atrium from Adult Sheep.

Cardiac excitation-contraction coupling can be different between regions of the heart. Little is known at the atria level, specifically in different regions of the left atrium. This is important given the role of cardiac myocytes from the pulmonary vein sleeves, which are responsible for ectopic activity during atrial fibrillation. In this study, we present a new method to isolate atrial cardiac myocytes from four different regions of the left atrium of a large animal model, sheep, highly relevant to humans. Using collagenase/protease we obtained calcium-tolerant atrial cardiac myocytes from the epicardium, endocardium, free wall and pulmonary vein regions. Calcium transients were slower (time to peak and time to decay) in free wall and pulmonary vein myocytes compared to the epicardium and endocardium. This is associated with lower t-tubule density. Overall, these results suggest regional differences in calcium transient and t-tubule density across left atria, which may play a major role in the genesis of atrial fibrillation.

The Role of Hypomagnesemia in Cardiac Arrhythmias: A Clinical Perspective.

The importance of magnesium (Mg2+), a micronutrient implicated in maintaining and establishing a normal heart rhythm, is still controversial. It is known that magnesium is the cofactor of 600 and the activator of another 200 enzymatic reactions in the human organism. Hypomagnesemia can be linked to many factors, causing disturbances in energy metabolism, ion channel exchanges, action potential alteration and myocardial cell instability, all mostly leading to ventricular arrhythmia. This review article focuses on identifying evidence-based implications of Mg2+ in cardiac arrhythmias. The main identified benefits of magnesemia correction are linked to controlling ventricular response in atrial fibrillation, decreasing the recurrence of ventricular ectopies and stopping episodes of the particular form of ventricular arrhythmia called torsade de pointes. Magnesium has also been described to have beneficial effects on the incidence of polymorphic ventricular tachycardia and supraventricular tachycardia. The implication of hypomagnesemia in the genesis of atrial fibrillation is well established; however, even if magnesium supplementation for rhythm control, cardioversion facility or cardioversion success/recurrence of AF after cardiac surgery and rate control during AF showed some benefit, it remains controversial. Although small randomised clinical trials showed a reduction in mortality when magnesium was administered to patients with acute myocardial infarction, the large randomised clinical trials failed to show any benefit of the administration of intravenous magnesium over placebo.

Usefulness of Triglyceride-glucose index for detecting prevalent atrial fibrillation in a type 2 diabetic population

Objectives Atrial fibrillation (AF) is the most common arrhythmias, which significantly jeopardizes global cardiovascular health through the complicated heart failure and stroke. Published studies have demonstrated the impact of insulin resistance on the genesis of AF. Hence, monitoring insulin resistance may be a possible way to improve the detection of early-stage AF. Accordingly, our work aimed to investigate the association between TyG, a surrogate of insulin resistance, and the prevalent AF, and to evaluate the potential of TyG to refine the detection of prevalent AF in a diabetic population. Methods This cross-sectional study was derived from the National Metabolic Management Center Program and included 3244 diabetic patients between September 2017 and December 2020. TyG was calculated as ln[fasting TG(mg/ dL)×FPG(mg/dL)/2]. AF was diagnosed according to electrocardiography and subjects’ self-reports. Results The prevalence of AF was 6.57%. In the fully adjusted model, each SD elevation of TyG cast a 40.6% additional risk for prevalent AF. In the quartile analysis, the top quartile showed a 2.120 times risk of prevalent AF compared with the bottom quartile. Smooth curve fitting demonstrated that the association was linear in the full range of TyG, and subgroup analysis suggested that the association was robust in several common subpopulations of AF. Furthermore, ROC results displayed an improvement for the detection of prevalent AF when adding TyG into conventional cardiovascular risk factors (0.812vs.0.825, P=0.019), and continuous net reclassification index (0.227, 95% CI: 0.088–0.365, P=0.001) and integrated discrimination index (0.007, 95% CI: 0.001–0.012, P=0.026) also showed the improvement achieved by TyG. Conclusion Our data supported a linear and robust correlation between TyG and the prevalent AF in a diabetic population. Moreover, our results implicated the potential usefulness of TyG to refine the detection of prevalent AF in a diabetic population.

Effect of macrophage migration inhibitory factor on pulmonary vein arrhythmogenesis through late sodium current.

Macrophage migration inhibitory factor (MIF), a pleiotropic inflammatory cytokine, is highly expressed in patients with atrial fibrillation (AF). Inflammation increases the risk of AF and is primarily triggered by pulmonary vein (PV) arrhythmogenesis. This study investigated whether MIF can modulate the electrical activity of the PV and examined the underlying mechanisms of MIF. A conventional microelectrode, a whole-cell patch clamp, western blotting, and immunofluorescent confocal microscopy were used to investigate electrical activity, calcium (Ca2+) regulation, protein expression, ionic currents, and cytosolic reactive oxygen species (ROS) in rabbit PV tissue and isolated single cardiomyocytes with and without MIF incubation (100 ng/mL, treated for 6 h). The MIF (100 ng/mL)-treated PV tissue (n = 8) demonstrated a faster beating rate (1.8 ± 0.2 vs. 2.6 ± 0.1 Hz, P < 0.05), higher incidence of triggered activity (12.5 vs. 100%, P < 0.05), and premature atrial beat (0 vs. 100%, P < 0.05) than the control PV tissue (n = 8). Compared with the control PV cardiomyocytes, MIF-treated single PV cardiomyocytes had larger Ca2+ transients (0.6 ± 0.1 vs. 1.0 ± 0.1, ΔF/F0, P < 0.05), sarcoplasmic reticulum Ca2+ content (0.9 ± 0.20 vs. 1.7 ± 0.3 mM of cytosol, P < 0.05), and cytosolic ROS (146.8 ± 5.3 vs. 163.7 ± 3.8, ΔF/F0, P < 0.05). Moreover, MIF-treated PV cardiomyocytes exhibited larger late sodium currents (INa-Late), L-type Ca2+ currents, and Na+/Ca2+ exchanger currents than the control PV cardiomyocytes. KN93 [a selective calcium/calmodulin-dependent protein kinase II (CaMKII) blocker, 1 μM], ranolazine (an INa-Late inhibitor, 10 μM), and N-(mercaptopropionyl) glycine (ROS inhibitor, 10 mM) reduced the beating rates and the incidence of triggered activity and premature captures in the MIF-treated PV tissue. Macrophage migration inhibitory factor increased PV arrhythmogenesis through Na+ and Ca2+ dysregulation through the ROS activation of CaMKII signalling, which may contribute to the genesis of AF during inflammation. Anti-CaMKII treatment may reverse PV arrhythmogenesis. Our results clearly reveal a key link between MIF and AF and offer a viable therapeutic target for AF treatment.

A New Hope: Sodium-Glucose Cotransporter-2 Inhibition to Prevent Atrial Fibrillation.

Atrial arrhythmias are common in patients with diabetes mellitus (DM), and despite recent advances in pharmaceutical and invasive treatments, atrial fibrillation (AF) and atrial flutter (AFl) are still associated with substantial mortality and morbidity. Clinical trial data imply a protective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on the occurrence of AF and AFl. This review summarizes the state of knowledge regarding DM-mediated mechanisms responsible for AF genesis and recurrence but also discusses the recent data from experimental studies, published trials and metanalyses.

Icariin attenuates excessive alcohol consumption-induced susceptibility to atrial fibrillation through SIRT3 signaling

Excessive alcohol consumption has long been identified as a risk factor for adverse atrial remodeling and atrial fibrillation (AF). Icariin is a principal active component from traditional Chinese medicine Herba Epimedii and has been demonstrated to exert potential antiarrhythmic effect. The present study was designed to evaluate the effect of icariin against alcohol-induced atrial remodeling and disruption of mitochondrial dynamics and furthermore, to elucidate the underlying mechanisms. Excessive alcohol-treated C57BL/6 J mice were infected with serotype 9 adeno-associated virus (AAV9) carrying mouse SIRT3 gene or negative control virus. Meanwhile, icariin (50 mg/kg/d) was administered to the animals in the presence or absence of AAV9 carrying SIRT3 shRNA. We noted that 8 weeks of icariin treatment effectively attenuated alcohol consumption-induced atrial structural and electrical remodeling as evidenced by reduced AF inducibility and reversed atrial electrical conduction pattern as well as atrial enlargement. Furthermore, icariin-treated group exhibited significantly enhanced atrial SIRT3-AMPK signaling, decreased atrial mitoSOX fluorescence and mitochondrial fission markers, elevated mitochondrial fusion markers (MFN1, MFN2) as well as NRF-1-Tfam-mediated mitochondrial biogenesis. Importantly, these beneficial effects were mimicked by SIRT3 overexpression while abolished by SIRT3 knockdown. These data revealed that targeting atrial SIRT3-AMPK signaling and preserving mitochondrial dynamics might serve as the novel therapeutic strategy against alcohol-induced AF genesis. Additionally, icariin ameliorated atrial remodeling and mitochondrial dysfunction by activating SIRT3-AMPK signaling, highlighting the use of icariin as a promising antiarrhythmic agent in this circumstance.

Association of Right Ventricular Afterload With Atrial Fibrillation Risk in Older Adults: The Atherosclerosis Risk in Communities Study

Atrial fibrillation (AF) is widely perceived to originate from the left atrium (LA). Whether increases in right ventricular (RV) afterload in older adults play an etiological role in AF genesis independent of LA and left ventricular (LV) remodeling is unknown. Is higher RV afterload associated with greater AF risk independent of LA and LV remodeling? In this observational prospective study, we included 2,246 community-dwelling older adults (mean age, 75 years) without known cardiovascular disease, with LV ejection fraction > 50%, LA volume index< 34mL/m2, and E/e' ratio< 14 and a measurable functional tricuspid regurgitation jet velocity. From 2D-echocardiograms, we estimated pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR). We ascertained incident AF (through 2018) from hospital discharge codes and death certificates. We estimated hazard ratios (HR) by Cox regression. During follow-up (median, 6.3 years; interquartile interval, 5.5-6.9 years), 215 participants developed AF. AF risk was significantly higher in the third (vs first) tertile of PASP (HR, 1.65; 95%CI, 1.08-2.54) and PVR (HR, 1.38; 95%CI, 1.00-2.08) independent of LA and LV structure and function, heart rate, BMI, prevalent sleep apnea, systemic BP, antihypertensive medications, and lung, kidney, and thyroid function. These associations persisted after further exclusion of participants with tricuspid regurgitation jet velocity > 2.8m/s and lateral and septal mitral annular velocity above age- and sex-specific reference limits. In older adults, higher RV afterload is associated with greater AF risk independent of LA and LV remodeling. Future research should focus on confirming this novel association and elucidate underlying mechanisms.

Atrial Fibrillation in a Patient with Interatrial Block after Successful Atrial Flutter Ablation: May Interatrial Block Be a Link for a Continuum of Atrial Arrhythmias?

Background: Electrocardiographic interatrial block (IAB) typically exists when a conduction delay over the Bachmann’s bundle is present. By analogy to other types of block, there is a continuum of IAB severity; partial IAB is defined as a P-wave duration 120 ms and advanced interatrial block (aIAB) is defined as a P-wave duration 120 ms in conjunction with biphasic P-wave morphology in inferior leads II, III, and aVF. Moreover, IAB seems to be a key factor in the genesis of atrial fibrillation (AF). On the contrary, it is not clear if the presence of advanced IAB may be associated with an occurrence of AF after cavotricuspid atrial flutter ablation in patients without previous episodes of atrial fibrillation. So, may be useful to evaluate on surface electrocardiogram the P-wave morphology and duration in sinus rhythm after the ablation procedure just to identify patients at high risk for atrial fibrillation development. Advanced IAB is frequently associated with atrial tachyarrhythmias, and it was found to predict AF and may be helpful for clinical decisions. Case presentation: In this case involving a man who underwent a typical atrial flutter ablation, we documented that aIAB during the post-ablation period which seems to induce atial fibrillation episodes. To our knowledge, it is unusual to detect an aIAB after cavotricuspid atrial flutter ablation and subsequently associate it with a new onset of AF. Conclusions: Our observation supports a possible aIAB induction of AF after cavotricuspid atrial flutter ablation and potentially may representing a link in the continuum of atrial arrhythmias. P-wave morphology and duration should be better evaluated soon after AFlu ablation to better stratify patients who are at high risk for atrial fibrillation development and eventually prolonged anti-coagulation therapy.

Bacteroides fragilis prevents aging-related atrial fibrillation in rats via regulatory T cells-mediated regulation of inflammation

BackgroundAging plays a critical role in the genesis of atrial fibrillation (AF) and also changes the gut microbes. Whether the aging-associated gut dysbiosis contributes to the development of aging-related AF and whether the gut microbes can be a target to prevent aging-related AF remains unknown. Methods and results16S rRNA gene sequencing was performed to reveal the changes of gut microbes in elderly patients with AF, and the result showed that the intestinal abundance of B. fragilis was significantly decreased in elderly patients with AF. Subsequently, we examined the impact of B. fragilis supplementation on AF promotion, atrial structural remodeling and inflammation response in D-galactose induced aging rats. We found that oral administration of B. fragilis prevented AF inducibility and duration, which was associated with attenuation of atrial senescence, apoptosis and fibrosis. Furthermore, B. fragilis significantly diminished the systemic and atrial inflammation, which is accompanied by an increase in the number of Treg cells in the spleen and blood. More importantly, we found that the circulation level of polysaccharide A (PSA), the metabolite synthesized by B. fragilis, was reduced in elderly patients with AF and could predict the occurrence of AF, and B. fragilis increased the circulation concentration of PSA in D-galactose induced aging rats. ConclusionsThe abundance of B. fragilis was lower in elderly patients with AF. Oral administration of B. fragilis significantly attenuated inflammatory response by increasing Treg cells, thereby preventing atrial structural remodeling and inhibiting AF promotion in D-galactose induced aging rats. This study provides experimental evidence for the effectiveness of targeting gut microbes in the prevention of aging-related AF.

The bidirectional relationship of thyroid disease and atrial fibrillation: Established knowledge and future considerations.

Atrial fibrillation (AF) tends to occur frequently in patients with thyroid disease, primarily hyperthyroidism. In hyperthyroidism, increased levels of thyroid hormones, via intra- and extranuclear mechanisms, have profound effects on cardiac electrophysiology. Hypothyroidism carries a lower risk for AF and is mainly associated with the overtreatment of hypothyroid patients. New-onset AF is frequently the only manifestation of thyroid disease, which renders screening for thyroid dysfunction in that scenario clinically useful. Managing thyroid disease and comorbid AF is essential. This includes thyroid hormones control along with conventional AF therapy. However, there are several open issues with this comorbid duo. The optimal management of thyroid disease and its impact on AF burden remains obscure. There is scanty information on clear-cut benefits for therapy of subclinical thyroid disease and screening of asymptomatic patients. Furthermore, the immunogenetic overlap between the autoantibodies in Graves' disease and AF genesis may lead to novel therapeutic implications. The objective of this review is to summarize the up-to-dateepidemiology,pathogenesis, pathophysiologyandmanagement of interactingthyroid disease and AF.

Regional Diversities in Fibrogenesis Weighed as a Key Determinant for Atrial Arrhythmogenesis.

Atrial fibrosis plays a key role in atrial myopathy, resulting in the genesis of atrial fibrillation (AF). The abnormal distribution of fibrotic tissue, electrical coupling, paracrine interactions, and biomechanical–electrical interactions have all been suggested as causes of fibrosis-related arrhythmogenesis. Moreover, the regional difference in fibrogenesis, specifically the left atrium (LA) exhibiting a higher arrhythmogenesis and level of fibrosis than the right atrium (RA) in AF, is a key contributor to atrial arrhythmogenesis. LA fibroblasts have greater profibrotic cellular activities than RA fibroblasts, but knowledge about the regional diversity of atrial regional fibrogenesis remains limited. This article provides a comprehensive review of research findings on the association between fibrogenesis and arrhythmogenesis from laboratory to clinical evidence and updates the current understanding of the potential mechanism underlying the difference in fibrogenesis between the LA and RA.

Activation of PKG-CREB-KLF15 by melatonin attenuates Angiotensin II-induced vulnerability to atrial fibrillation via enhancing branched-chain amino acids catabolism

Mitochondrial reactive oxygen species (ROS) damage and atrial remodeling serve as the crucial substrates for the genesis of atrial fibrillation (AF). Branched-chain amino acids (BCAAs) catabolic defect plays critical roles in multiple cardiovascular diseases. However, the alteration of atrial BCAA catabolism and its role in AF remain largely unknown. This study aimed to explore the role of BCAA catabolism in the pathogenesis of AF and to further evaluate the therapeutic effect of melatonin with a focus on protein kinase G (PKG)-cAMP response element binding protein (CREB)-Krüppel-like factor 15 (KLF15) signaling. We found that angiotensin II-treated atria exhibited significantly elevated BCAA level, reduced BCAA catabolic enzyme activity, increased AF vulnerability, aggravated atrial electrical and structural remodeling, and enhanced mitochondrial ROS damage. These deleterious effects were attenuated by melatonin co-administration while exacerbated by BCAA oral supplementation. Melatonin treatment ameliorated BCAA-induced atrial damage and reversed BCAA-induced down-regulation of atrial PKGIα expression, CREB phosphorylation as well as KLF15 expression. However, inhibition of PKG partly abolished melatonin-induced beneficial actions. In summary, these data demonstrated that atrial BCAA catabolic defect contributed to the pathogenesis of AF by aggravating tissue fibrosis and mitochondrial ROS damage. Melatonin treatment ameliorated Ang II-induced atrial structural as well as electrical remodeling by activating PKG-CREB-KLF15. The present study reveals additional mechanisms contributing to AF genesis and highlights the opportunity of a novel therapy for AF by targeting BCAA catabolism. Melatonin may serve as a potential therapeutic agent for AF intervention.

Comprehensive analysis of autophagy-related genes and patterns of immune cell infiltration in valvular atrial fibrillation

BackgroundThe development of atrial fibrillation (AF) following valvular heart disease (VHD) remains a common disease and is associated with substantial adverse complications. However, valid molecular diagnostic and therapeutic tools for post-VHD AF have not been fully established. This study was conducted to discover the molecular mechanisms and immune microenvironment underlying AF following VHD.MethodsGene expression profiles of the GSE41177 dataset were assessed to construct a protein–protein interaction network, and then, autophagy-related hub genes were identified. In addition, to determine the functions of immune cell infiltration in valvular AF, we used the CIBERSORT algorithm to estimate the composition of 22 immune cell types in valvular heart disease. Finally, correlation analysis was carried out to identify the relationship between differentially expressed autophagy-related genes (DEARGs) and significant immune cell subpopulations to reveal potential regulatory pathways.ResultsA total of 153 DEARGs were identified in AF-VHD patients compared with controlled donors. Moreover, we screened the top ten hub nodes with the highest degrees through a network analysis. The ten hub nodes were considered hub genes related to AF genesis and progression. Then, we revealed six significant immune cell subpopulations through the CIBERSORT algorithm. Finally, correlation analysis was performed, and six DEARGs (BECN1, GAPDH, ATG7, MAPK3, BCL2L1, and MYC) and three immune cell subpopulations (T cells CD4 memory resting, T cells follicular helper, and neutrophils) were identified as the most significant potential regulators.ConclusionThe DEARGs and immune cells identified in our study may be critical in AF development following VHD and provide potential predictive markers and therapeutic targets for determining a treatment strategy for AF patients.