Maintenance Of Atrial Fibrillation Research Articles

Conventional and Novel Inflammatory Biomarkers in Chronic Heart Failure Patients with Atrial Fibrillation.

(1) Background and Objectives: Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased morbidity and mortality both in the general population and heart failure patients. Inflammation may promote the initiation, maintenance and perpetuation of AF, but the impact of inflammatory molecular signaling on the association between AF and heart failure remains elusive. (2) Materials and Methods: In 111 patients with chronic stable heart failure, baseline values of conventional (IL-6 and hsCRP) and selected novel inflammatory biomarkers (IL-10, IL-6/IL-10 ratio, orosomucoid and endocan) were determined. Inflammatory biomarkers were compared with respect to the presenting cardiac rhythm. (3) Results: Patients aged below 75 years with AF had significantly higher values of IL-6 and IL-6/IL-10 ratio; IL-6 levels were a significant predictor of AF in both univariate (OR 1.175; 95%CI 1.013-1.363; p = 0.034) and multivariate logistic regression analysis when accounting for other inflammatory biomarkers (OR 1.327; 95% CI 1.068-1.650; p = 0.011). Conversely, there was no association between other novel inflammatory biomarkers and AF. (4) Conclusions: IL-6 levels and the IL-6/IL-10 ratio are associated with AF in patients with chronic stable heart failure under the age of 75 years, suggesting that inflammatory molecular signaling may play a role in the development of AF in the heart failure population.

Targeting Nrf2/HO-1 and NF-κB/TNF-α signaling pathways with empagliflozin protects against atrial fibrillation-induced acute kidney injury in rats

A bidirectional relationship exists between atrial fibrillation (AF) and kidney function. Uncontrolled AF may lead to kidney injury, whereas renal dysfunction may contribute to AF initiation and maintenance. This study aimed to investigate the protective effect of the sodium glucose cotransporter-2 inhibitor empagliflozin (EMPA) on acute kidney injury (AKI) associated with AF induced by acetylcholine and calcium chloride (ACh/CaCl2) in rats and elucidate the potential underlying mechanism. Rats were randomly divided as follows: control (CTRL) group: administered vehicles only; AF group: intravenously injected 1 ml/kg of an ACh/CaCl2 mixture for seven days to induce AF; EMPA group: orally administered EMPA (30 mg/kg) for seven days; AF+EMPA10 and AF+EMPA30 groups: co-administered the induction mixture and EMPA (10 and 30 mg/kg, respectively) for seven days. Our results showed that EMPA (10 and 30 mg/kg) effectively maintained kidney function and demonstrated a significant antioxidant potential. EMPA also suppressed AF-induced renal tubulointerstitial injury and fibrotic changes concurrently with reducing renal levels of the pro-inflammatory cytokines tumour necrosis factor-α (TNF-α) and interleukin-6, as well as the pro-fibrotic marker transforming growth factor beta-1 and collagen type I. Mechanistically, EMPA boosted nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) renal tissue expression while repressing nuclear factor kappa B (NF-κB) activation. In addition, these beneficial effects of EMPA on kidneys were concurrent with its ability to effectively inhibit AF-related electrocardiographic changes, reduce incidence and duration of AF episodes, and markedly suppress serum B-type natriuretic peptide and C-reactive protein levels. In conclusion, EMPA protected against AKI associated with AF induced by ACh/CaCl2 in rats through simultaneous modulation of the Nrf2/HO-1 and the NF-κB/TNF-α signaling pathways, exerting antioxidant, anti-inflammatory, and anti-fibrotic effects.

Inflammation Burden and Atrial Fibrillation Burden: A Bidirectional Relationship.

Atrial fibrillation (AF) burden is defined as the proportion of time the patient remains in AF over a given period of time; thus, it is theoretically highest in permanent AF and lowest in paroxysmal AF. Inflammation is associated with the initiation and maintenance of AF. However, the relationship between systemic immune-inflammation index (SII) and AF burden is unknown. In the present study, we investigated the relationship between SII and AF burden. The present study is a cross-sectional analysis of 453 patients (252 females and 201 males, aged 44 to 94 years) with AF (138 with paroxysmal AF and 315 with permanent AF) who visited the cardiology outpatient clinic between October 2022 and June 2023. SII was calculated as (neutrophils × platelets/lymphocytes). The predictive role of SII and other inflammatory markers in the likelihood of AF pattern was evaluated by logistic regression analyses, and p value < 0.05 was considered statistically significant. Age, diastolic blood pressure, heart rate, diabetes mellitus, neutrophil, platelet-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, SII, C-reactive protein, red blood cell distribution width, hemoglobin A1c, and left atrial diameter were significantly higher in the permanent AF group. According to the logistic regression analysis, age (p = 0.038), diabetes mellitus (p = 0.024), red blood cell distribution width (p = 0.023), C-reactive protein (p = 0.010), SII (p = 0.001), and left atrial diameter (p < 0.001) significantly contributed to the prediction of the likelihood of permanent AF. SII is independently associated with the AF burden. Prospective studies are needed to determine whether SII may be useful in identifying patients at high risk for AF progression.

Predictors of neuromodulation during single-shot thermal atrial fibrillation ablation: a computed tomography imaging analysis

Abstract Background Ganglionated plexi (GPs) are part of the cardiac autonomic nervous system (CANS), which play an important role in the induction and maintenance of atrial fibrillation (AF). Because of the anatomic proximity of the pulmonary veins with GPs, pulmonary vein isolation (PVI) using thermal (radiofrequency (RF) or cryo) ablation, has been shown to concomitantly affect the GPs, as suggested by increased heart rate (HR) after ablation. Right superior pulmonary vein (RSPV) isolation has been reported to have the most evident inhibitory responses to the CANS via modulation of the anterior right ganglionated plexus. Nonetheless, there are also cases with little to no effect on neuromodulation post-ablation. Purpose To assess the clinical and anatomical predictors of thermal ablation-induced CANS changes, as assessed via variations in resting HR post-ablation. Methods We retrospectively analyzed consecutive patients with symptomatic paroxysmal AF who underwent first-time PVI by cryoballoon (CB) or RF balloon (RFB) between January 2022 to November 2022. Patients who were not in sinus rhythm, had cardiac implantable electronic devices, or did not have a contrast-enhanced computed tomography before the ablation were excluded. Pre-ablation and 24-hour post-ablation ECGs in sinus rhythm were collected and analyzed to assess HR. Results A total of 83 patients (CB group, n = 43 vs RFB group, n = 40) were included in the analysis. Baseline patients’ characteristics were similar between the two groups (Table 1). A significant HR increase (ΔHR ≥ 15 bpm) at 24h post-ablation occurred in 31 patients [CB group 16 (52 %), RFB group 15 (48 %)]. Predictors of increased HR were the distance between superior vena cava (SVC) and RSPV (OR 0.51, CI 0.35 - 0.75, p value &amp;lt; 0.01) and age (OR 0.94, CI 0.89 - 0.99, p value &amp;lt; 0.01) (Table 2). Conclusions Single-shot thermal PVI influences the CANS, especially in patients with a shorter SVC - RSPV distance and in younger patients.Table 1Table 2

Conduction velocity-based functional substrate mapping during atrial fibrillation (AF) enhances identification of AF drivers compared to mapping during sinus rhythm

Abstract Background Conduction velocity (CV) heterogeneity is known to play a role in the initiation and maintenance of atrial fibrillation (AF) [1,2]. CV has been shown to decrease with cycle lengths (CLs) &amp;lt;600ms in low voltage areas (LVAs) [3,4], and with CLs &amp;lt;300ms in non-LVAs [4]. Yet, the impact of rhythm and CL on voltage-independent, CV-based atrial substrate mapping remains uncertain. Purpose This study evaluates CV differences based on mapping protocol and explores the relationship between CV and AF pathologic conduction patterns (PCPs) identified through global, non-contact, charge density mapping (CDM) [5]. Methods CDM was performed in twelve patients with persistent AF, presenting for de novo ablation. All mapping was performed prior to any ablation. Sinus rhythm (SR) CV was assessed during atrial pacing at two CLs (380ms and 800ms). To mitigate the impact of wavefront direction, pacing was performed at three sites: mid coronary sinus, left atrial appendage, and right atrial appendage. AF CV was determined from a 20-second continuous recording of global propagation. PCPs were identified as: focal firing (FF), rotational propagation (Localised Rotational Activation [LRA]), and pivoting propagation (Localised Irregular Activity [LIA]) [5]. Patients’ left atrial geometries consisted of approximately 3000 vertices, facilitating paired comparisons of spatial data. At each vertex, values for median CV dependent on mapping protocol and frequency of PCPs were utilised for analysis. Variables are presented as mean±standard deviation, median (interquartile range), and count (percentage) as appropriate. All analyses were performed using R (version 4.1.2). CV distributions were compared using the Analysis of Variance test. Results Mean age was 64±12 years, eight (67%) were male, median time since AF diagnosis was 3.1 (2-3.5) years, and median CHA2DS2-VASc score was 2 (2-4). Median CV across our cohort was significantly lower during AF than SR with either long or short CL pacing (0.37mm/ms vs 0.66mm/ms vs 0.61mm/ms, p&amp;lt;0.001). Histograms of CV vs left atrial surface area demonstrated similar distributions for both CLs. However, there was poor overlap with AF, which was prominently skewed towards slower CVs (Figure 1). Slower CVs during AF were associated with an increased frequency of PCPs (Figure 2), particularly FF with CVs &amp;lt;0.2mm/ms, and LRA and LIA with CVs &amp;lt;0.4mm/ms. This association was absent during SR. Conclusions Rhythm has a significant impact on CV-based functional substrate mapping. Slower CVs observed during AF likely result from the presence of CLs shorter than 300ms, which impact both LVA and non-LVA areas. Crucially, areas of slow CV during AF were associated with the location of PCPs. Mapping performed during AF may improve identification of areas where functional remodelling has preceded structural. Such areas, characterised by CV heterogeneity, may serve as promising targets for catheter ablation.Figure 1.Figure 2.

Heart rate dynamics after pulmonary vein isolation: pulsed-field vs. radiofrequency ablation

Abstract Background The autonomic nervous system (ANS) plays a pivotal role in the onset and maintenance of atrial fibrillation (AF). During thermal ablation, the epicardial ganglionated plexi (GP) can inadvertently be affected, as indicated by a post-ablation increase in heart rate (HR), potentially impacting post-procedural outcomes. Pulsed-field ablation (PFA) offers a safer and potentially more effective alternative, as lesion transmurality is not inversely related to safety as in thermal ablation. However, PFA's tissue selectivity may limit its effectiveness in ablating potential AF triggers like GP. Purpose We aimed to assess the impact of PF and RF energy on GP ablation by examining HR changes following PVI procedures. Methods We examined consecutive paroxysmal AF patients undergoing PVI at a single center, using either a variable-loop circular PFA catheter, as part of the inspIRE trial, or a conventional point-by-point RF catheter (1:2 ratio). ECGs were collected before and after ablation at multiple time points, including 1-hour, 1-day, 1-month, and 3-month intervals, with a 24-hour Holter ECG at 3 months. Patients without obtainable sinus rhythm ECGs at these time points were excluded. We also gathered data on post-ablation antiarrhythmic drug and beta-blocker usage. Data are reported as mean±SD, and analysis employed Student’s t-tests, paired t-tests, chi-squared tests, and multiple linear regression analysis to identify influencing factors. Results A total of 105 patients were included (PF = 35, RF = 70). Baseline demographics were similar (Table A). In the RF group, HR significantly increased at all measured time-points. In contrast, this trend was not observed in the PF group (Figure A and B). Following the procedure, the RF cohort exhibited a significantly higher HR compared to PF (7.3±10.3 vs. 0.8±11 at 1-day, p=0.018), and this difference persisted after 3 months (8.5±10.1 vs. 0.9±9, p&amp;lt;0.001, Figure C). These findings remained consistent when HR was assessed using Holter ECG data (HR at 3 months: mean 72.1±8.8 vs 65.8±9.4, min 55.2 vs 48.9; p=0.002, p=0.001, Figure D). The use of RF energy was the only predictor of HR increase after the ablation procedure (β = 7.687, p &amp;lt; 0.001, Table B). Conclusion Our findings indicates that PFA does not increase resting HR as seen with thermal RF ablation, suggesting limited effect on ANS modulation. The role of adjunctive GP ablation during PVI procedures remains a topic of debate.While PFA shows promising improvement in lesion durability, current evidence does not conclusively establish its advantage over RF. This invites contemplation about whether the addition of GP ablation in RF procedures could be a contributing factor. The absence of HR acceleration may pose issues for patients with sick sinus syndrome or pure vagally mediated AF. Further research is essential to confirm these findings and their clinical implications.Central illustrationTables

Multielectrode catheter-based pulsed field ablation of persistent and long-standing persistent atrial fibrillation

Abstract Background Rhythm control of non-paroxysmal atrial fibrillation (AF) is significantly more challenging, as a result of arrhythmia perpetuation promoting atrial substrate changes and AF maintenance. Purpose We describe a tailored ablation strategy targeting multiple left atrial (LA) sites via the multielectrode FarawaveTM pulsed field ablation (PFA) catheter in patients with persistent AF sustained beyond 6 months (PerAF&amp;gt;6m) and long-standing persistent AF (LSPAF). Methods The ablation protocol included the following stages: pulmonary vein antral and posterior wall isolation plus anterior roof line ablation (Stage 1); electrogram-guided substrate ablation (Stage 2); atrial tachyarrhythmia (AT) regionalization and ablation (Stage 3). Results Seventy-two [age:68±10y, 61.1%males; AF history: 25 (18-45) months] patients with PerAF&amp;gt;6m (52.8%) and LSPAF (47.2%) underwent their first PFA via the FarapulseTM system. LA substrate ablation (Stage 1 and 2) led to AF termination in 95.8% of patients. AF termination occurred while ablating the mitral edge of the postero-lateral ridge (40.3%), the inferior left atrium above the proximal coronary sinus (27.4%), the interatrial septum (22.6%), the superior aspect of the postero-lateral ridge (6.5%), the base of the appendage (3.2%). AF organized into a left-sided atrial flutter (AFlu) in 46 (74.2%) patients. The FarawaveTM catheter was used to identify LA sites showing diastolic, low-voltage electrograms and entrainment from its splines was performed to confirm the pacing site was inside the AFlu circuit (Figure 1). Left AFlu termination was achieved in all cases via PFA delivery. Total procedural and LA dwell times were 112±25min and 59±22 min, respectively. Major complications occurred in 2 (2.8%) patients with pre-existing left ventricular systolic dysfunction (EF&amp;lt;35%) who required inotropic therapy due to acute heart failure. Hemodynamics normalized within 24h and both patients were discharged after 2 and 3 additional hospital days. Transient ST-segment elevation was documented in 4 patients after peri-mitral PFA; timely nitrate administration led to ECG normalization within 10 minutes. Single-procedure success rate was 81.8% after 13.3±1.9 months of follow-up; AF-free survival was 93.1% (Figure 2). A subgroup of 36 patients completed a follow-up transthoracic echocardiography study to assess left atrial mechanical contraction changes after ablation. Median A-wave velocity was 30 (IQR: 20-35) cm/s post-ablation and 50 (IQR: 41-70) cm/s after a mean of 7.3±1.8 months post-ablation. Conclusions In our cohort, PFA-based AF substrate ablation led to AF termination in 95.8% of cases. Very favorable clinical outcomes were observed at one year of follow-up.Entrainment from the PFA Catheter.Kaplan-Meier Analysis.

Association of superior vena cava isolation with improved outcomes in atrial fibrillation ablation

Abstract Background Pulmonary vein isolation (PVI) is the mainstay in atrial fibrillation (AF) ablation. However, additional arrhythmogenic foci seem to contribute to AF initiation and maintenance. A great proportion of those non-PV foci have been reported to be located in the superior vena cava. Purpose We aimed to investigate the effectiveness of SVC isolation as an adjunctive therapy to PVI isolation. Methods We performed a systematic review of MEDLINE, CENTRAL, and Embase. Inclusion criteria were cohort studies with control group or randomized clinical trials, comparing patients undergoing PVI only and patients undergoing PVI with concurrent SVC isolation, in effects of freedom from atrial tachycardia, need for cardioversion, hospitalization and all-cause mortality. Results A total of 7 studies, incorporating 1.550 patients, were included. The combination of SVC and PVI isolation in patients undergoing AF ablation was more effective than PVI isolation alone (risk ratio = 0.689; 95% confidence interval, 0.505-0.942). In a subgroup analysis, the isolation of SVC after identifying focal potentials demonstrated effectiveness (risk ratio = 0.573; 95% confidence interval, 0.364-0.902), while the isolation of SVC when the focal potentials were induced after isoprotenerol infusion or rapid atrial pacing did not alter the clinical outcomes (risk ratio = 0.798; 95% confidence interval, 0.493, 1.292). Conclusions The outcomes of AF ablation are favorable when additional SVC isolation is conducted. The effect is pronounced when spontaneous SVC potentials are identified.

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.

Coagulation Factor Xa Has No Effects on the Expression of PAR1, PAR2, and PAR4 and No Proinflammatory Effects on HL-1 Cells.

Atrial fibrillation (AF), characterised by irregular high-frequency contractions of the atria of the heart, is of increasing clinical importance. The reasons are the increasing prevalence and thromboembolic complications caused by AF. So-called atrial remodelling is characterised, among other things, by atrial dilatation and fibrotic remodelling. As a result, AF is self-sustaining and forms a procoagulant state. But hypercoagulation not only appears to be the consequence of AF. Coagulation factors can exert influence on cells via protease-activated receptors (PAR) and thereby the procoagulation state could contribute to the development and maintenance of AF. In this work, the influence of FXa on Heart Like-1 (HL-1) cells, which are murine adult atrial cardiomyocytes (immortalized), was investigated. PAR1, PAR2, and PAR4 expression was detected. After incubations with FXa (5-50 nM; 4-24 h) or PAR1- and PAR2-agonists (20 µM; 4-24 h), no changes occurred in PAR expression or in the inflammatory signalling cascade. There were no time- or concentration-dependent changes in the phosphorylation of the MAP kinases ERK1/2 or the p65 subunit of NF-κB. In addition, there was no change in the mRNA expression of the cell adhesion molecules (ICAM-1, VCAM-1, fibronectin). Thus, FXa has no direct PAR-dependent effects on HL-1 cells. Future studies should investigate the influence of FXa on human cardiomyocytes or on other cardiac cell types like fibroblasts.

Atrial fibrillation and malignant neoplasms: state of the problem

Patients with malignant neoplasms have an increased risk of atrial fibrillation. Prevalence of this pathology among oncological patients is 20–30 %, and it significantly varies depending on tumor type, chemotherapy treatment and initial comorbid status. Atrial fibrillation and malignant neoplasms have similar risk factors. Researchers have identified several possible causes characteristic of these diseases, primarily, systemic inflammation. Some chemotherapies cause abnormalities in ionic channels of atrial cardiomyocytes which leads to changes in the action potential and refractory period, which promote maintenance of atrial fibrillation. The most known groups of chemotherapy drugs associated with atrial fibrillation are alkylating agents (cisplatin, cyclophosphamide), anthracyclines used in sarcoma treatment, as well as anti-HER2 drugs (HER2 – human epidermal growth factor receptor 2), antimetabolites (capecitabine, 5-fluorouracil) and tyrosine kinase inhibitors. However, pathophysiological mechanisms linking together atrial fibrillation and malignant neoplasms require further study.

Distribution of triggers in the left atrial posterior wall in AF patients undergoing catheter ablation

Abstract Introduction Having a common embryologic origin with the pulmonary veins (PVs), left atrial posterior wall (LAPW) is considered to be a source of non-PV triggers that facilitate maintenance of atrial fibrillation (AF). However, the benefits of electrical isolation of the posterior wall (PWI) is still debated with contradictory data originating from different ablation approaches. Purpose We report the distribution of triggers in the LAPW area in AF patients undergoing repeat ablation. Methods Consecutive AF patients undergoing catheter ablation between 2015 and 2022 were included in this analysis. PVs were isolated first. Next, high-dose isoproterenol challenge (up to 30µg/min) was used to disclose triggers in the PW by moving the circular mapping catheter along the PW down to the level of coronary sinus, which were targeted using additional RF energy. We defined lower part of LAPW as the area between the line joining the inferior borders of the inferior PV-encircling lesions and the coronary sinus. The endpoint was to achieve electrical isolation, as documented by absence of any electrical activity in the PW. Results Of the 10,963 AF ablations performed during the specified time period, 6249 (57%) had triggers mapped and ablated in the LAPW area. Triggers were seen to be originating from the part of the PW between the PVs in 4124 (66%) and from the lower part of the PW in 2125 (34%) patients. Of these, 1624 (26%) patients had focal triggers detected in both the area between the PVs and the lower PW. All triggers from in between PVs were targeted for ablation, whereas lower PW sites were ablated in 1296 (61%) and not targeted for ablation the remaining 829 (39%). Figure 1 demonstrates the triggers arising from lower PW. At 1 year, amongst patients with lower PW triggers, 1049/1296 (81%) vs 326/829 (39.3%) (p&amp;lt;0.001) were arrhythmia-free. Conclusion Ectopic triggers in the LAPW were documented to be arising from the lower part of the PW in approximately 1/3rd of cases and ablation of those sites resulted in significantly higher success rate.

Abstract 14702: Roles of Atrial Mass Reduction and Gaps on the Anti-Atrial Fibrillatory Effects of Pulmonary Vein Isolation: A Computational Modeling Study

Background: Although pulmonary vein isolation (PVI) is the basis of atrial fibrillation (AF) catheter ablation (AFCA), the conditional changes of an anti-AF effect and the wave-dynamic mechanism are poorly understood. Therefore, we compared the effects of PVI based on the ablation circumference, width, and number or locations of gaps with or without amiodarone at the same condition in realistic computational modeling of human AF. Hypothesis: An anatomical level of PVI and characteristics of the PVI gap would affect the anti-AF effects of the AFCA. Methods: We included 50 patients (76.0% persistent AF) who underwent AFCA. Realistic AF modeling reflecting the computed tomography (CT) and the electroanatomical map was performed on each patient. We compared the AF defragmentation rate (DeFR; change to atrial tachycardia (AT) or termination), termination rate (TnR), and changes in the dominant frequency (DF) and the number of phase singularities (PSs) based on the PVI level (antral vs. ostial), PVI width (single vs. 3х width), number and location of 2-mm PVI gaps with or without amiodarone (10mM). We randomly assigned the number and location of the PVI gaps to the AF models. Results: The antral PVI had a significantly higher DeFR (p for trend &lt;0.001) and TnR (p for trend &lt;0.001) than the ostial PVI, PVI gaps, or baseline AF. However, there was no difference depending on PVI width. Among the PVI gaps, the DeFR (p for trend&lt;0.001) decreased as the gap number increased. Additional amiodarone increased DeFR (p=0.003) and TnR (p=0.034) and reduced DF (p&lt;0.001) and the number of PSs (p&lt;0.001) with PVI-gap, especially with a single PVI-gap. Conclusions: In this realistic computational modeling study with integrated patients’ atrial anatomy and electrophysiology, the atrial mass reduction depending on the anatomical PVI level, number of PVI gaps, and additional antiarrhythmic drug significantly affected the AF maintenance mechanisms.

Dapagliflozin attenuates the vulnerability to atrial fibrillation in rats with lipopolysaccharide-induced myocardial injury

BackgroundOxidative stress is an essential component participating in the development and maintenance of atrial fibrillation (AF). Dapagliflozin, a SGLT2 inhibitor, has been shown to exert cardioprotective effects by ameliorating oxidative stress in multiple heart disease models. However, its potential to attenuate lipopolysaccharide (LPS)-induced myocardial injury in rats remains unknown. AimThis study aims to investigate the role of dapagliflozin in LPS-induced myocardial injury and the potential mechanisms involved. MethodsRats were intraperitoneally administered LPS to induce sepsis-like condition. The intervention was conducted with intraperitoneal injection of dapagliflozin or saline 1 h in advance. The effects of dapagliflozin were detected by electrophysiological recordings, western blot, qPCR, ELISA, HE staining, immunohistochemistry and fluorescence. We further validated the mechanism in vitro using HL-1 cells. ResultsDapagliflozin significantly improved LPS-induced myocardial injury, reduced susceptibility to AF, and mitigated atrial tissue inflammatory cell infiltration and atrial myocyte apoptosis. These were correlated with the Nrf2/HO-1 signaling pathway, which subsequently reduced oxidative stress. Subsequently, we used a specific inhibitor of the Nrf2/HO-1 pathway in vitro, reversed the anti-oxidative stress effects of dapagliflozin on HL-1 cells, further confirming the Nrf2/HO-1 pathway’s pivotal role in dapagliflozin-mediated cardioprotection. ConclusionDapagliflozin ameliorated myocardial injury and susceptibility to AF induced by LPS through anti-oxidative stress, which relied on upregulation of the Nrf2/HO-1 pathway.

Epicardial Adipose Tissue and Atrial Fibrillation Recurrence following Catheter Ablation: A Systematic Review and Meta-Analysis.

(1)Introduction: Catheter ablation has become a cornerstone for the management of patients with atrial fibrillation (AF). Nevertheless, recurrence rates remain high. Epicardial adipose tissue (EAT) has been associated with AF pathogenesis and maintenance. However, the literature has provided equivocal results regarding the relationship between EAT and post-ablation recurrence.(2) Purpose: to investigate the relationship between total and peri-left atrium (peri-LA) EAT with post-ablation AF recurrence. (3) Methods: major electronic databases were searched for articles assessing the relationship between EAT, quantified using computed tomography, and the recurrence of AF following catheter ablation procedures. (4) Results: Twelve studies (2179 patients) assessed total EAT and another twelve (2879 patients) peri-LA EAT. Almost 60% of the included patients had paroxysmal AF and recurrence was documented in 34%. Those who maintained sinus rhythm had a significantly lower volume of peri-LA EAT (SMD: -0.37, 95%; CI: -0.58-0.16, I2: 68%). On the contrary, no significant difference was documented for total EAT (SMD: -0.32, 95%; CI: -0.65-0.01; I2: 92%). No differences were revealed between radiofrequency and cryoenergy pulmonary venous isolation. No publication bias was identified. (5) Conclusions: Only peri-LA EAT seems to be predictive of post-ablation AF recurrence. These findings may reflect different pathophysiological roles of EAT depending on its location. Whether peri-LA EAT can be used as a predictor and target to prevent recurrence is a matter of further research.

Downregulation of fibromodulin attenuates inflammatory signaling and atrial fibrosis in spontaneously hypertensive rats with atrial fibrillation via inhibiting TLR4/NLRP3 signaling pathway.

Myocardial fibrosis is an important factor in the induction and maintenance of atrial fibrillation (AF). Fibromodulin (FMOD) promotes fibrotic gene expression. However, its specific role in spontaneously hypertensive rats (SHR)-AF remains unclear. We analyzed FMOD mRNA and protein expression in rat atrial tissues using RT-qPCR, Western blot analysis, and immunohistochemistry. Histopathological examination of atrial tissues was performed using hematoxylin and eosin (H&E), Masson's trichrome, and Picrosirius red staining. The levels of inflammatory and fibrosis-related proteins were measured using Western blot analysis. FMOD relative mRNA and protein expression levels were notably upregulated in atrial tissues of both AF groups (normal-AF and SHR-AF groups) than that in atrial tissues of the no-AF group (normal and SHR group). This effect was particularly pronounced in the SHR-AF group. Pathological changes revealed that the extracellular matrix, collagen, collagen fibers, and left atrial diameter were notably increased in the atrial tissues from the SHR-AF group compared to those in the atrial tissues from the SHR group, whereas the left ventricular fractional shortening and left ventricular ejection fraction were notably lower. Expression of TLR4, MyD88, NLRP3, TGF-β1, collagen I, and collagen II mRNA were clearly higher in atrial tissues from the SHR-AF group than in those from the SHR group. Protein levels of TLR4, MyD88, NLRP3, Cleavage-Caspase-1, Cleavage-IL-1β, TGF-β1, p-Smad2, collagen I, and collagen II were clearly higher in atrial tissues from the SHR-AF group than in those from the SHR group. FMOD knockdown inhibited atrial fibrosis, collagen accumulation, and the TLR4/MyD88/NLRP3 signaling pathway. Downregulation of FMOD attenuated inflammatory signaling and atrial fibrosis in SHR-AF by inhibiting the TLR4/NLRP3 signaling pathway. Therefore, FMOD may be a promising therapeutic target in AF.

The inter-chamber differences in the contractile function between left and right atrial cardiomyocytes in atrial fibrillation in rats.

The left and right atria (LA, RA) work under different mechanical and metabolic environments that may cause an intrinsic inter-chamber diversity in structure and functional properties between atrial cardiomyocytes (CM) in norm and provoke their different responsiveness to pathological conditions. In this study, we assessed a LA vs. RA difference in CM contractility in paroxysmal atrial fibrillation (AF) and underlying mechanisms. We investigated the contractile function of single isolated CM from LA and RA using a 7-day acetylcholine (ACh)-CaCl2 AF model in rats. We compared auxotonic force, sarcomere length dynamics, cytosolic calcium ([Ca2+]i) transients, intracellular ROS and NO production in LA and RA CM, and analyzed the phosphorylation levels of contractile proteins and actin-myosin interaction using an in vitro motility assay. AF resulted in more prominent structural and functional changes in LA myocardium, reducing sarcomere shortening amplitude, and velocity of sarcomere relengthening in mechanically non-loaded LA CM, which was associated with the increased ROS production, decreased NO production, reduced myofibrillar content, and decreased phosphorylation of cardiac myosin binding protein C and troponin I. However, in mechanically loaded CM, AF depressed the auxotonic force amplitude and kinetics in RA CM, while force characteristics were preserved in LA CM. Thus, inter-atrial differences are increased in paroxysmal AF and affected by the mechanical load that may contribute to the maintenance and progression of AF.

The roles of long noncoding RNAs in atrial fibrillation

Atrial fibrillation (AF) is a common cardiac arrhythmia that often occurs in patients with structural heart disease and is a significant cause of morbidity and mortality in clinical settings. AF is typically associated with significant changes of both the structure of the atria and the cardiac conduction system. AF can result in reduced heart function, heart failure, and various other complications. Current drug therapy for AF patients is often ineffective and may have adverse effects. Radiofrequency ablation is more effective than traditional drug therapy, but this invasive procedure carries potential risks and may lead to postoperative recurrence, limiting the clinical benefits to some extent. Therefore, in-depth research into the molecular mechanisms of AF and exploration of new treatment strategies based on research findings are prerequisites for improving the treatment of AF and the associated cardiac conditions. Long noncoding RNAs (lncRNAs) are a new class of noncoding RNA (ncRNAs) with a length exceeding 200 nt, which regulate gene expression at multiple levels. Increasing evidence suggests that lncRNAs participate in many pathological processes of AF initiation, development, and maintenance, such as structural remodeling, electrical remodeling, renin-angiotensin system anomalies, and intracellular calcium deregulation s. LncRNAs that play key roles in structural and electrical remodeling may become molecular markers and targets for AF diagnosis and treatment, respectively, while lncRNAs critical to autonomic nervous system remodeling may bring new insights into the prognosis and recurrence of AF. This review article provides a synopsis on the up-to-date research findings relevant to the roles of lncRNAs in AF.

Abstract P3126: Atrial Fibrillation Is Associated With Decreased Claudin-5 In Cardiomyocyte

Background: Although it is critically important to understand the underlying molecular and electrophysiological changes that predispose to the induction and maintenance of atrial fibrillation (Af), the underlying mechanism of Af is still poorly defined. Af is characterized as the electrophysiological and membrane integrity abnormality of the atrial cells, and claudin-5, a tight junction protein, may be involved in the pathophysiology of Af, however, the role of claudin-5 in Af is unknown. Methods and Results: Cardiac tissues from the left atrial appendage were obtained from AF patients with rheumatic valvular heart disease undergoing modified radiofrequency ablation maze procedure with approval from local human research ethic review and normal left atrial appendages were obtained from non-AF donors. Western blot, immunofluorescence and transmission electron microscope showed the expression of claudin-5 significantly decreased in cardiomyocytes from left atrium of AF patients compared to non-AF donors. Then proteomics analysis was performed to screen the specific protein expression and signal pathway changed in AF heart tissue vs. non-AF heart tissue, and showed that 83 proteins were downregulated and 102 proteins were upregulated in the left atrial appendage of AF patients. Among them, DAG, CACNA2D2, MYL2 were downregulated and MCU was upregulated. KEGG pathway analysis showed these changes would lead to hypertrophic and dilated cardiomyopathy. Finally, claudin-5 shRNA AAV was injected in mouse left ventricle to knockdown claudin-5 in cardiomyocytes to observe whether change of claudin-5 affects the protein expression in KEGG pathway analysis. We found claudin-5 deficiency caused severe ventricular dilation, ST elevation and arrythmia, and the protein level of DAG, CACNA2D2 and MYL2 were downregulated and MCU was upregulated. Co-immunoprecipitation also confirmed the specific protein-protein interaction between these targeted proteins and claudin-5. Conclusion: We demonstrated that the decrease of claudin-5 in the left atrium of AF patients with rheumatic valvular heart disease. The mechanism of AF might be associated with claudin-5 downregulation-induced decrease of DAG, CACNA2D2, MYL2 and increase of MCU in cardiomyocytes.