Common Sustained Arrhythmia Research Articles

Abstract 4114694: A Large Animal Model of Persistent Atrial Fibrillation

Purpose: Persistent atrial fibrillation (AFib), the most common sustained cardiac arrhythmia in the United States, poses substantial health hazards, such as the formation of blood clots, stroke, and heart failure. Despite available therapies such as ablation and antiarrhythmic drugs, there still is no definitive cure for AFib. Our study aims to bridge this gap by investigating the genetic and molecular factors underlying AFib through the development of an AFib model using Yucatan mini swine as the medium that closely mimics human cardiac physiology. Methods: We selected Yucátan mini swine as animal models because they closely resemble humans physiologically and are of a convenient size for performing extended experiments. We surgically implanted pacing leads, implantable cardiac monitors (ICMs), and pacing generators into the swine, along with external Fitbark 2.0 Collars to use activity levels as a measurement of quality of life. After the procedures the swine underwent rapid atrial pacing with the intention to induce persistent atrial fibrillation. Findings: An electrocardiogram (ECG) showed that the method of stimulating the right atrium of the heart induced persistent atrial fibrillation in pigs and decreased levels of activity, indicating a decline in their general health. This continued for >7 days after atrial pacing was terminated. Overcoming challenges associated with animal dimensions and model design, we devised specific surgical techniques, including jugular cut-down, lateral cervical implantation coupled with antibiotic support, long sheaths, and customized styluses. These innovations were instrumental in achieving a successful AFib model and overcoming anatomical obstacles. Summary: Our study demonstrates the feasibility of creating a large animal model of AFib using Yucatan mini swine. This model closely resembles the clinical presentation of human AFib and could provide valuable insights into the disease mechanism and potential therapeutic strategies. Animal heart and vascular dimensions were the most challenging surgically.

Aging-associated mechanisms of atrial fibrillation progression and their therapeutic potential

Atrial fibrillation (AF) is the most common sustained arrhythmia, with a particularly high prevalence in the elderly. As the global aging population rapidly expands, it is increasingly important to examine how alterations to the aging heart contribute to an increased AF susceptibility. This work critically reviews the key molecular mechanisms that may underpin the complex association between aging and AF. Moreover, we identify emerging novel opportunities for therapeutic intervention that may be able to prevent and/or improve the current treatment paradigms for age-related AF. This review contributes to a holistic understanding of the intricate relationship between aging and AF.

Assessment of Coronary Artery Disease in Non-Valvular Atrial Fibrillation: Is This Light at the End of the Tunnel?

Non-valvular atrial fibrillation (NVAF) is the most common sustained arrhythmia worldwide, and is associated with significant morbidity and mortality. Increasing life expectancy, coupled with a surge in comorbidity burden, has resulted in a sharp increase in NVAF prevalence over the last three decades. Coronary artery disease (CAD) is an important and clinically relevant risk factor of AF. Concomitant CAD has significant implications for AF management and is a major determinant of the overall outcomes. Shared risk factors, a common pathophysiological basis, and heightened thrombogenesis culminating in cardiovascular adverse events, highlight the close association between the two. The clinical course of AF is worse when associated with CAD, resulting in poor heart rate control, increased propensity to develop stroke and myocardial infarction, increased likelihood of acute presentation with hemodynamic collapse and pulmonary edema, increased bleeding tendencies, and poor response to ablation therapies. Emerging research highlighting the significant role of underlying CAD as an independent predictor of thromboembolic risk has paved the way for the adoption of CAD beyond prior myocardial infarction into the symbol "V" of the CHA2DS2-VASc score. In our opinion, elderly patients aged >65 years with AF, with a history of one or more cardiovascular comorbidities, or evidence of atherosclerosis in other vascular beds should warrant a closer look and a dedicated effort to look for associated CAD. This would allow for a more holistic and comprehensive approach to patients with AF and ultimately help reduce the disease burden and improve the overall outcomes.

Dysfunctional atrial fibroblast processing of filamin A in atrial fibrillation

Abstract Background/Introduction Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is associated with atrial structural remodelling, hallmarked by fibrosis. Atrial fibrosis is instigated by atrial fibroblasts (AFBs). It was previously uncovered the hormone calcitonin (CT) is produced in the heart and, via binding to the CT-receptors (CTR), inhibits atrial fibrogenesis and fibroblast profibrotic activity. [1] In AF, abnormally increased CTR internalisation causes loss of physiological surface CTR and prevents fibroblast activation by CT. The molecular mechanisms of this phenomenon in ACFs are unknown. Aim To explore the role of filamin A (FLNa), an actin cross-linking protein that was previously shown to interact with CTR, [2] in the regulation of CTR trafficking. Methods AFBs were enzymatically isolated from left atrial appendage biopsies collected from 30 patients in persistent AF or normal sinus rhythm (SR, controls) undergoing elective heart surgery. Immunostaining assessed the localisation of CTR and its overlap with the nucleus (stained with DAPI) and FLNa in AFBs. Co-localisation was quantified by the JACoP BIOP plugin for ImageJ. Target mRNA expression was assessed by RT-qPCR and protein levels by immunoblot. Immunoprecipitation (IP) then immunoblot (IB) validated protein-protein interactions. Calpain activity was assessed with a fluorescence-based assay. The effects of calpains on FLNa proteolytic processing was examined with calpain inhibitor calpeptin (10nM–100nM vs DMSO loading control). Results Immunostaining revealed aberrant, intracellular localisation of CTR in AF-AFBs (A) with increased nuclear localisation (p=0.03) and reduced co-localisation with FLNa (p=0.03). FLNa gene expression showed a trend towards reduction in AF (by 36%, p=0.06; B). Meanwhile, although full-length FLNa protein was unaltered in AF, there was a striking 67% reduction (p=0.02) in the expression of FLNa’s c-terminal fragment (FLNaCT), which contains the CTR binding domain (C). Co-immunoprecipitation confirmed a physical interaction between CTR and FLNaCT (D) in both SR and AF AFBs. FLNaCT is typically generated when FLNa is cleaved by the protease calpain 1, whose protein (F) but not mRNA (E), was significantly downregulated (71%, p<0.001) in AF. Puzzlingly, a ~70% loss of calpain 1 protein was associated with unchanged calpain activity (G) and FLNaCT levels in AFBs treated with calpain inhibitor calpeptin (H). Conclusions Persistent AF is associated with an aberrant CTR localisation and FLNa proteolytic processing, not attributable to altered calpain activity. Further characterisation of the molecular determinants of the altered CTR localisation may uncover novel and potentially druggable facets of structural remodelling in AF.

Long-term changes in frailty and incident atrial fibrillation: multicenter prospective cohort study

Abstract Background Atrial fibrillation is the most common sustained cardiac arrhythmia and is prevalent among the elderly. Previous findings indicated a higher prevalence of AF in frail adults and frailty prevalent in AF patients. However, the association between dynamic changes of frailty and risk of new-onset AF is unclear. Purpose We aimed to investigate the associations of long-term changes in frailty with incident AF. Its associations with heart failure (HF), coronary heart disease (CHD), and stroke were also evaluated as a secondary aim. Methods Over 50,000 participants from UK Biobank cohort were included, with available frailty index (FI) data and free of AF, HF, CHD or stroke in both baseline and final follow-up assessments. Participants were categorized into nonfrailty, prefrailty and frailty based on their FI scores. Changes of frailty status from baseline to final follow-up assessment included alleviation, maintenance, and aggravation. Thus, transitions of frailty status included 7 categories: nonfrailty maintenance, nonfrailty aggravation (nonfrailty to prefrailty or frailty), prefrailty alleviation (prefrailty to nonfrailty), prefrailty maintenance, prefrailty aggravation (prefrailty to frailty), frailty alleviation (frailty to prefrailty or nonfrailty), and frailty maintenance. FI in baseline and follow-ups are used to calculate the trajectories of frailty (ΔFI). Cox proportional hazard models were used. Results Compared with nonfrailty at baseline, the HRs (95% CI) of AF for prefrailty and frailty were 1.32 (1.29, 1.36) and 1.89 (1.83, 1.96) in the multivariable-adjusted model. During a median of 5.1 years of follow-up from the final assessment, 1729 cases of AF were recorded. Frailty trajectory analysis showed that even a 0.01 point/year increase in ΔFI was associated with 14% (95% CI 1.08-1.20) higher risk of AF, independent of baseline FI and the risk rose to 1.89 (1.45, 2.46) with per 0.05 point/year increase in ΔFI. This association was strengthened in low genetic risk of AF, but sex, age, smoking status, alcohol intake, obesity, hypertension, diabetes and cancer did not materially modify the associations. Moreover, compared with nonfrailty maintenance, sustained frailty had the highest risk of AF (HR 1.95, 1.61-2.36). Alleviation from frailty reduced the risk of AF by 30% (95%CI 0.53-0.94), compared to sustained frailty. These associations were similar in HF and CHD, however, not significant in stroke. Conclusions Middle aged and elderly people, including those with diabetes, obesity and hypertension, may gain substantial benefits in risk of AF, HF and CHD by becoming less frail or maintaining nonfrailty, irrespective of past frailty status and established risk factors, delivering public health implications for the necessity of early identification and timely interventions of frailty in heart health management.

Combined class I and class III antiarrhythmic effects of sotagliflozin - insights from heterologous expressions systems and atrial cardiomyocytes

Abstract Background The demand for more effective treatment options for atrial fibrillation (AF), the most common sustained arrhythmia, is driven by its direct impact on morbidity and mortality. Current therapies, such as antiarrhythmic drugs and catheter ablation, are limited by suboptimal efficacy and adverse effects or periinterventional complications. Therefore, safe and effective treatment of AF remains a major unmet clinical need. Sodium-glucose cotransporter (SGLT) inhibitors have shown promise in reducing the incidence of AF in large cardiovascular endpoint trials. However, the exact mechanisms of action remain unclear. While only two SGLT2 inhibitors are approved and clinically used in Europe, sotagliflozin, which inhibits both SGLT1 and SGLT2, might also have potential for the treatment of AF. Purpose This study aims to elucidate the effects of sotagliflozin on cardiac action potential formation. This understanding could optimise its clinical use, identify new targets for the treatment of atrial fibrillation and ultimately improve the quality of life of patients suffering from AF. Methods The effects of sotagliflozin on cardiac ionic currents were assessed using two-electrode voltage clamp measurements of several sodium and potassium channels heterologously expressed in Xenopus laevis oocytes. Subsequently, ascending concentrations of sotagliflozin were administered to isolated human atrial cardiomyocytes during patch-clamp measurements to investigate its effect on atrial action potential morphology. Results At a concentration of 100 µM, sotagliflozin showed significant inhibitory effects on three out of ten ion channels tested: NaV1.5 sodium channel current was reduced by 22,3 % %, hERG and KV4.3 potassium currents were reduced by 30,4 % and 22,5 % respectively. Patch-clamp experiments, performed on isolated human atrial cardiomyocytes showed a dose-dependent reduction in upstroke velocity and action potential amplitude by 20,8 % and 13,8 % at a concentration of 20 µM, reflecting class-I-antiarrhythmic effects. Furthermore, a prolongation of AP duration measured at 50 % (APD50) and 90 % (APD90) of repolarization by 57,7 % and 27,9 % at a sotagliflozin concentration of 20 µM was noted, implying additional class-III-antiarrhythmic action. Conclusions Sotagliflozin exerts direct inhibitory effects on heterologously expressed NaV1.5, hERG and KV4.3 channels, resulting in a reduction in upstroke velocity and action potential amplitude, as well as a prolongation of APD50 and APD90 levels in isolated human atrial cardiomyocytes. These results extend the pharmacological profile of sotagliflozin and suggest a potential role for the clinical use of combined SGLT1/SGLT2 inhibitors in the treatment of AF.

Strategic timing- early and delayed catheter ablation in atrial fibrillation

Abstract Background Atrial fibrillation (AF) is the most common sustained arrhythmia. AF catheter ablation (CA) is superior to antiarrhythmic drug (AAD) therapy in maintaining sinus rhythm. However, not much is known regarding the optimal timing of the ablation. Purpose This review aims to examine the evidence supporting both early and delayed ablation approaches, as well as explore their respective disadvantages. Methods We performed an electronic search in databases such as PubMed, ScienceDirect, Springer, Wiley Online Library, focusing on studies published from 2013 until 2022 and including both observational studies and randomized controlled trials (RCTs). Left atrial diameter and ejection fraction (EF) were assessed. The limit between early and delayed ablation was set to be 3 years, considering delayed CA studies with a diagnosis-to-ablation-time (DAT) of 3 years or more, and early CA studies with a DAT of less than 3 years. Included studies were selected according to our eligibility criteria: observational studies or RCTs that included patients with symptomatic paroxysmal or persistent AF that underwent ablation using either radiofrequency or cryoballoon approach or both approaches, studies that reported DAT, studies that included a follow-up period, studies that evaluated AF recurrence or AF burden. Studies that included a surgical ablation, a hybrid ablation approach, or ablation for arrhythmias other than AF were excluded. Results Ten studies were selected out of 1387 identified records. After a follow-up period of 1 year, the early ablation subgroup had a lower mean AF recurrence rate (31.1%) compared to that of the delayed ablation subgroup (37.7%) ( p<0.0004). The median AF recurrence rate in radiofrequency ablation group was (47.8%) in comparison to the AF recurrence rate in cryoablation group which was (27.4%) (p<0.0001). In studies that included paroxysmal AF patients exclusively, the AF recurrence rate was directly proportional to the DAT(R=0.95). Conclusion Our results demonstrate that DAT correlates with recurrence rate at 1 year following AF CA, the shorter the DAT the better the outcome especially in paroxysmal AF population.Prisma study selection flow diagramCorrelation between DAT-AF recurrence

Prediction of new-onset atrial fibrillation in patients with hypertrophic cardiomyopathy using plasma proteomics profiling.

Atrial fibrillation (AF) is the most common sustained arrhythmia among patients with hypertrophic cardiomyopathy (HCM), increasing symptom burden and stroke risk. We aimed to construct a plasma proteomics-based model to predict new-onset AF in patients with HCM and determine dysregulated signalling pathways. In this prospective, multi-centre cohort study, we conducted plasma proteomics profiling of 4986 proteins at enrolment. We developed a proteomics-based machine learning model to predict new-onset AF using samples from one institution (training set) and tested its predictive ability using independent samples from another institution (test set). We performed a survival analysis to compare the risk of new-onset AF among high- and low-risk groups in the test set. We performed pathway analysis of proteins significantly (univariable P < 0.05) associated with new-onset AF using a false discovery rate (FDR) threshold of 0.001. The study included 284 patients with HCM (training set: 193, test set: 91). Thirty-seven (13%) patients developed AF during median follow-up of 3.2 years [25-75 percentile: 1.8-5.2]. Using the proteomics-based prediction model developed in the training set, the area under the receiver operating characteristic curve was 0.89 (95% confidence interval 0.78-0.99) in the test set. In the test set, patients categorized as high risk had a higher rate of developing new-onset AF (log-rank P = 0.002). The Ras-MAPK pathway was dysregulated in patients who developed incident AF during follow-up (FDR < 1.0 × 10-6). This is the first study to demonstrate the ability of plasma proteomics to predict new-onset AF in HCM and identify dysregulated signalling pathways.

Activation of IP3R in atrial cardiomyocytes leads to generation of cytosolic cAMP.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Excessive stimulation of the inositol (1,4,5)-trisphosphate (IP3) signaling pathway has been linked to AF through abnormal calcium handling. However, little is known about the mechanisms involved in this process. We expressed the fluorescence resonance energy transfer (FRET)-based cytosolic cyclic adenosine monophosphate (cAMP) sensor EPAC-SH187 in neonatal rat atrial myocytes (NRAMs) and neonatal rat ventricular myocytes (NRVMs). In NRAMs, the addition of the α1-agonist, phenylephrine (PE, 3 µM), resulted in a FRET change of 21.20 ± 7.43%, and the addition of membrane-permeant IP3 derivative 2,3,6-tri-O-butyryl-myo-IP3(1,4,5)-hexakis(acetoxymethyl)ester (IP3-AM, 20 μM) resulted in a peak of 20.31 ± 6.74%. These FRET changes imply an increase in cAMP. Prior application of IP3 receptor (IP3R) inhibitors 2-aminoethyl diphenylborinate (2-APB, 2.5 μM) or Xestospongin-C (0.3 μM) significantly inhibited the change in FRET in NRAMs in response to PE. Xestospongin-C (0.3 μM) significantly inhibited the change in FRET in NRAMs in response to IP3-AM. The FRET change in response to PE in NRVMs was not inhibited by 2-APB or Xestospongin-C. Finally, the localization of cAMP signals was tested by expressing the FRET-based cAMP sensor, AKAP79-CUTie, which targets the intracellular surface of the plasmalemma. We found in NRAMs that PE led to FRET change corresponding to an increase in cAMP that was inhibited by 2-APB and Xestospongin-C. These data support further investigation of the proarrhythmic nature and components of IP3-induced cAMP signaling to identify potential pharmacological targets.NEW & NOTEWORTHY This study shows that indirect activation of the IP3 pathway in atrial myocytes using phenylephrine and direct activation using IP3-AM leads to an increase in cAMP and is in part localized to the cell membrane. These changes can be pharmacologically inhibited using IP3R inhibitors. However, the cAMP rise in ventricular myocytes is independent of IP3R calcium release. Our data support further investigation into the proarrhythmic nature of IP3-induced cAMP signaling.

Association of Atrial Fibrillation and Cognitive Dysfunction: A Comprehensive Narrative Review of Current Understanding and Recent Updates.

Atrial fibrillation (AF) is the most common sustained arrhythmia in adults. The prevalence of both AF and dementia is steadily rising and is expected to rise further in the coming decades. There is increasing evidence to suggest an association between AF and various degrees of cognitive dysfunction, from mild cognitive impairment to severe dementia. In this review, we aimed to discuss the epidemiological aspects, pathophysiological mechanisms, role of neuroimaging, impact of treatment modalities, and clinical and socioeconomic impact of this association. Numerous observational studies and meta-analyses have revealed this association to exist in AF patients with and without a history of stroke, and the association also persists after adjusting for shared risk factors such as hypertension and diabetes mellitus. Various pathophysiological mechanisms have been proposed for this association, including silent cerebral infarcts, cerebral microbleeds, cerebral hypoperfusion, inflammation, and atherosclerosis. While neuroimaging findings have been utilized to suggest some of these pathophysiological mechanisms, more studies are needed to further elucidate this and to determine the potential role of neuroimaging in altering anticoagulation and other treatment decisions. Anticoagulants have shown effectiveness in reducing the rate of cognitive decline in AF patients; however, their role in low-risk AF patients remains under investigation. Even though AF patients receiving catheter ablation may have post-operative cognitive dysfunction in the short term, long-term follow-up studies have shown an improvement in cognitive function following ablation. Cognitive decline in AF patients often occurs with greater functional decline and other psychosocial impairments such as depression and anxiety and future research on this association must incorporate aspects of social determinants of health and associated outcomes.

Thirty-day mortality risk in patients following radiofrequency and cryoballoon ablation for atrial fibrillation across the entire nation of Poland: An 8-year analysis from the National Health Fund of Poland.

Atrial fibrillation (AF) is the most common sustained arrhythmia, and catheter ablation (CA) is a primary therapeutic option. However, the 30-day all-cause mortality risk associated with CA for AF may be underestimated due to selection bias. Our study aimed to assess 30-day mortality in an unselected cohort of patients. Data from the National Health Fund-Poland covered over 99% of nationwide radiofrequency ablation (RF) or cryoballoon ablation for AF, with 100% recorded deaths. The study included consecutive CA procedures in adult patients between 2012 and 2019. Thirty-day mortality rates were calculated for each age group. A total of 31 214 CAs for AF were performed on 26 767 patients (34.8% female). Forty-four percent of patients had hypertension, 31.2% had coronary artery disease, 14.4% had heart failure, 11% had diabetes mellitus, 5.6% had malignant neoplasms, 2.7% had a previous myocardial infarction, 2.5% had a previous stroke, and 2.2% had kidney disease. Thirty-two deaths (0.1%) occurred within 30 days, with the highest mortality in the oldest age group (>80 years). Statistical analysis revealed higher incidences of kidney disease (p < 0.001) and heart failure (p = 0.001) in patients who died within 30 days. Mortality risk did not significantly differ between cryoballoon and RF ablation, as well as first and subsequent ablation for AF. The risk of death within 7 days postablation for AF was 1 in 2750 procedures, while the risk of death on the same day postablation was 1 in 6250 procedures. The 30-day mortality rate in a large, unselected AF ablation cohort, covering 99% of procedures in the country, is low except for the oldest patients. This factor should be taken into consideration when offering CA for AF.

BMP2 Diminishes Angiotensin II-Induced Atrial Fibrillation by Inhibiting NLRP3 Inflammasome Signaling in Atrial Fibroblasts.

Atrial fibrillation (AF) is the most common sustained arrhythmia to affect 1% of the global population and increases with age. Atrial fibrosis is a crucial substrate for promoting structural remodeling to cause atrial arrhythmogenesis. Bone morphogenic protein 2 (BMP2) has been reported to be involved in cardiac fibrogenesis. However, its role in modulating atrial fibrosis to affect AF development remains unknown. Our study aimed to investigate the expression of BMP2 under different AF conditions and the effect of BMP2 on the progression of atrial fibrosis using an angiotensin II (Ang II) rat model and an ex vivo cardiac fibroblast model. The qRT-PCR and Western blot assay showed increased BMP2 mRNA and protein levels in the atria of chronic AF patients and the right atria of a tachypacing rabbit model. In contrast, the levels of BMP2 receptor mRNA were comparable. The AF incidence of the Ang II rat was higher than that of a control rat, which was reduced by BMP2 treatment. Masson staining demonstrated an anti-fibrogenic impact on BMP2-subjected rat atria compared to only Ang II-treated rat atria. RNA-sequencing indicated the potential function of blocking NLRP3-associted inflammasome activation in BMP2-treated rat atrial tissues. In vitro, transfecting BMP2 shRNA into neonatal rat atrial fibroblasts upregulated the mRNA levels of NLRP3/Caspase-1/p20/ASC and the secretion of IL-1β and IL-6. In contrast, recombinant BMP2 protein attenuated the increased levels of the NLRP3 inflammasome pathway induced by Ang II. In summary, BMP2 opposes atrial fibrosis to alleviate AF susceptibility by inhibiting the activation of the inflammasome in atrial fibroblasts.

Tissue-resident memory T cells in epicardial adipose tissue comprise transcriptionally distinct subsets that are modulated in atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia and carries an increased risk of stroke and heart failure. Here we investigated how the immune infiltrate of human epicardial adipose tissue (EAT), which directly overlies the myocardium, contributes to AF. Flow cytometry analysis revealed an enrichment of tissue-resident memory T (TRM) cells in patients with AF. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell T cell receptor (TCR) sequencing identified two transcriptionally distinct CD8+ TRM cells that are modulated in AF. Spatial transcriptomic analysis of EAT and atrial tissue identified the border region between the tissues to be a region of intense inflammatory and fibrotic activity, and the addition of TRM populations to atrial cardiomyocytes demonstrated their ability to differentially alter calcium flux as well as activate inflammatory and apoptotic signaling pathways. This study identified EAT as a reservoir of TRM cells that can directly modulate vulnerability to cardiac arrhythmia.

Spectrum of Non-Obstructive Coronary Artery Disease and Its Relationship with Atrial Fibrillation.

This article aims to analyze the relationship between non-obstructive coronary artery disease (NOCAD) and atrial fibrillation (AF), exploring the underlying pathophysiological mechanisms and implications for clinical management. NOCAD and AF are prevalent cardiovascular conditions that often coexist, yet their interrelation is not well understood. NOCAD can lead to ischemic necrosis of cardiomyocytes and their replacement with fibrous tissue, sustaining focal ectopic activity in atrial myocardium. Atrial fibrillation, on the other hand, the most common sustained cardiac arrhythmia, is able to accelerate atherosclerosis and increase oxygen consumption in the myocardium, creating a mismatch between supply and demand, and thus promoting the development or worsening of coronary ischemia. Therefore, NOCAD and AF seem to be a complex interplay with one begets another.

Convergent ablation for persistent atrial fibrillation: A UK multicentre perspective.

Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide and remains a major cause of morbidity and mortality. Unfortunately, a significant proportion of patients have persistent AF, for which conventional catheter ablation is less effective. However, convergent ablation has emerged in recent years as a hybrid treatment targeting both the epicardium and endocardium in a multidisciplinary joint cardiothoracic and electrophysiology procedure, with promising efficacy outcomes in recent studies. This treatment is increasingly being performed in the United Kingdom. This review article discusses the rationale and evidence behind convergent ablation, along with factors that need to be considered when setting up a successful ablation service.

Multidisciplinary Approach in Atrial Fibrillation: As Good as Gold.

Atrial fibrillation (AF) represents the most common sustained arrhythmia necessitating dual focus: acute complication management and sustained longitudinal oversight to modulate disease progression and ensure comprehensive patient care over time. AF is a multifaceted disorder; due to such a great number of potential exacerbating conditions, a multidisciplinary team (MDT) should manage AF patients by cooperating with a cardiologist. Effective management of AF patients necessitates the implementation of a well-coordinated and tailored care pathway aimed at delivering optimized treatment through collaboration among various healthcare professionals. Management of AF should be carefully evaluated and mutually agreed upon in consultation with healthcare providers. It is crucial to recognize that treatment may evolve due to the emergence of new risk factors, symptoms, disease progression, and advancements in treatment modalities. In the context of multidisciplinary AF teams, a coordinated approach involves assembling a diverse team tailored to meet individual patients' unique needs based on local services' availability.

Abstract Mo055: CHD4 Interacts With TBX5 to Maintain the Gene Regulatory Network of Postnatal Atrial Cardiomyocytes

Atrial fibrillation (AF) is the most common sustained arrhythmia in humans, leading to increased mortality due to increased incidence of stroke and heart failure. Over 200 genes are associated with AF by GWAS studies, suggesting a nuanced gene regulatory network (GRN) is required to maintain atrial cardiomyocyte (aCM) function and rhythm. Among these genes is the transcription factor TBX5, which we and others have shown is a master regulator of aCM identity that is essential for atrial rhythm homeostasis. We showed that TBX5 is required to maintain the chromatin looping, accessibility, and activity of atrial enhancers. Chromodomain helicase DNA binding protein 4 (CHD4), a chromatin remodeling protein that interacts with TBX5, is canonically thought to repress transcription as a component of the NuRD complex. Here, we investigated the contribution of CHD4 to TBX5 regulation of aCM gene expression. Methods: We inactivated CHD4 specifically within atrial cardiomyocytes using Cre recombinase driven by the aCM-specific Nppa promoter delivered postnatally with AAV9. Atrial remodeling, transcriptomic changes and AF susceptibility were examined. Results: We show that inactivating CHD4 in postnatal aCMs resulted in fibrotic atrial remodeling, spontaneous AF in a subset of mice, and increased AF susceptibility and burden after electrical pacing. Transcriptomic profiling of CHD4 aCM KO atria revealed gene expression changes that were highly correlated to altered gene expression downstream of TBX5 inactivation. Mechanistically, we show TBX5 recruits CHD4 to 33,170 genomic regions that are important for aCM gene regulation, whose expression is concordantly regulated downstream of TBX5 and CHD4. Together, these data reveal that CHD4 is required by TBX5 to promote accessibility of enhancers and activate many TBX5 target genes to maintain atrial rhythm.

Leveraging 3D Atrial Geometry for the Evaluation of Atrial Fibrillation: A Comprehensive Review.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia associated with significant morbidity and mortality. Managing risk of stroke and AF burden are pillars of AF management. Atrial geometry has long been recognized as a useful measure in achieving these goals. However, traditional diagnostic approaches often overlook the complex spatial dynamics of the atria. This review explores the emerging role of three-dimensional (3D) atrial geometry in the evaluation and management of AF. Advancements in imaging technologies and computational modeling have enabled detailed reconstructions of atrial anatomy, providing insights into the pathophysiology of AF that were previously unattainable. We examine current methodologies for interpreting 3D atrial data, including qualitative, basic quantitative, global quantitative, and statistical shape modeling approaches. We discuss their integration into clinical practice, highlighting potential benefits such as personalized treatment strategies, improved outcome prediction, and informed treatment approaches. Additionally, we discuss the challenges and limitations associated with current approaches, including technical constraints and variable interpretations, and propose future directions for research and clinical applications. This comprehensive review underscores the transformative potential of leveraging 3D atrial geometry in the evaluation and management of AF, advocating for its broader adoption in clinical practice.

Genetic aspects associated with increased risk of developing atrial fibrillation

Abstract Atrial Fibrillation (AF) is the most common sustained arrhythmia in clinical practice with increasing prevalence and association with increased morbidity and mortality. Studies have suggested a greater contribution of the genetic factor to the etiopathogenesis of arrhythmia, which could indicate up to 40% more risk for the individual who has a family member with the arrhythmia, and later in the form of single nucleotide polymorphisms (SNPs). Objective To verify the association of polymorphisms in the PITX2, HCN4, CAV1 and KCNN3 genes with the occurrence of AF. Method The study is cross-sectional with group comparison, prospective with a quantitative approach. 505 randomly selected subjects were included (357 cases and 148 controls). The real-time PCR methodology was used, using the TAQMAN® system (Thermo scientific, CA, USA). Result The sample was matched by sex and age. The most common type of AF was permanent (69%) followed by paroxysmal (23%). When comparing the groups selected for CAV1, statistical significance was found for AA vs AG genotypes (p 0.003; OR= 2.2; CI 1.29-3.7). For the HCN4 gene allele and genotypes A vs G (p 0.024; OR= 0.66; CI 0.47-0.9) and AA vs AG (p 0.014, OR= 0.57; CI 0.37-0.88), respectively. Regarding the comparison of the dominant and recessive genetic model of each gene, the following models/genes presented statistical significance: in the genotypic model of the CAV1 gene (AA vs AG vs GG) p 0.013, as well as the same model applied to the HCN4 gene (AA vs AG vs GG) (p 0.03); when comparing the dominant models, the HCN4 gene (AA vs AG/GG) presented (p 0.01; OR=0.58; 95% CI 0.38 – 0.88), with the recessive model of the CAV1 gene (AA vs AG/GG) with (p 0.008; OR=2.0; 95% CI: 1.19 – 3.34). Regarding allelic associations between the two groups, a greater chance of susceptibility to developing AF was observed in patients who had the "G" allele (25.6%; p 0.024; OR= 0.66, CI 0.47-0.9) in the HCN4 gene polymorphism. Polymorphisms in the CAV1 (rs3807989) and HCN4 (rs7164883) genes were also included in the multivariate analysis with maintenance of the risk factor for AF. However, only HCN4 rs7164883 showed statistical significan, thus showing it to be an independent variable regarding the probability of the patient with this polymorphism presenting AF. The present study showed a significant association with a greater chance of susceptibility to developing atrial fibrillation in patients with a polymorphism in the CAV1 gene (rs3807989) in a univariate and multivariate model and for patients with the HCN4 gene SNP (rs7164883). Conclusion Therefore, the results revealed an association between the HCN4 gene polymorphism rs7164883 and susceptibility to the development of AF, suggesting that the presence of the G allele may be one of the genetic factors related to the arrhythmia. The CAV1 rs3807989 gene polymorphism also seemed to suggest a risk for the development of AF, also relating the G allele.

Atrial Fibrillation, Atrial Myopathy, and Thromboembolism: The Additive Value of Echocardiography and Possible New Horizons for Risk Stratification.

Atrial fibrillation (AF) is the most common cardiac sustained arrhythmia, and it is associated with increased stroke and dementia risk. While the established paradigm attributes these complications to blood stasis within the atria and subsequent thrombus formation with cerebral embolization, recent evidence suggests that atrial myopathy (AM) may play a key role. AM is characterized by structural and functional abnormalities of the atria, and can occur with or without AF. Moving beyond classifications based solely on episode duration, the 4S-AF characterization has offered a more comprehensive approach, incorporating patient's stroke risk, symptom severity, AF burden, and substrate assessment (including AM) for tailored treatment decisions. The "ABC" pathway emphasizes anticoagulation, symptom control, and cardiovascular risk modification and emerging evidence suggests broader benefits of early rhythm control strategies, potentially reducing stroke and dementia risk and improving clinical outcomes. However, a better integration of AM assessment into the current framework holds promise for further personalizing AF management and optimizing patient outcomes. This review explores the emerging concept of AM and its potential role as a risk factor for stroke and dementia and in AF patients' management strategies, highlighting the limitations of current risk stratification methods, like the CHA2DS2-VASc score. Echocardiography, particularly left atrial (LA) strain analysis, has shown to be a promising non-invasive tool for AM evaluation and recent studies suggest that LA strain analysis may be a more sensitive risk stratifier for thromboembolic events than AF itself, with some studies showing a stronger association between LA strain and thromboembolic events compared to traditional risk factors. Integrating it into routine clinical practice could improve patient management and targeted therapies for AF and potentially other thromboembolic events. Future studies are needed to explore the efficacy and safety of anticoagulation in AM patients with and without AF and to refine the diagnostic criteria for AM.