Atrial Fibrillation Phenotype Research Articles

Predictors of quality of life improvement in patients undergoing catheter ablation for atrial fibrillation: a cluster-based analysis

Abstract Introduction Traditional classification of Atrial Fibrillation (AF) based on temporal patterns doesn't fully encompass the condition's complexity. Unsupervised cluster analyses have been used for classifying patients into groups with similar comorbid profiles. However, inconsistent comorbidity patterns have been found across different cohorts. Bayesian profile regression, a semi-supervised machine learning technique, may improve the precision of clustering by integrating outcome data, diminishing the variability observed with previous methods. Since quality of life (QoL) primarily drives the indication for AF ablation, we utilized the AF Effect on QualiTy-of-Life (AFEQT) questionnaire to cluster patients. Purpose Our aim is to use patient-reported outcome measures to identify clinically relevant phenotypes of AF that benefit the most from catheter ablation. Methods We implemented a single center follow-up (FUP) program for patients with AF referred for ablation since august 2020, including scheduled visits and remote monitoring through a digital health platform. AFEQT score reported by patients was analyzed using a non-linear mixed model and change in AFEQT by month 12 was used as outcome. Comorbidities, echocardiographic data, and biomarkers were collected. Profile regression mixture modelling guided by QoL improvement was performed to create clinically relevant patient groupings. Penalized multinomial logistic regression model was used for validation. Results From the 466 ablations performed, 354 patients were enrolled until July 2023. 211 patients had FUP > 12 months (age 59±10 years, 31% female, 80% paroxysmal). The overall AFEQT questionnaire completeness rate was 72%. Patients were classified into 3 clusters: 1) patients with long duration AF, left heart cavities enlargement and diastolic dysfunction (n=57); 2) patients with self-reported anxiety/depression (n=50); and 3) patients with low rates of comorbidities (n=104). For clinical application, 8 variables (dyslipidemia, AF type and duration since diagnosis, mitral E/A ratio, systolic pulmonary arterial pressure, left ventricle ejection fraction, and PROMIS T-score for anxiety and depression) were sufficient for classifying patients (85% accuracy in internal cross-validation). Patients with higher depressive and anxiety burden (cluster 2) had worse baseline AFEQT score (median: 46, IQR: 39-60) and derived less benefit (median improvement: 21, IQR: 12-32), while patients with low comorbid burden (cluster 3) displayed higher baseline (median: 58, IQR: 48-62) and final QoL (median improvement: 28, IQR: 21-36, p<0.01). Conclusion Our analysis identified 3 reproducible clinically relevant phenotypes of AF using widely available clinical data. These clusters have distinct associations with QoL, underscoring the heterogeneity of AF and importance of comorbidities and substrates. This approach may allow for the prediction of which patients are most likely to benefit from treatment.

URIC ACID SIGNIFICANTLY CORRELATES WITH THE PRESENCE OF LOW–VOLTAGE AREAS AT THE ENDOCARDIAL MAPPING IN PATIENTS WITH NON–VALVULAR ATRIAL FIBRILLATION

Abstract Background Interest in the role of atrial substrate in maintaining Atrial Fibrillation (AF) is growing. Fibrosis is the culprit in the electrical derangement of the myocites. Many cardiovascular risk factors are known to be linked to atrial scarring; among them Uric Acid (UA) is emerging. The purpose of our study is to evaluate whether UA is associated with atrial fibrosis in AF patients. Methods 81 patients who underwent radiofrequency transcatheter ablation for nonvalvular AF at the cardiological department of the Niguarda Hospital were enrolled. UA levels were analysed before the procedure as well as known predictors of atrial fibrosis. High density electroanatomic mapping of the left atrium was performed and patients were divided according to the presence or not of areas of pathological substrate (bipolar voltage < 0.5mV in sinus rhythm). Results 19 patients showed a pathological atrial substrate. The population of patients with pathological atrial substrate was older (64.7±1.6 vs 58.2±10.9 years, p=0.032) and had more often a persistent phenotype of AF (84.3 vs 35.8%, p<0.001). UA levels were significantly higher in the pathological group (6.8±1.9 vs 5.3±1.4, p<0.001) as well as the prevalence of hyperuricemia (26.5 vs 6.5%, p=0.021). The association between uric acid and pathological atrial substrate remains significant even after correction for confounding factors (age, left ventricular dysfunction, valvular disease, AF phenotype and furosemide use). Conclusions In a population of patients who underwent atrial fibrillation’s ablation, higher uric acid’s levels were significantly associated with pathological left atrium’s substrate at electro–anatomical mapping.

Impact of atrial fibrillation phenotype and left atrial volume on outcome after pulmonary vein isolation.

Pulmonary vein isolation (PVI) is increasingly performed in patients with atrial fibrillation (AF). Both AF phenotype and left atrial (LA) volume have been shown to influence ablation outcome. The inter-relationship of the two is incompletely understood. We aimed to investigate the impact of AF phenotype vs. LA volume on outcome after PVI. In a retrospective analysis of a prospective registry of patients undergoing a first PVI, the association of AF phenotype and LA volume index (LAVI) was assessed as well as their impact on AF recurrence during follow-up. Overall, 476 patients were enrolled (median age 63 years, 29% females, 65.8% paroxysmal AF). Obesity, hypertension, chronic kidney disease, and heart failure were all significantly more frequent in persistent AF. After 1 year, single-procedure, freedom from arrhythmia recurrence was 61.5%. Patients with paroxysmal AF had better outcomes compared with patients with persistent AF (65.6 vs. 52.7%, P = 0.003), as had patients with no/mild vs. moderate/severe LA dilation (LAVI <42 mL/m2 67.1% vs. LAVI ≥42 mL/m2 53%, P < 0.001). The combination of both parameters refined prediction of 1-year recurrence (P < 0.001). After adjustment for additional clinical risk factors in multivariable Cox proportional hazard analysis, both AF phenotype and LAVI ≥42 mL/m2 contributed significantly towards the prediction of 1-year recurrence. Atrial fibrillation phenotype and LA volume are independent predictors of outcome after PVI. Persistent AF with no/mild LA dilation has a similar risk of recurrence as paroxysmal AF with a moderate/severe LA dilation and should be given similar priority for ablation.

A Comparison of the Impact of Pharmacological Treatments on Cardioversion, Rate Control, and Mortality in Data-Driven Atrial Fibrillation Phenotypes in Critical Care.

Critical care physicians are commonly faced with patients exhibiting atrial fibrillation (AF), a cardiac arrhythmia with multifaceted origins. Recent investigations shed light on the heterogeneity among AF patients by uncovering unique AF phenotypes, characterized by differing treatment strategies and clinical outcomes. In this retrospective study encompassing 9401 AF patients in an intensive care cohort, we sought to identify differences in average treatment effects (ATEs) across different patient groups. We extract data from the MIMIC-III database, use hierarchical agglomerative clustering to identify patients' phenotypes, and assign them to treatment groups based on their initial drug administration during AF episodes. The treatment options examined included beta blockers (BBs), potassium channel blockers (PCBs), calcium channel blockers (CCBs), and magnesium sulfate (MgS). Utilizing multiple imputation and inverse probability of treatment weighting, we estimate ATEs related to rhythm control, rate control, and mortality, approximated as hourly and daily rates (%/h, %/d). Our analysis unveiled four distinctive AF phenotypes: (1) postoperative hypertensive, (2) non-cardiovascular mutlimorbid, (3) cardiovascular multimorbid, and (4) valvulopathy atrial dilation. PCBs showed the highest cardioversion rates across phenotypes, ranging from 11.6%/h (9.35-13.3) to 7.69%/h (5.80-9.22). While CCBs demonstrated the highest effectiveness in controlling ventricular rates within the overall patient cohort, PCBs and MgS outperformed them in specific phenotypes. PCBs exhibited the most favorable mortality outcomes overall, except for the non-cardiovascular multimorbid cluster, where BBs displayed a lower mortality rate of 1.33%/d [1.04-1.93] compared to PCBs' 1.68%/d [1.10-2.24]. The results of this study underscore the significant diversity in ATEs among individuals with AF and suggest that phenotype-based classification could be a valuable tool for physicians, providing personalized insights to inform clinical decision making.

Pulmonary Vein Isolation in Elderly Patients ≥ 75 Years: A Propensity Score-Matched Analysis With Focus on Differences Among Atrial Fibrillation Types

BackgroundAge is a major risk factor for development of atrial fibrillation (AF) and associated with increased recurrence rates in the setting of rhythm control. Current data tend to support catheter ablation in elderly patients, but uncertainties exist regarding efficacy and safety of ablation in elderly patients. MethodsThis was a prospective single-centre observational study with propensity score matching (PSM) to investigate the influence of age on efficacy and safety of cryoballoon ablation (CBA) stratified by age (< 75 years vs ≥ 75 years) and AF phenotype (paroxysmal vs persistent). Primary efficacy endpoint was recurrence of atrial arrhythmia after a 90-day blanking period. Safety endpoints were death, stroke, or procedure-associated complications. ResultsConsecutive patients (n = 953) underwent CBA for first-time AF ablation. Median follow-up was 18 months. By means of PSM, 268 matches were formed. At 1 year, primary efficacy endpoint occurred in 22.4% of young vs 33.2% of elderly patients, including both AF phenotypes (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.47-0.90; P = 0.01). AF relapse occurred in 19.7% of young vs 28.5% of elderly patients with paroxysmal (HR, 0.63; 95% CI, 0.40-0.99; P = 0.046) compared with 25.9% (30 of 116, young) vs 38.8% (45 of 116, elderly) patients with persistent AF (HR, 0.62; 95% CI, 0.39-0.97; P = 0.038). No difference was observed regarding the incidence of safety endpoints between young and elderly patients (P = 0.38). ConclusionsCBA is associated with higher recurrence rates in elderly (≥ 75 years) than in younger patients, with highest recurrence rates in elderly patients with persistent AF.

Oxidative Stress, Inflammation, and Mitochondrial Dysfunction: A Link between Obesity and Atrial Fibrillation.

The adipose tissue has long been thought to represent a passive source of triglycerides and fatty acids. However, extensive data have demonstrated that the adipose tissue is also a major endocrine organ that directly or indirectly affects the physiological functions of almost all cell types. Obesity is recognized as a risk factor for multiple systemic conditions, including metabolic syndrome, type 2 diabetes mellitus, sleep apnea, cardiovascular disorders, and many others. Obesity-related changes in the adipose tissue induce functional and structural changes in cardiac myocytes, promoting a wide range of cardiovascular disorders, including atrial fibrillation (AF). Due to the wealth of epidemiologic data linking AF to obesity, the mechanisms underlying AF occurrence in obese patients are an area of rich ongoing investigation. However, progress has been somewhat slowed by the complex phenotypes of both obesity and AF. The triad inflammation, oxidative stress, and mitochondrial dysfunction are critical for AF pathogenesis in the setting of obesity via multiple structural and functional proarrhythmic changes at the level of the atria. The aim of this paper is to provide a comprehensive view of the close relationship between obesity-induced oxidative stress, inflammation, and mitochondrial dysfunction and the pathogenesis of AF. The clinical implications of these mechanistic insights are also discussed.

Current management of atrial fibrillation in routine practice according to the last ESC guidelines: an EHRA physician survey-how are we dealing with controversial approaches?

Although guidelines for the management of atrial fibrillation (AF) are regularly published, many controversial issues remain, limiting their implementation. We aim to describe current clinical practice among European Heart Rhythm Association (EHRA) community according to last guidelines. A 30 multiple-choice questionnaire covering the most controversial topics related to AF management was distributed through the EHRA Research Network, National Societies, and social media between January and February 2023. One hundred and eighty-one physicians responded the survey, 61% from university hospitals. Atrial fibrillation screening in high-risk patients is regularly performed by 57%. Only 42% has access to at least one programme aiming at diagnosing/managing comorbidities and lifestyle modifications, with marked heterogeneity between countries. Direct oral anticoagulants are the preferred antithrombotic (97%). Rhythm control is the preferred strategy in most AF phenotypes: symptomatic vs. asymptomatic paroxysmal AF (97% vs. 77%), low vs. high risk for recurrence persistent AF (90% vs. 72%), and permanent AF (20%). I-C drugs and amiodarone are preferred while dronedarone and sotalol barely used. Ablation is the first-line therapy for symptomatic paroxysmal AF (69%) and persistent AF with markers of atrial disease (57%) and is performed independently of symptoms by 15%. In persistent AF, 68% performs only pulmonary vein isolation and 32% also additional lesions. There is marked heterogeneity in AF management and limited accordance to last guidelines in the EHRA community. Most of the discrepancies are related to the main controversial issues, such as those related to AF screening, management of comorbidities, pharmacological treatment, and ablation strategy.

AF in the AFternoon: The circadian pattern of incident atrial fibrillation in a loop recorder population

Abstract Introduction Loop recorders have provided the opportunity to systematically screen individuals for arrhythmias, and in doing so provide new appreciated mechanistic insights to arrhythmia pathophysiology. Atrial fibrillation (AF) is a complex arrhythmia with a multitude of precipitants and substrates. Previous studies looking at the circadian rhythm of AF, have required patient symptoms to define onset. All studies on the circadian rhythm of AF suggest that AF does not occur randomly. It has been suggested that the circadian variation in autonomic function may provide an underlying substrate for AF initiation. This is the largest study to utilise loop recorder detected AF to explore the circadian pattern of AF. Purpose We sought to ascertain how the detection of incident AF varied throughout the day, in patients monitored with a loop recorder Methods This was a single-centre retrospective observational study. Consecutive adult patients referred for ILR implantation between March 2009 and November 2019, without prevalent AF or atrial flutter, were included. Demographic and anthropometric data was identified from the individuals medical notes. The time of incident AF episodes was identified from loop recorder reports. Results A total of 1168 AF episodes of any duration were identified by the ILR, of which onset time was available for 1118 episodes. Onset of AF episodes in our data for the entire population demonstrated a monophasic distribution (figure 1a). The OR for developing AF between 13.00-14.59 compared to 03.00-04.59 was 4.89 (95% CI 3.47-6.90). Amongst the ESUS population time of onset distribution showed multiple daytime peaks (figure 1b). The OR for developing AF between 10.00-11.59 compared to 03.00-04.59 was 4.39 (95% CI 2.68-7.20). Amongst the non- ESUS population time of onset distribution (figure 1c) shows a monophasic pattern with the peak at time blocks 12.00-14.59. The OR for developing AF between 13.00-14.59 compared to 02.00-03.59 was 6.75 (95% CI 4.17-10.93). Conclusion(s) Our study demonstrated that there is a diurnal variation for incident AF detection using a loop recorder. There is a general propensity for episodes to occur in the afternoon, with a nadir at night. This is in contrast to previous reports which have suggested that the nocturnal and morning peaks are more apparent. Moreover, different cohorts appear to show different temporal patterns, with ESUS patients having multiple time peaks, whereas the non-stroke cohort had a solitary peak period. Understanding the diurnal variation of AF may help to shed more light on the complex pathogenesis of AF, and whether different AF phenotypes are associated with stroke risk. Moreover, the finding of a day-time propensity for AF, adds weight to the utilisation of consumer facing non-invasive monitoring tools during the day for AF identification in high-risk populations.

Abstract 15636: NFATC1 Modulates Atrial Excitability and Arrhythmogenesis

Transcription factors have emerged as important loci for atrial fibrillation (AF) susceptibility. We identified a novel mutation (M527L) in a conserved site of the transcription factor NFATC1 in a multigenerational family with an autosomal dominant young onset AF (&lt;40 years old) phenotype. M527L reduces NFATC1 nuclear translocation (nuclear/total cellular ratio: M527L 0.50±0.02; WT 0.64±0.04, p&lt;1E-5; n=10/each), DNA binding (M527L 0.69±0.02; WT 0.83±0.01, p=0.02; n=3/ each), and transcriptional activity (M527L 0.0003±0.00005; WT 0.0009±0.0002, p=0.01; n=5/each) in expression systems, underscoring the functional consequences of this mutation. To study the broader role of NFATC1 in atrial excitability we employed a CRISPR/Cas9 strategy to create an nfatc1 null (KO) zebrafish. KO fish exhibited reduced survival, with ~80% of juvenile fish succumbing to sudden death (log rank test p=0.0001), with no observable change in body or heart gross morphology. Explanted juvenile atria displayed spontaneous tachyarrhythmias or irregular rhythm (29 /40 KO atria vs 11/28 WT atria; Chi-Squared, p=0.0013) accompanied by irregular Ca 2+ handling (10/11 KO atria vs 5/16 WT atria). Furthermore, we found an abbreviated action potential duration in KO atrium (80±1 ms in KO (n=607) vs 91±1 ms in WT (n=441), p=0.0001), but not ventricle (186±3 ms in KO (n=109) vs 191±2 ms in WT (n=160), p=0.8). Taken together, our data suggests that NFATC1 is a modulator of atrial excitability and plays a role in AF susceptibility. Experiments are ongoing to further define the mechanisms underlying arrhythmia susceptibility and to identify the gene networks downstream of NFATC1 in the atria.

Abstract 14079: Inhibition of NOX2 Prevents Obesity-Mediated Atrial Fibrillation

Introduction: Obesity is an independent risk factor for atrial fibrillation (AF). While oxidative stress plays an important role in obesity-mediated AF, the specific pathways that cause atrial remodeling remain unclear. NADPH oxidase 2 (NOX2), a major source of cytosolic reactive oxygen species (ROS) production in the heart, is increased in diet-induced obese (DIO) mice and can independently predispose to post-operative AF via atrial remodeling. Hypothesis: We used a Nox2 -knock-out (KO) mouse model and mature human iPSC-derived atrial cardiomyocytes (hiPSC-aCMs) to test the hypothesis that NOX2 increase modulates ion channel remodeling in obesity-mediated AF. Methods: DIO mice and palmitic acid (PA)-treated hiPSC-aCMs were given a NOX blocker (apocynin), and GSK2793059, a NOX2-specific small molecule inhibitor respectively. Trans-esophageal rapid (TE) pacing was used to examine changes to the AF phenotype. Whole-cell patch clamping, qPCR, Western blotting, and electrical mapping were performed to study ion channel remodeling in both models. Results: DIO, DIO-Apocynin, and DIO Nox2 -KO mice displayed increased weight compared to control and Nox2 -KO mice (Figure A). After TE pacing, DIO-Apocynin mice displayed 28.2 ± 25.4 s and DIO Nox2 -KO mice displayed 17.4 ± 31.8 s compared to 167.3 ± 168.9 s in DIO mice (Figure B). Electrophysiological studies show that Nox2 inhibition reverses ion channel remodeling in I Na , I Ks , and I Ca,L (Figure D-F), and atrial fibrosis (Figure H) and prolongs the atrial action potential (AP; Figure C) and increases conduction velocity (CV; Figure G-I) in both DIO mice (Figure C-I) and PA-hiPSC-aCMs (Figure J-L). Conclusions: Collectively, genetic and pharmacological inhibition of NOX2 in DIO mice and PA-treated hiPSC-aCMs abrogate ion channel and structural remodeling and prevents the development of obesity-mediated AF. These findings have important implications for targeted antioxidant therapy for obese patients with AF.

Plasma myeloperoxidase: association with atrial fibrillation progression and recurrence after catheter ablation.

Myeloperoxidase (MPO), released by activated neutrophils, is significantly increased in atrial fibrillation (AF). MPO may play a role in the progression of atrial fibrillation and further involved in AF recurrence after catheter ablation. We compared plasma MPO levels in paroxysmal and persistent AF and explored their role in AF recurrence after catheter ablation. Plasma MPO levels were measured in consecutive patients with paroxysmal AF (n = 225) and persistent AF (n = 106). Samples of patients were collected from the femoral vein during catheter ablation and all patients included were followed up after catheter ablation. Plasma MPO levels increased from paroxysmal AF to persistent AF patients (56.31 [40.33-73.51] vs. 64.11 [48.65-81.11] ng/ml, p < 0.001). MPO significantly correlated with left atrium volume (LAV) and there existed a significant interaction between the two in relation to AF recurrence (p for interaction <0.05). During a median follow-up of 14 months, 28 patients with paroxysmal AF (12.44%) and 27 patients with persistent AF (25.47%) presented with recurrence after catheter ablation. The percentage of recurrence increased stepwise with increasing tertiles of MPO levels in both paroxysmal AF and persistent AF. MPO levels remained independently associated with AF recurrence after adjusting for potential confounding variables. MPO levels were higher in persistent AF than in paroxysmal AF and MPO was positively correlated with LAV in AF. Elevated MPO levels may predispose a switch in AF phenotype and AF recurrence after catheter ablation.

Uric acid significantly correlates with the presence of low-voltage areas at the endocardial mapping in patients with non-valvular atrial fibrillation

Background and aimsInterest in the role of atrial substrate in maintaining Atrial Fibrillation (AF) is growing. Fibrosis is the culprit in the electrical derangement of the myocytes. Many cardiovascular risk factors are known to be linked to atrial scarring; among them Uric Acid (UA) is emerging. The purpose of our study is to find whether UA is associated with Left Atrium (LA) with pathological substrate. Methods and results81 patients who underwent radiofrequency transcatheter ablation for nonvalvular AF at the cardiological department of the Niguarda Hospital were enrolled in an observational, cross-sectional, single-center study. UA levels were analysed before the procedure. High density electroanatomic mapping of the LA was performed and patients were divided according to the presence or not of areas of pathological substrate (bipolar voltage <0.5 mV in sinus rhythm). 19 patients showed a LA with pathological substrate. These subjects showed a significant higher prevalence of persistent phenotype of AF (84.2 vs. 25.8%, p < 0.001). UA levels were significantly higher in the group of patients with LA with pathological substrate (6.8 ± 1.9 vs 5.3 ± 1.4 mg/dL, p < 0.001) as well as the prevalence of hyperuricemia (26.5 vs. 6.5%, p = 0.021). The association between uric acid LA with pathological substrate remains significant even after correction for confounding factors (age, left ventricular dysfunction, valvular disease, arrythmia phenotype and furosemide use) and also when the ratio UA/creatinine was evaluated. ConclusionsIn a population of patients who underwent AF ablation, higher UA levels were significantly associated with pathological LA substrate at electro-anatomical mapping.

PO-01-108 ELUCIDATING THE MECHANISM OF ATRIAL FIBRILLATION IN LAMIN A/C HEART DISEASE USING HUMAN IPSC-DERIVED ATRIAL CARDIOMYOCYTES

Mutations in the LMNA gene, encoding the nuclear envelope proteins lamin A/C, cause cardiac arrhythmias, conduction disease, and dilated cardiomyopathy. Malignant arrhythmias such as atrial fibrillation (AF) and ventricular tachycardia are common and pose an increased risk of stroke and sudden cardiac death. To investigate the etiological mechanisms by which a heterozygous pathogenic LMNA-S143P mutation causes early-onset AF using mature human iPSC-derived atrial cardiomyocytes (hiPSC-aCM) generated from a large kindred with a strong cardiac phenotype. Detailed phenotyping of a 4-generation family pedigree and generation of hiPSCs from the proband using a comprehensive approach for the differentiation of mature hiPSC-aCMs. Action potential duration was measured by optical voltage mapping. Calcium transients were measured by confocal microscopy. The proband (III-3) is a 42-year-old female of European and Asian descent who developed symptomatic early-onset AF at age 35. She underwent direct current cardioversion (DCCV), pulmonary vein isolation, and implantation of a biventricular pacemaker. Cardiac MRI showed an enlarged left atrium with preserved left ventricular systolic function (EF 56%). A detailed family history revealed early-onset AF and AV block, congestive heart failure (CHF), and sudden death (Fig. 1). Genetic testing of the proband revealed a pathogenic missense mutation in LMNA (c427T>Cp. Ser143Pro). Mature LMNA-S143P-hiPSC-aCMs displayed prolongation of the atrial action potential duration (APD90) with delayed afterdepolarizations, abnormal calcium transients, and AF as compared to wild-type hiPSC-aCMs. Detailed phenotyping of a large LMNA kindred revealed a phenotype of AF, cardiac conduction disease, dilated cardiomyopathy, and sudden death. Our hiPSC-aCM studies uncovered a triggered mechanism for the AF with ion channel remodeling and pave the way for targeting calcium handling proteins as a potential therapeutic strategy in LMNA associated arrhythmias.

Overview of programmed electrical stimulation to assess atrial fibrillation susceptibility in mice.

Atrial fibrillation (AF) is the most common human arrhythmia and is associated with increased risk of stroke, dementia, heart failure, and death. Among several animal models that have been used to investigate the molecular determinants of AF, mouse models have become the most prevalent due to low cost, ease of genetic manipulation, and similarity to human disease. Programmed electrical stimulation (PES) using intracardiac or transesophageal atrial pacing is used to induce AF as most mouse models do not develop spontaneous AF. However, there is a lack of standardized methodology resulting in numerous PES protocols in the literature that differ with respect to multiple parameters, including pacing protocol and duration, stimulus amplitude, pulse width, and even the definition of AF. Given this complexity, the selection of the appropriate atrial pacing protocol for a specific model has been arbitrary. Herein we review the development of intracardiac and transesophageal PES, including commonly used protocols, selected experimental models, and advantages and disadvantages of both techniques. We also emphasize detection of artifactual AF induction due to unintended parasympathetic stimulation, which should be excluded from results. We recommend that the optimal pacing protocol to elicit an AF phenotype should be individualized to the specific model of genetic or acquired risk factors, with an analysis using several definitions of AF as an endpoint.

Abstract 14496: NOX2 Inhibition Reverses Atrial Remodeling Caused by Increased Oxidative Stress and Reduces AF in Diet Induced Obese Mice

Introduction: Diet induced obese (DIO) mice display increased inducible atrial fibrillation (AF) and an overall increase in reactive oxygen species (ROS) production. NADPH oxidase 2 (NOX2), a major source of cytosolic ROS production in human atria, has been implicated in AF independent of obesity and is significantly increased in the atria of DIO mice. Although treatment with MitoTEMPO, a mitochondrial specific antioxidant reduced AF burden in DIO mice, the actual role of NOX2 in increasing ROS production and atrial remodeling in the context of obesity-induced AF remains unclear. Hypothesis: To test the hypothesis that increased NOX2 modulates atrial remodeling in obesity-induced AF, we used control mice, DIO and Nox2 -KO mice fed with a 60% HFD for 10 weeks (DIO-KO) and DIO mice treated with a NOX2 blocker, apocynin (DIO-Apocynin). Methods: Trans-esophageal rapid (TE) pacing was used to look at the AF phenotype. Cellular electrophysiology (EP), Western blotting, whole-cell patch clamping were performed to study ion channel remodeling and ROS production. Results: All three DIO mouse groups displayed significantly greater body weight compared to their respective controls (Figure A) After TE pacing, DIO-Apocynin mice displayed 28.26 ± 25.40 s and DIO-KO mice displayed 17.43 ± 31.80 s compared to 167.3 ± 168.9 s in DIO mice (Figure B). NOX2 inhibition reversed obesity-induced ion channel remodeling of potassium channels such as KCNQ1 and KCNE1 encoding for the IKs current and KCNA5 encoding for the IKur current and also reduced mediators of oxidative stress. (Figure C-M) Lastly, voltage clamp in DIO-KO mice showed that NOX2 inhibition reverses obesity-induced IK current increase. (Figure N-O) Conclusions: Thus, these results prove that antioxidant therapy targeting Nox2 abrogated ion channel remodeling and reversed the obesity-induced AF burden. Our findings show the importance of targeting specific antioxidant pathways to manage the AF in patients with obesity.

Atrial fibrillation prediction by combining ECG markers and CMR radiomics

Atrial fibrillation (AF) is the most common cardiac arrhythmia. It is associated with a higher risk of important adverse health outcomes such as stroke and death. AF is linked to distinct electro-anatomic alterations. The main tool for AF diagnosis is the Electrocardiogram (ECG). However, an ECG recorded at a single time point may not detect individuals with paroxysmal AF. In this study, we developed machine learning models for discrimination of prevalent AF using a combination of image-derived radiomics phenotypes and ECG features. Thus, we characterize the phenotypes of prevalent AF in terms of ECG and imaging alterations. Moreover, we explore sex-differential remodelling by building sex-specific models. Our integrative model including radiomics and ECG together resulted in a better performance than ECG alone, particularly in women. ECG had a lower performance in women than men (AUC: 0.77 vs 0.88, p < 0.05) but adding radiomics features, the accuracy of the model was able to improve significantly. The sensitivity also increased considerably in women by adding the radiomics (0.68 vs 0.79, p < 0.05) having a higher detection of AF events. Our findings provide novel insights into AF-related electro-anatomic remodelling and its variations by sex. The integrative radiomics-ECG model also presents a potential novel approach for earlier detection of AF.

A novel murine model of atrial fibrillation by diphtheria toxin-induced injury.

The treatment of atrial fibrillation (AF) continues to be a significant clinical challenge. While genome-wide association studies (GWAS) are beginning to identify AF susceptibility genes (Gudbjartsson et al., Nature, 2007, 448, 353-357; Choi et al., Circ. Res., 2020, 126, 200-209; van Ouwerkerk et al., Circ. Res., 2022, 127, 229-243), non-genetic risk factors including physical, chemical, and biological environments remain the major contributors to the development of AF. However, little is known regarding how non-genetic risk factors promote the pathogenesis of AF (Weiss et al., Heart Rhythm, 2016, 13, 1868-1877; Chakraborty et al., Heart Rhythm, 2020, 17, 1,398-1,404; Nattel et al., Circ. Res., 2020, 127, 51-72). This is, in part, due to the lack of a robust and reliable animal model induced by non-genetic factors. The currently available models using rapid pacing protocols fail to generate a stable AF phenotype in rodent models, often requiring additional genetic modifications that introduce potential sources of bias (Schüttler et al., Circ. Res., 2020, 127, 91-110). Here, we report a novel murine model of AF using an inducible and tissue-specific activation of diphtheria toxin (DT)-mediated cellular injury system. By the tissue-specific and inducible expression of human HB-EGF in atrial myocytes, we developed a reliable, robust and scalable murine model of AF that is triggered by a non-genetic inducer without the need for AF susceptibility gene mutations.

Human-induced pluripotent stem cell-atrial-specific cardiomyocytes and atrial fibrillation.

Patient-specific human-induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs) may be produced, genome-edited, and differentiated into multiple cell types for regenerative medicine, disease modeling, drug testing, toxicity screening, and three-dimensional tissue fabrication. There is presently no complete model of atrial fibrillation (AF) available for studying human pharmacological responses and evaluating the toxicity of potential medication candidates. It has been demonstrated that hiPSC-aCMs can replicate the electrophysiological disease phenotype and genotype of AF. The hiPSC-aCMs, however, are immature and do not reflect the maturity of aCMs in the native myocardium. Numerous laboratories utilize a variety of methodologies and procedures to improve and promote aCM maturation, including electrical stimulation, culture duration, biophysical signals, and changes in metabolic variables. This review covers the current methods being explored for use in the maturation of patient-specific hiPSC-aCMs and their application towards a personalized approach to the pharmacologic therapy of AF.

Alterations of gut viral signals in atrial fibrillation: complex linkage with gut bacteriome.

The gut microbiota has a known complex association with atrial fibrillation (AF) progression, but the association of gut viruses with AF is undefined. Metagenomic data in a cohort of 50 AF patients and 50 matched controls were examined to profile the gut viral signals and determine their associations with intestinal bacteria and the AF phenotype. The gut viral alterations were examined, and the marked elevation of viral diversity, including increased Simpson, Shannon, and Pielou index, was revealed in AF patients. The specific alteration of the intestinal viral population, such as overgrowth of Streptococcus virus DT1 and Pseudomonas phage, as well as imbalanced gut viral function, dominated by integral component of the membrane, and metal ion binding were detected in AF patients. Moreover, regarding co-occurrence networks connecting viruses and bacterial organisms, increasingly disordered virus-bacteria linkages were seen in AF cases with severe AF progression. Notably, the associations of Synechococcus phage S−SM1 and Cronobacter phage CR5 with bacterial species were very tight in control individuals but markedly dampened in AF cases. Furthermore, the viral score built by the selected discriminative taxa between AF cases with or without recurrence after ablation was still significantly associated with recurrence (HR = 2.959, P = 0.0085), with a survival AUC of 0.878. We demonstrated for the first time that gut viral signatures are associated with AF, and suppressed viral-bacterial associations in AF suggest the gut virus might participate in AF progression, which has a potential value in predicting ablation outcomes.

RNA‐seq‐driven expression analysis to investigate cardiovascular disease genes with associated phenotypes among atrial fibrillation patients

RNA‐seq‐driven expression analysis to investigate cardiovascular disease genes with associated phenotypes among atrial fibrillation patients