Substrate For Atrial Fibrillation Research Articles

PO-03-092 MACHINE LEARNING ANALYSIS OF THE PREDICTORS OF AF RECURRENCE POST-ABLATION IN PATIENTS UNDERGOING PRE-ABLATION MRI

Catheter ablation, a widely performed rhythm control strategy for atrial fibrillation (AF), has variable results in the complete suppression of arrhythmia recurrence, especially in obese patients. Structural remodeling of the left atrium (LA), evidenced by LA enlargement and fibrosis, is a well-known substrate for AF. Epicardial adipose tissue (EAT) is thought to be a crucial factor mediating cardiovascular disease in obesity, it can result in electrical heterogeneity and local conduction block forming a substrate for AF. We aimed to apply a machine learning approach to assess the predictors of AF recurrence following catheter ablation in AF patients undergoing pre-ablation cardiac magnetic resonance (CMR). 101 AF patients underwent CMR prior to catheter ablation. Fibrotic remodeling was assessed using the late gadolinium enhancement sequence. EAT was assessed using the novel fat-water separation 3D Dixon sequence. Panel A shows posterior and anterior views of a representative LA model showing fibrotic remodeling and EAT. Patients were followed for AF recurrence using ambulatory monitoring and 12-lead ECGs. A random forest classifier with 5x stratified cross-validation was trained to predict AF recurrence post-ablation and SHapley Additive exPlanations (SHAP) analysis was used to assess feature importance in the prediction of AF recurrence. During an average follow-up period of 1 year, post-ablation AF recurrence occurred in 31 (30.7%) patients. Patients with AF recurrence post-ablation had higher LA EAT index (20.7 [16.9, 30.4] vs 13.7 [10.5, 20.1] mL/m2, p<0.001), and higher LA volume index (66 [52.6, 77.5] vs 49.9 [37.7, 61.8] mL/m2, p=0.001). There was a trend toward a higher fibrosis burden in patients who had an AF recurrence (18.6% vs 16.1%, p=0.076). The classifier predicted AF recurrence post-ablation with an AUC of 0.67 ± 0.09 (Panel B). SHAP analysis revealed that for the overall population, the three most important features in the prediction of AF recurrence post-ablation were LA volume index, LA EAT index, and LA fibrosis (Panel C). LA enlargement, fibrosis and EAT, markers with clear ties to AF pathophysiology, are predictors of AF recurrence after ablation. Future studies testing the value of an imaging-based ablation failure prediction calculator, as well as studies to elucidate the mechanism of ablation failure, are required.

PO-01-151 DEGREE OF FIBROSIS REMODELING ALTERS ATRIAL FIBRILLATION INDUCIBILITY

Mechanistically, the role of remodeled substrate in atrial fibrillation (AF) inducibility is not well understood. Here we assess the changes in AF reentrant-drivers (RDs) based on different levels of fibrotic remodeling – as visualized by degree of enhancement in late gadolinium enhancement (LGE) MRI. We compare the inducibility of the native fibrotic substrates in patients undergoing first-time ablation (FtA) and in those of repeat ablation (ReA) and characterize the regions most involved in RD maintenance. To investigate how different levels of fibrotic remodeling (enhancement in LGE MRI) affect AF inducibility. Ten LGE MRIs were obtained from AF patients undergoing FtA (n=5) or ReA (n=5). Fibrotic tissue was differentiated using personalized image intensity ratio (IIR) threshold; for scar, we used IIR=1.61; and the IIR for dense fibrosis was the midpoint between the two (Fig. 1B). For each patient, two personalized bi-atrial models were constructed: baseline and multi-level fibrosis. The baseline model includes only two tissue types – normal myocardium and fibrotic tissue; the multi-level fibrosis model for FtA has the addition of dense fibrosis, and for ReA, dense fibrosis and scar (Fig. 1C). Each model was tested for AF inducibility by rapid pacing from 40 uniformly distributed bi-atrial sites (Fig. 1D). RD-harboring regions were “cut out” (Fig. 1E) and the volumetric fraction of each substrate in each region was calculated (Fig. 1F). The ReA group had on average more remodeled tissue (29.11%) than the FtA group (20.05%). While the ReA group did not have more RDs than the FtA group, their RDs were more frequently inducible (from different pacing sites) compared to the RDs in the FtA group (usually inducible from just one pacing site). In general, one model was not found to be more arrhythmogenic than the other. For 7/10 patients, the model-pair produced at least one common RD. In all models, RDs required at least 30% of remodeled tissue within the local RD region. In ReA multi-level fibrosis models, RD-harboring regions had tissue significantly more remodeled (72.34%) than RD-harboring regions in baseline models (36.59%; p<0.0001). Different levels of fibrotic remodeling result in different levels of AF inducibility. These insights might be important in predicting ablation targets in AF patients.

PO-01-158 MODELING AN ATRIAL FIBRILLATION-CAUSING TITIN MUTATION USING HUMAN IPSC-DERIVED ATRIAL CARDIOMYOCYTES

Atrial fibrillation (AF) affects more than 33 million people worldwide and, if left untreated, can lead to increased morbidity and mortality. Although AF has been classified as an ‘ion channelopathy’, next-generation sequencing has identified mutations in sarcomeric proteins like TTN, the gene encoding titin, that are associated with AF. Despite progress in understanding the genetic basis of AF, the translation of these discoveries to the bedside care of patients has been limited due to challenges in understanding the myocardial substrate for AF, especially that develops from the mutation in the structural protein. As human atrial tissue is rarely available and animal models are mechanistically limited, our goal is to model AF using mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs) by a CRISPR-Cas9-mediated single amino acid substitution of a rare missense ethnic-specific mutation (TTN_T32756I) in an immunoglobulin (Ig)-like domain of the A-band of titin that is enriched in AF-causing pathogenic variants. Isogenic TTN_T32756I hiPSC-aCM mutants were generated using the CRISPR-Cas9 technique. Cells were matured either with metabolic conditioning or co-culturing with atrial fibroblasts in a micropatterned platform. We used confocal microscopy to assess sarcomeric integrity, MuscleMotion to assess contractility, and optical voltage mapping to assess the electrophysiological properties of TTN_T32756I hiPSC-aCMs. T32756I results in a non-conservative amino acid change, which in-silico tools have previously predicted results in an impairment in titin function. Here, we show that TTN_T32756I hiPSC-aCM mutants display aberrant contractility (Fig. 1A-C) and Ca2+ homeostasis (Fig. 1D) leading to abnormal electrophysiology (Fig. 1E-F) at the cellular level without compromising the sarcomeric integrity of the atrial cardiomyocytes (Fig. 1G-H). Our results suggest that a single amino acid change could have a profound effect on titin function, further establishing titin as a major signaling hub for contractility. Ongoing studies will not only identify the key pathways and transcription factors involved in the pathogenesis of TTN_ T32756I mutant but also uncover the impact of the mutation on atrial action potential and cardiac ion channel activity. Our study will shed new light on the mechanisms by which TTN mutation cause AF and identify novel therapeutic targets for patients carrying AF-associated rare variants in the structural genes.

PO-01-231 IDENTIFICATION OF ATRIAL ENDO-EPICARDIAL ASYNCHRONY USING SIGNAL FINGERPRINTING

Atrial three-dimensional (3D) dissociation in conduction facilitates the development of atrial fibrillation (AF). Previous mapping studies revealed that patients with persistent AF have more endo-epicardial asynchrony (EEA) during SR than those without AF. Areas of EEA can be accurately identified by using unipolar electrograms (EGM). Alterations in endo-epicardial unipolar EGM features within EEA areas may provide novel insight into the electrical substrate of AF. To develop a novel method for estimating the degree of EEA by using unipolar EGM characteristics recorded from either the endo- and/or epicardium. During SR, intra-operative simultaneous endo-epicardial mapping (256 electrodes, 2 mm interelectrode distance) of the right atrium was performed in 86 patients. EEA was defined as an endo-epicardial dissociation exceeding 15 ms. EGM features, including voltages, low voltage areas (LVAs, <1.0 mV), potential types (single, short/long double and fractionated potentials) and fractionation duration (FD) were analyzed and correlated to EEA areas. The Asynchrony Fingerprinting Score (AFS) was developed based on uni- and multivariable logistic regression analyses. Three AFSs (Epi-AFS, Endo-AFS and EE-AFS) were established and assessed. EEA areas were characterized by a decrease in potential voltages, an increase in the number of long double potentials (LDPs) and fractionated potentials (FPs) and prolongation of double potentials (DPs) and FPs compared to non-EEA areas. Epi-AFS contained epicardial median voltage and the proportion of LDP, whereas the Endo-AFS contained the endocardial proportion of LVAs and single potentials (SPs). The EE-AFS, containing the proportion of endocardial LVAs, and the FD of epicardial DPs, showed the highest predictive value (AUC: 0.913) in determining the degree of EEA, although both Epi- and Endo-AFS also showed good predictive value with AUCs of 0.830 and 0.901 respectively. EEA is characterized by increased amounts of LVAs, LDPs and FPs, as well as an increase in the duration of both DPs and FPs. Epi-, Endo- and EE-AFS all showed good accuracy in identifying EEA areas. Therefore, AFS, as a novel approach utilizing integrated data from endo- or/and epicardium, may enable precise identification of EEA degree, including potentially arrhythmogenic substrates.

PO-02-191 LEFT ATRIAL STRAIN CAN PREDICT THE OCCURRENCE OF ATRIAL FIBRILLATION: A SYSTEMATIC REVIEW AND META-ANALYSIS

Despite the broadening spectrum of heart rhythm monitoring techniques, the most appropriate modality and duration to detect atrial fibrillation (AF) are not consensual. 2D speckle tracking for left atrial (LA) strain analysis seems feasible to detect atrial cardiomyopathy (ACM), which represents a substrate for AF. We aimed to perform a systematic review and meta-analysis on global longitudinal atrial strain (GLAS) and contraction strain rate (Sra) differences as primary outcomes measured in sinus rhythm (SR) between patients with and without future AF during follow-up (FU). The random effects model was used. For continuous outcomes, we calculated weighted mean differences (WMD) to compare the two groups. We identified eight eligible articles consisting of 1,230 patients. Six articles were eligible for quantitative GLAS analysis, while three were eligible regarding Sra. The baseline parameters of future AF and SR patients were comparable in most of the papers. The GLAS value in patients developing future AF was significantly lower compared to patients with no AF (WMD: -5.55% 95% CI -7.06 to -4.03 %). Pooled WMD of Sra between the groups was -0.44 1/sec, 95% CI: -0.56 to -0.33 1/sec. Baseline GLAS and Sra values of future AF patients were significantly lower than those of patients who remained in SR during FU. GLAS and Sra seem to be sensitive parameters, which can be implemented in a predictive model for AF enabling us to find patients who need prolonged heart rhythm monitoring, and it can serve also as guidance for anticoagulation indication setting.

PO-02-214 JK07 PREVENTS HYPERTENSION-INDUCED ATRIAL FIBROSIS AND ATRIAL FIBRILLATION INDUCIBILITY IN A PIG MODEL

An important substrate of atrial fibrillation (AF) is atrial fibrosis, and a higher burden of fibrosis correlates with worse prognosis and therapy resistance. Currently, no therapies exist that target atrial fibrosis. JK07 is a long-acting neuregulin-fusion protein that activates the ERBB4 receptor, which mitigates ventricular fibrosis in models of heart failure. To test the ability of JK07 to reduce atrial fibrosis and AF inducibility in the minipig model of deoxycorticosterone acetate (DOCA, an aldosterone agonist) induced hypertension. Eighteen Aachener minipigs were randomized into three groups: control (CTRL), DOCA + Vehicle (DOCA+VEH) and DOCA+JK07. The control group did not undergo disease induction or therapeutic intervention. To induce hypertension and atrial fibrosis in minipigs in the DOCA+VEH and DOCA+JK07 groups, DOCA pellets were implanted releasing 10 mg/kg DOCA over a period of 60 days. The DOCA-implanted animals underwent weekly treatment with JK07 (0.3 mg/kg; DOCA + JK07) or vehicle control (DOCA + VEH), starting on the day of implantation (total of 9 administrations). After 60 days, arterial blood pressure was measured invasively and a decapolar catheter was placed in the right atrium. AF inducibility was tested by performing 50 burst pacing episodes and quantified as the percentage of “successful” episodes where an AF run ≥ 5 sec could be induced after the burst, out of the 50 attempts. Atrial fibrosis was quantified using AFAT software on Masson trichrome staining of left atrial appendage specimens, isolated after euthanizing the animals. Mean arterial pressure was significantly higher in the DOCA+VEH (142 ± 10 mmHg) and DOCA+JK07 (132 ± 15 mmHg) groups than in the CTRL group (105 ± 8 mmHg, p<0.01), without an effect of JK07. AF inducibility in the DOCA+VEH group was significantly higher than in the CTRL group (66/250 vs. 9/300, p<0.001), and the DOCA + JK07 group (66/250 vs. 8/300, p<0.001). Likewise, the degree of atrial fibrosis was significantly higher in the DOCA+VEH group compared to CTRL (10.32% ± 4.74% surface area vs. 5.28% ± 3.06%, p<0.001) and compared to DOCA+JK07 (10.32% ± 4.74% vs. 3.82% ± 2.68%, p<0.001). JK07 prevents atrial fibrosis and AF inducibility in a porcine DOCA model. The effect of JK07 is unrelated to effects on blood pressure, but probably related to reduced atrial fibrogenesis.

PO-02-243 IMPACT OF PARTIAL CONSTRICTION OF THE ARTERIAL PULMONARY TRUNK ON THE DEVELOPMENT OF SUSCEPTIBILITY TO ATRIAL FIBRILLATION IN RATS

Atrial Fibrillation (AF) is the most frequent and clinically important form of cardiac arrhythmia. It has been demonstrated that cardiovascular comorbidities such as myocarditis, myocardial infarction, obesity, or pulmonary hypertension (PH) promote cardiac remodeling associated with the development of atrial arrhythmogenic substrates. Right-heart disease (RHD), characterized by chronic right-sided cardiac structural and functional anomalies, has also been designated among AF risk factors. Inflammation is one of the common denominators between cardiovascular risk factors and AF vulnerability. However, no study has described the progression of the molecular and cellular changes involved in the causal link relating RHD, the activation of atrial inflammation, and the development of AF substrate. This study aims to establish the characterization of the progression of atrial arrhythmogenic inflammation in a rat model of RHD. Hypothesis Permanent constriction of the pulmonary artery trunk (PAT) provokes severe RHD associated with progressive atrial inflammation and fibrosis responsible for enhanced AF vulnerability. Pulmonary Artery Banding (PAB) reducing the PAT diameter to 1 mm, was surgically performed on 225-275g Wistar rats to induce permanent PH and severe RHD. Sham animals received PAB-mimicking intervention without ligation. Echocardiography and electrophysiological studies (EPS) were performed in vivo, on all the animals at Day0, Day7, Day14 and Day21 post-surgery. The atrial tissues were analyzed by optical mapping, histology (Masson's Trichrome), qPCR and immunoblotting. Within three weeks, PAB rats developed severe right heart remodeling characterized by progressive ventricular and atrial hypertrophy and dilation. Right atrial (RA) optical mapping revealed a reduction in conduction velocity and refractory periods in PAB rats compared to Sham. PAB rats were more vulnerable to AF than Sham starting at 7th-day until the 21st-day post-surgery. Histological analysis shows that since the 14th day until the 21st-day post-surgery RA fibrosis significantly increased in PAB rats compared to sham. Quantitative polymerase chain reaction performed on inflammation and fibrosis-related genes such as IL6, Tgfb1 or Col1a1 revealed a progressive aggravation of RA inflammatory and fibrotic status in PAB rats from Day7, Day14 to Day2 Severe RHD is associated with progressive and unresolved RA inflammation and fibrosis provoking an aggravation of AF vulnerability overtime

PO-01-161 PIRFENIDONE MITIGATES THE DEVELOPMENT OF ARRHYTHMOGENIC ATRIAL FIBROSIS DUE TO PREMATURE ATRIAL COMPLEXES IN A SWINE MODEL

Atrial fibrosis is one of the major pathophysiologic mechanisms underlying the progression of atrial arrhythmias. We previously demonstrated in a swine model that frequent premature atrial complexes (PACs) promote atrial fibrillation (AF) via atrial fibrosis and slow conduction. Whether such fibrosis can be reversed or prevented is unknown. To evaluate the effect of (1) PAC eradication and (2) the antifibrotic drug pirfenidone (PFD) on atrial fibrosis in a swine model of frequent, dyssynchronous PACs. Thirty-five swine were exposed to 50% paced PACs from the lateral left atrium (LA) via the coronary sinus for 16 weeks in 4 groups: (1) controls without PACs (CTRL, n=10); (2) PAC group (PAC; n=10); 3) PACs followed by additional 6 weeks of PAC cessation (Rec-PAC, n=10); and (4) PACs treated with oral PFD (801mg 2 times per day) (PFD-PAC; n=5). Detailed EP study and echocardiography were performed at baseline and prior to sacrifice followed by blinded histological quantification of LA fibrosis. In the PAC group, peak atrial strain declined significantly at 16 weeks compared to CTRL. Compared to the PAC group, both the Rec-PAC and PFD-PAC groups had a less significant decline in peak atrial strain (terminal - baseline: PAC -17.7±3.3% vs. Rec-PAC -8.3±3.2% vs. PFD-PAC -11.5±3.0% vs. CTRL -0.7±4.2%; p<0.001). Conduction velocity (CV) was significantly decreased in PAC and Rec-PAC, but this decrease was attenuated in the PFD-PAC group (PAC CV 1.1±0.2m/s vs. Rec-PAC 1.2±0.1 m/s vs. PFD-PAC 1.3±0.1m/s vs. CTRL 1.5±0.2m/s; p<0.001). Posterior wall LA fibrosis was significantly increased in the PAC group, with no significant change after 6 weeks of recovery without PACs. However, the PFD-PAC group showed significantly lower fibrosis than either the PAC or Rec-PAC groups (Figure, Panel A). The PFD-PAC group also had less AF inducibility compared to the PAC and Rec-PAC groups (Panel B). In a swine model, frequent PACs produce atrial fibrosis and arrhythmogenic AF substrate. This fibrotic substrate did not regress after 6 weeks without PACs. However, treatment with PFD significantly attenuated the development of atrial fibrosis and AF inducibility. These findings suggest: (1) early management may be important for preventing ectopy-induced adverse atrial remodeling, and (2) pharmacological therapy targeted at the fibrotic substrate may play an important, novel role in the prevention of atrial remodeling and the substrate for developing AF.

PO-455617-17 PIRFENIDONE MITIGATES THE DEVELOPMENT OF ARRHYTHMOGENIC ATRIAL FIBROSIS DUE TO PREMATURE ATRIAL COMPLEXES IN A SWINE MODEL

Atrial fibrosis is one of the major pathophysiologic mechanisms underlying the progression of atrial arrhythmias. We previously demonstrated in a swine model that frequent premature atrial complexes (PACs) promote atrial fibrillation (AF) via atrial fibrosis and slow conduction. Whether such fibrosis can be reversed or prevented is unknown. To evaluate the effect of (1) PAC eradication and (2) the antifibrotic drug pirfenidone (PFD) on atrial fibrosis in a swine model of frequent, dyssynchronous PACs. Thirty-five swine were exposed to 50% paced PACs from the lateral left atrium (LA) via the coronary sinus for 16 weeks in 4 groups: (1) controls without PACs (CTRL, n=10); (2) PAC group (PAC; n=10); 3) PACs followed by additional 6 weeks of PAC cessation (Rec-PAC, n=10); and (4) PACs treated with oral PFD (801mg 2 times per day) (PFD-PAC; n=5). Detailed EP study and echocardiography were performed at baseline and prior to sacrifice followed by blinded histological quantification of LA fibrosis. In the PAC group, peak atrial strain declined significantly at 16 weeks compared to CTRL. Compared to the PAC group, both the Rec-PAC and PFD-PAC groups had a less significant decline in peak atrial strain (terminal - baseline: PAC -17.7±3.3% vs. Rec-PAC -8.3±3.2% vs. PFD-PAC -11.5±3.0% vs. CTRL -0.7±4.2%; p<0.001). Conduction velocity (CV) was significantly decreased in PAC and Rec-PAC, but this decrease was attenuated in the PFD-PAC group (PAC CV 1.1±0.2m/s vs. Rec-PAC 1.2±0.1 m/s vs. PFD-PAC 1.3±0.1m/s vs. CTRL 1.5±0.2m/s; p<0.001). Posterior wall LA fibrosis was significantly increased in the PAC group, with no significant change after 6 weeks of recovery without PACs. However, the PFD-PAC group showed significantly lower fibrosis than either the PAC or Rec-PAC groups (Figure, Panel A). The PFD-PAC group also had less AF inducibility compared to the PAC and Rec-PAC groups (Panel B). In a swine model, frequent PACs produce atrial fibrosis and arrhythmogenic AF substrate. This fibrotic substrate did not regress after 6 weeks without PACs. However, treatment with PFD significantly attenuated the development of atrial fibrosis and AF inducibility. These findings suggest: (1) early management may be important for preventing ectopy-induced adverse atrial remodeling, and (2) pharmacological therapy targeted at the fibrotic substrate may play an important, novel role in the prevention of atrial remodeling and the substrate for developing AF.

Molecular mechanisms of postoperative atrial fibrillation in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) promotes atrial remodeling and fibrosis, providing a substrate for atrial fibrillation (AF). Herein, we investigate the pathophysiological mechanisms of AF in association with OSA in a cohort of cardiac surgery patients. A prospective study including patients undergoing cardiac surgery. Biomarkers reflective of AF pathophysiology (interleukin [IL-6], C-reactive protein [CRP], von Willebrand factor [vWF], N-terminal pro-brain natriuretic peptide [NT-proBNP], high-sensitivity Troponin T [hs-TnT], and Galectin-3 [Gal-3]) was assessed by functional or immunological assays. miRNAs involved in AF were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Using atrial tissue samples, fibrosis was assessed by Masson's trichrome. Connexin 40 and 43 (Cx40; Cx43) were evaluated by immunolabeling. Fifty-six patients (15 with OSA and 41 non-OSA) were included in this hypothesis-generating pilot study. OSA group had a higher incidence of postoperative AF (POAF) (46.7% vs. 19.5%; p = .042), presented an increased risk of POAF (OR 3.61, 95% CI 1.01-12.92), and had significantly higher baseline levels of NT-proBNP (p = .044), vWF (p = .049), Gal-3 (p = .009), IL-6 (p = .002), and CRP (p = .003). This group presented lower levels of miR-21 and miR-208 (both p < .05). Also, lower Cx40 levels in POAF and/or OSA patients (50.0% vs. 81.8%, p = .033) were found. The presence of interstitial fibrosis (according to myocardial collagen by Masson's trichrome) was raised in OSA patients (86.7% vs. 53.7%, p = .024). Several biomarkers and miRNAs involved in inflammation and fibrosis were dysregulated in OSA patients, which together with a higher degree of interstitial fibrosis, altered miRNA, and Cxs expression predisposes to the development of a substrate that increases the AF risk.

Simultaneous pulmonary vein isolation and ablation of the substrate of biatrial flutter in a patient with a mechanical mitral valve prosthesis: a case report

Catheter radiofrequency ablation of the atrial fibrillation substrate may be difficult in patients after open heart surgery. Difficulties may arise in the presence of a mitral valve prosthesis, atrial arrhythmias of several morphologies (more often left atrial atypical flutter), including incisional ones. These cases require a thorough and scrupulous approach to achieve complete isolation of all available arrhythmia substrates. A distinctive feature of this observation is the successful simultaneous pulmonary vein isolation and two atrial arrhythmias in a patient with a mechanical mitral prosthesis.

Review of Ex Vivo Cardiac Electrical Mapping and Intelligent Labeling of Atrial Fibrillation Substrates

With the development of computer hardware and the growth of clinical database, tremendous progress has been made in the application of deep learning to electrocardiographic data, which provides new ideas for the ex vivo cardiac electrical mapping of atrial fibrillation (AF) substrates. The AF mechanism and current status of AF substrate research are first summarized. Then, the advantages and limitations of cardiac electrophysiological mapping techniques are analyzed. Finally, the application of deep learning to electrocardiogram (ECG) data is reviewed, the problems with the ex vivo intelligent labeling of an AF substrate and the possible solutions are discussed, an outlook on future development is provided.

ABO Blood Groups as a Disease Marker to Predict Atrial Fibrillation Recurrence after Catheter Ablation

Chronic inflammation harbors a vulnerable substrate for atrial fibrillation (AF) recurrence after catheter ablation. However, whether the ABO blood types are associated with AF recurrence after catheter ablation is unknown. A total of 2106 AF patients (1552 men, 554 women) who underwent catheter ablation were enrolled retrospectively. The patients were separated into two groups according to the ABO blood types, the O-type (n = 910, 43.21%) and the non-O-type groups (A, B, or AB type) (n = 1196, 56.79%). The clinical characteristics, AF recurrence, and risk predictors were investigated. The non-O type blood group had a higher incidence of diabetes mellitus (11.90 vs. 9.03%, p = 0.035), larger left atrial diameters (39.43 ± 6.74 vs. 38.20 ± 6.47, p = 0.007), and decreased left ventricular ejection fractions (56.01 ± 7.33 vs. 58.65 ± 6.34, p = 0.044) than the O-type blood group. In the non-paroxysmal AF (non-PAF) patients, the non-O-type blood groups have significantly higher incidences of very late recurrence (67.46 vs. 32.54%, p = 0.045) than those in the O-type blood group. The multivariate analysis revealed the non-O blood group (odd ratio 1.40, p = 0.022) and amiodarone (odd ratio 1.44, p = 0.013) were independent predictors for very late recurrence in the non-PAF patients after catheter ablation, which could be applied as a useful disease marker. This work highlighted the potential link between the ABO blood types and inflammatory activities that contribute to the pathogenic development of AF. The presence of surface antigens on cardiomyocytes or blood cells in patients with different ABO blood types will have an impactful role in risk stratification for AF prognosis after catheter ablation. Further prospective studies are warranted to prove the translational benefits of the ABO blood types for the patients receiving catheter ablation.

Impact of pre-existing left atrial appendage occluder on catheter ablation of atrial fibrillation

BackgroundPatients with drug-refractory atrial fibrillation (AF) and pre-existing left atrial appendage occluder (LAAO) device may need pulmonary vein isolation (PVI). In this pioneer study, we investigated the impact of pre-existing...

An objective tool for quantifying atrial fibrillation substrate in rats.

The utility of rodents for research related to atrial fibrillation (AF) is growing exponentially. However, the obtained arrhythmic waveforms are often mixed with ventricular signals and the ability to analyze regularity and complexity of such events is limited. Recently, we introduced an implantable quadripolar electrode adapted for advanced atrial electrophysiology in ambulatory rats. Notably, we have found that the implantation itself leads to progressive atrial remodeling, presumably because of mechanical loading of the atria. In the present study, we developed an algorithm to clean the atrial signals from ventricular mixing and thereafter quantify the AF substrate in an objective manner based on waveform complexity. Rats were sequentially examined 1-, 4-, and 8-wk postelectrode implantation using a standard AF triggering protocol. Preburst ventricular mixing was sampled and automatically subtracted based on QRS detection in the ECG. Thereafter, the "pure" atrial signals were analyzed by Lempel-Ziv complexity algorithm and a complexity ratio (CR) was defined for each signal by normalizing the postburst to the preburst values. Receiver operating characteristic (ROC) curve analysis indicated an optimal CR cutoff of 1.236 that detected irregular arrhythmic events with high sensitivity (94.5%), specificity (93.1%), and area under the curve (AUC) (0.96, 95% confidence interval, 0.945-0.976). Automated and unbiased analysis indicated a gradual increase in signal complexity over time with augmentation of high frequencies in power spectrum analysis. Our findings indicate that CR algorithm detects irregularity in a highly efficient manner and can also detect the atrial remodeling induced by electrode implantation. Thus, CR analysis can strongly facilitate standardized AF research in rodents.NEW & NOTEWORTHY Rodents are increasingly used in AF research. However, because of technical difficulties including atrial waveform mixing by ventricular signals, most studies do not discriminate between irregular (i.e., AF) and regular atrial arrhythmias. Here, we develop an unbiased computerized tool to "pure" the atrial signals from ventricular mixing and thereafter analyze AF substrate based on the level of irregularity in an objective manner. This novel tool can facilitate standardized AF research in rodents.

Increased β1-adrenergic receptor antibody confers a vulnerable substrate for atrial fibrillation via mediating Ca2+ mishandling and atrial fibrosis in active immunization rabbit models.

Autoimmune disorder is the emerging mechanism of atrial fibrillation (AF). The β1-adrenergic receptor antibody (β1-AAb) is associated with AF progress. Our study aims to investigate whether β1-AAbs involves in atrial vulnerable substrate by mediating Ca2+ mishandling and atrial fibrosis in autoimmune associated AF. Active immunization models were established via subcutaneous injection of the second extracellular loop (ECL2) peptide for β1 adrenergic receptor (β1AR). Invasive electrophysiologic study and ex vivo optical mapping were used to evaluate the changed electrophysiology parameters and calcium handling properties. Phospho-proteomics combined with molecular biology assay were performed to identify the potential mechanisms of remodeled atrial substrate elicited by β1-AAbs. Exogenous β1-AAbs were used to induce the cellular phenotypes of HL-1 cells and atrial fibroblasts to AF propensity. β1-AAbs aggravated the atrial electrical instability and atrial fibrosis. Bisoprolol alleviated the alterations of action potential duration (APD), Ca2+ transient duration (CaD), and conduction heterogeneity challenged by β1-AAbs. β1-AAbs prolonged calcium transient refractoriness and promoted arrhythmogenic atrial alternans and spatially discordant alternans, which were partly counteracted through blocking β1AR. Its underlying mechanisms are related to β1AR-drived CaMKII/RyR2 activation of atrial cardiomyocytes and the myofibroblasts phenotype formation of fibroblasts. Suppressing β1-AAbs effectively protects the atrial vulnerable substrate by ameliorating intracellular Ca2+ mishandling and atrial fibrosis, preventing the process of the autoimmune associated AF.

Abnormal Conduction Zone Detected by Isochronal Late Activation Mapping Accurately Identifies the Potential Atrial Substrate and Predicts the Atrial Fibrillation Ablation Outcome After Pulmonary Vein Isolation.

The presence of abnormal substrate of left atrium is a predictor of atrial fibrillation (AF) recurrence after pulmonary vein isolation. We aimed to investigate the isochronal late activation mapping to access the abnormal conduction velocity for predicting AF ablation outcome. Forty-five paroxysmal AF patients (30 males, 57.8±8.7 years old) who underwent pulmonary vein isolation were enrolled. Isochronal late activation mapping was retrospectively constructed with 2 different windows of interest: from onset of P wave to onset of QRS wave on surface electrocardiography (W1) and 74 ms tracking back from the end of P wave (W2). Deceleration zone was defined as regions with 3 isochrones (DZa) or ≥4 isochrones (DZb) within a 1 cm radius on the isochronal late activation mapping, and the estimated conduction velocity (ECV) are 0.27 m/s and <0.20 m/s for DZa and DZb, respectively in W2. The distribution of deceleration zone was compared with the location of low-voltage zone (bipolar voltage ≤0.5 mV). Any recurrence of atrial arrhythmias was defined as the primary end point during follow ups after a 3-month blanking period. Pulmonary vein isolation was performed in all patients, and there were 2 patients (4.4%) received additional extrapulmonary vein ablation. After a mean follow-up of 12.7±4.5 months, recurrence of AF occurred in 14 patients (31.1%). Patients with the presence of DZb in W2 had higher AF recurrence (Kaplan-Meier event rate estimates: HR, 9.41 [95% CI, 2.61-33.90]; log-rank P<0.0001). There were 52.6% of the DZb locations in W2 comparable to the distributions of low-voltage zone and 47.4% DZb were distributed in the area without low-voltage zone. Deceleration zone detected by isochronal late activation mapping represents a critical AF substrate, it accurately predicts the AF recurrence following ablation in patients with paroxysmal AF.

Melatonin increases susceptibility to atrial fibrillation in obesity via Akt signaling impairment in response to lipid overload.

Melatonin has been proven to have antiarrhythmic potential; however, several studies have recently challenged this view. Herein, using a mouse model of obesity-induced atrial fibrillation (AF), we tentatively explored whether exogenous melatonin supplementation could increase AF susceptibility in the context of obesity. We observed that an 8-week drinking administration of melatonin (60 µg/ml in water) induced a greater susceptibility to AF in obese mice, although obesity-induced structural remodeling was alleviated. An investigation of systemic insulin sensitivity showed that melatonin treatment improved insulin sensitivity in obese mice, whereas it inhibited glucose-stimulated insulin secretion. Notably, melatonin treatment inhibited protein kinase B (Akt) signaling in the atria of obese mice and palmitate-treated neonatal rat cardiomyocytes, thereby providing an AF substrate. Melatonin increased lipid stress in obesity, as evidenced by elevated lipid accumulation and lipolysis-related gene expression, thus contributing to the impairment in atrial Akt signaling. Taken together, our results demonstrated that melatonin could increase AF susceptibility in obesity, probably due to increased lipid stress and resultant impairment of atrial Akt signaling. Our findings suggest that special precautions should be taken when administering melatonin to obese subjects.

Structural and electrophysiological determinants of atrial cardiomyopathy identify remodeling discrepancies between paroxysmal and persistent atrial fibrillation.

Progressive atrial fibrotic remodeling has been reported to be associated with atrial cardiomyopathy (ACM) and the transition from paroxysmal to persistent atrial fibrillation (AF). We sought to identify the anatomical/structural and electrophysiological factors involved in atrial remodeling that promote AF persistency. Consecutive patients with paroxysmal (n = 134) or persistent (n = 136) AF who presented for their first AF ablation procedure were included. Patients underwent left atrial (LA) high-definition mapping (1,835 ± 421 sites/map) during sinus rhythm (SR) and were randomized to training and validation sets for model development and evaluation. A total of 62 parameters from both electro-anatomical mapping and non-invasive baseline data were extracted encompassing four main categories: (1) LA size, (2) extent of low-voltage-substrate (LVS), (3) LA voltages and (4) bi-atrial conduction time as identified by the duration of amplified P-wave (APWD) in a digital 12-lead-ECG. Least absolute shrinkage and selection operator (LASSO) and logistic regression were performed to identify the factors that are most relevant to AF persistency in each category alone and all categories combined. The performance of the developed models for diagnosis of AF persistency was validated regarding discrimination, calibration and clinical usefulness. In addition, HATCH score and C2HEST score were also evaluated for their performance in identification of AF persistency. In training and validation sets, APWD (threshold 151 ms), LA volume (LAV, threshold 94 mL), bipolar LVS area < 1.0 mV (threshold 4.55 cm2) and LA global mean voltage (GMV, threshold 1.66 mV) were identified as best determinants for AF persistency in the respective category. Moreover, APWD (AUC 0.851 and 0.801) and LA volume (AUC 0.788 and 0.741) achieved better discrimination between AF types than LVS extent (AUC 0.783 and 0.682) and GMV (AUC 0.751 and 0.707). The integrated model (combining APWD and LAV) yielded the best discrimination performance between AF types (AUC 0.876 in training set and 0.830 in validation set). In contrast, HATCH score and C2HEST score only achieved AUC < 0.60 in identifying individuals with persistent AF in current study. Among 62 electro-anatomical parameters, we identified APWD, LA volume, LVS extent, and mean LA voltage as the four determinant electrophysiological and structural factors that are most relevant for AF persistency. Notably, the combination of APWD with LA volume enabled discrimination between paroxysmal and persistent AF with high accuracy, emphasizing their importance as underlying substrate of persistent AF.

Atrial fibrillation: 2023 novelties for the general practitioner

Atrial fibrillation (AF) is the most frequent tachyarrhythmia with a significant morbimortality. The diagnosis is based on a 12 lead ECG. New technologies such as connected watches have shown similar sensibility and specificity. The new 4S scheme (Stroke risk, Symptoms, Severity of AF burden and Substrate) allows a global evaluation. Rhythm control mainly by catheter ablation is increasingly indicated. Management of cardiovascular risk factors is an essential part of the treatment of these patients.