Maintenance Of Atrial Fibrillation Research Articles

Management of patients with arterial hypertension and atrial fibrillation

Arterial hypertension (AH) is a leading risk factor for cardiovascular disease as well as it is the most common, independent and potentially reversible risk factor for atrial fibrillation (AF). AH contributes to the occurrence and maintenance of AF due to hemodynamic disorders, alterations in cardiomyocyte electrophysiological properties and structural remodeling in the atria. AF, which is also associated with an increased risk of cardiovascular events, is the most common arrhythmia. AH and AF often coexist, and their prevalence increases with age. This consensus provides the key features of the management of patients with these nosological units. The pathogenesis, risk stratification, and features of the selection of antihypertensive, antiarrhythmic and antithrombotic therapy are described in detail.

Identification of high priority focal activations in persistent atrial fibrillation using a novel mapping strategy.

Focal activation is believed to be an atrial fibrillation (AF) driver; however, little is known about whether all focal activations are necessary for AF persistence. The purpose of this study was to assess the electrical nature of focal activation and identify high-priority focal activations using a novel mapping system (CARTOFINDER). Thirty-five patients with persistent AF who underwent catheter ablation were assessed. Cycle length (CL) and CL standard deviation (CLSD) on unipolar recordings and voltage amplitude and electrogram morphologies on bipolar recordings were evaluated at all points of interest. The most frequent CL at each mapping site was defined as the dominant CL. We identified dominant focal activations (DFAs) that had a shorter dominant CL on the integrated CARTOFINDER map. The effect of elimination of DFAs on AF maintenance was assessed by the composite endpoint (termination to sinus rhythm, organization of the rhythm to atrial tachycardia, and AF CL slowing). In all, 450 focal activations were identified among 10,868 points, and 50.4% of focal activations were DFAs. Focal activations showed relatively long CL and regularity with short CLSD. Most focal activations showed an isoelectric baseline and were located outside of the fractionated electrogram area. Both DFAs and non-DFAs were typically observed in the normal voltage range. Elimination of DFAs was achieved in 19 (54.3%) patients, with a remarkable impact on AF maintenance (68.4% vs. 25.0%, p = 0.018). In conclusion, DFAs may play an important role in AF maintenance and could be an attractive therapeutic target for AF.

Unveiling the impact of fibrosis presence in fibrillatory electrograms

Abstract Introduction Complexity and fragmentation presence in atrial fibrillation (AF) electrograms (EGMs) has been extensively studied in the literature, with areas exhibiting complex fractionated atrial electrograms (CFAEs) postulated as responsible for AF maintenance. Computational simulations based on in silico models are widely employed to support AF initiating and maintenance theories. However, they are still limited when trying to mimic the effect of fibrosis in live cardiac cells and its impact in the clinical context, i.e., EGM morphologies in electroanatomical mapping studies. Controlled experiments on cultivated cardiomyocytes and optical mapping signals can better explain the role of fibrosis and its effect on EGM recordings. Purpose To study the effect of fibrosis in fibrillatory scenarios by comparing the temporal and frequency domains of EGMs and Ca2+ transient signals in cardiomyocyte cell cultures. Methods A total of 51 HL1 cardiomyocytes cell line monolayers experiments were cultured until confluence. Optical mapping (OM) was performed to evaluate the electrophysiological activity of the samples through Ca2+ transient quantification under the effect of Rhod2 dye. Activation frequency and calcium transient signals were acquired, and virtual EGMs were calculated from the signals virtually after post-processing the cell cultures at 16 different positions in the culture, see Figure 1A. Results The DF ratio between the OM and the virtual EGMs obtained for the different fibrosis levels are summarized and represented in Figure 1B. The Pearson's correlation coefficient was adjusted for all the samples and the significance level was stablished at p-value<0.01. Conclusions Optical mapping signal morphologies strongly correlate with EGM recordings when a clear dominant frequency (DF) dominates the complete area of the cell culture and no fibrosis is present. However, for patchy distributions of the DF, usually associated with higher concentrations of fibrosis, morphologies do not correlate for increasing fibrosis levels, and DF measurements differ with poor match between EGM-DF and OM-DF. Results on higher fibrotic experiments, i.e., 40–50% fibrosis level, show that DF correlates due to the poor and degraded cardiac activity in the EGMs and optical mapping recordings. The results reveal the importance and impact of fibrosis in the remodeling of atrial tissue and the correct interpretation of endocardial EGMs in the presence of heterogeneous tissue. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III and Ministerio de Ciencia, Innovaciόn y Universidades

Posterior left atrial epicardial adipose tissue: scope of the problem and impact of new technology.

Patients with persistent forms of atrial fibrillation are seeking treatments based on the promise of better restoration of sinus rhythm with newer therapies. Successful catheter ablation and maintenance of atrial fibrillation in this subgroup is negatively impacted by the presence of epicardial adipose tissue (EAT) associated with the posterior left atrium. EAT is now understood to be hormonally active and promotes adverse atrial remodelling, including fibrosis and myopathy. Despite being dominantly adipose tissue, it is known to be electrically active, comprising ganglia, neural tissue and ectopic atrial myocardium that may contribute to endo-epicardial dissociation and persistent electrical activity and atrial fibrillation despite good endocardial electrical silencing. Hybrid procedures that include direct epicardial ablation of the posterior wall, including the EAT, are associated with superior outcomes in nonparoxysmal atrial fibrillation. Therapies for persistent atrial fibrillation that also ablate the EAT as part of a well tolerated transmural posterior wall ablation may improve outcomes in this challenging subset of patients.

Molecular Insights in Atrial Fibrillation Pathogenesis and Therapeutics: A Narrative Review.

The prevalence of atrial fibrillation (AF) is bound to increase globally in the following years, affecting the quality of life of millions of people, increasing mortality and morbidity, and beleaguering health care systems. Increasingly effective therapeutic options against AF are the constantly evolving electroanatomic substrate mapping systems of the left atrium (LA) and ablation catheter technologies. Yet, a prerequisite for better long-term success rates is the understanding of AF pathogenesis and maintenance. LA electrical and anatomical remodeling remains in the epicenter of current research for novel diagnostic and treatment modalities. On a molecular level, electrical remodeling lies on impaired calcium handling, enhanced inwardly rectifying potassium currents, and gap junction perturbations. In addition, a wide array of profibrotic stimuli activates fibroblast to an increased extracellular matrix turnover via various intermediaries. Concomitant dysregulation of the autonomic nervous system and the humoral function of increased epicardial adipose tissue (EAT) are established mediators in the pathophysiology of AF. Local atrial lymphomononuclear cells infiltrate and increased inflammasome activity accelerate and perpetuate arrhythmia substrate. Finally, impaired intracellular protein metabolism, excessive oxidative stress, and mitochondrial dysfunction deplete atrial cardiomyocyte ATP and promote arrhythmogenesis. These overlapping cellular and molecular alterations hinder us from distinguishing the cause from the effect in AF pathogenesis. Yet, a plethora of therapeutic modalities target these molecular perturbations and hold promise in combating the AF burden. Namely, atrial selective ion channel inhibitors, AF gene therapy, anti-fibrotic agents, AF drug repurposing, immunomodulators, and indirect cardiac neuromodulation are discussed here.

CXCL12/CXCR4 axis as a key mediator in atrial fibrillation via bioinformatics analysis and functional identification

Atrial fibrillation (AF) is an increasingly prevalent arrhythmia with significant health and socioeconomic impact. The underlying mechanism of AF is still not well understood. In this study, we sought to identify hub genes involved in AF, and explored their functions and underlying mechanisms based on bioinformatics analysis. Five microarray datasets in GEO were used to identify the differentially expressed genes (DEGs) by Robust Rank Aggregation (RRA), and hub genes were screened out using protein–protein interaction (PPI) network. AF model was established using a mixture of acetylcholine and calcium chloride (Ach-CaCl2) by tail vein injection. We totally got 35 robust DEGs that mainly involve in extracellular matrix formation, leukocyte transendothelial migration, and chemokine signaling pathway. Among these DEGs, we identified three hub genes involved in AF, of which CXCL12/CXCR4 axis significantly upregulated in AF patients stands out as one of the most potent targets for AF prevention, and its effect on AF pathogenesis and underlying mechanisms were investigated in vivo subsequently with the specific CXCR4 antagonist AMD3100 (6 mg/kg). Our results demonstrated an elevated transcription and translation of CXCL12/CXCR4 axis in AF patients and mice, accompanied with the anabatic atrial inflammation and fibrosis, thereby providing the substrate for AF maintenance. Blocking its signaling via AMD3100 administration in AF model mice reduced AF inducibility and duration, partly ascribed to decreased atrial inflammation and structural remodeling. Mechanistically, these effects were achieved by reducing the recruitment of CD3+ T lymphocytes and F4/80+ macrophages, and suppressing the hyperactivation of ERK1/2 and AKT/mTOR signaling in atria of AF model mice. In conclusion, this study provides new evidence that antagonizing CXCR4 prevents the development of AF, and suggests that CXCL12/CXCR4 axis may be a potential therapeutic target for AF.

Diminished PLK2 Induces Cardiac Fibrosis and Promotes Atrial Fibrillation.

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B-PO02-029 REDUCED ATRIAL FIBRILLATION DRIVERS IN RESPONSE TO REACTIVE OXYGEN SCAVENGING - A NOVEL THERAPEUTIC TARGET IN ATRIAL FIBRILLATION?

Oxidative Stress (OS) is thought to be a mediator of atrial fibrillation (AF), but the precise role of OS in AF is unknown. We assessed reactive oxygen species (ROS) scavenging on slow conduction and maintenance of rotational drivers. We hypothesized that ROS are dynamically involved in a vulnerable substrate and that ROS scavenging reduces AF drivers and arrhythmogenic slow conduction zones. AF was induced in 48 dogs by rapid atrial pacing (RAP) for 3-14 weeks. Epicardial high-density mapping was performed (130 electrodes, dist. 2.5mm) in the atrial regions: posterior left atrium (PLA), left atrial free wall (LAFW), left atrial appendage (LAA), posterior right atrium (PRA), right atrial free wall (RAFW), right atrial appendage (RAA). N-acetylcysteine (NAC) was given intravenously (100mg/kg) in 15 AF dogs. We mapped all atrial regions pre and post NAC. We detected rotational activity in activation time maps and quantified slow conduction as activation delay in neighboring electrodes. We detected rotational activity in all regions (Figure A) with the stability of 376±255ms in the LAA, 422±174ms in the PLA, and 317±174ms in the LAFW (Figure B). The cycle length of rotational activity was shorter in the PLA (CL 94±7 ms) compared to other regions (P<0.05) (Figure C) and increased in remote regions with increasing distance to the PLA (Figure D). After providing NAC, rotational activities reduced in the left atrium by 40% in the LAFW, by 39% in the PLA, and by 12% in the LAFW (Figure E). Acute scavenging of ROS reduces arrhythmogenic slow conduction and AF triggers. These results show that ROS is dynamically involved in the maintenance of AF.

Autonomic modulation of the arrhythmogenic substrate in the evolution of atrial fibrillation and therapeutic approaches.

The autonomic nervous system (ANS) plays an important role in atrial arrhythmogenesis and is one of the factors responsible for the initiation and maintenance of atrial fibrillation (AF). Over the past few decades, neuromodulation has been shown to help in the management of AF. This review focuses on the correlation between AF and the ANS and how different approaches to identifying and modulating the autonomic substrate impact outcomes in AF. The authors conclude that the ANS is one of the key components in the development of AF and that modulation of autonomic nerve function may contribute to the management of AF. Therapeutic approaches such as catheter ablation of ganglionated plexi (GP), renal denervation and transcutaneous vagus nerve stimulation are viable treatment options that need further confirmation in larger randomised controlled trials. In addition, new imaging technologies were able to identify GPs accurately and reproducibly, which promises exciting prospects for the future.

Reduction of Conduction Velocity in Patients with Atrial Fibrillation.

It is unknown to what extent atrial fibrillation (AF) episodes affect intra-atrial conduction velocity (CV) and whether regional differences in local CV heterogeneities exist during sinus rhythm. This case-control study aims to compare CV assessed throughout both atria between patients with and without AF. Patients (n = 34) underwent intra-operative epicardial mapping of the right atrium (RA), Bachmann’s bundle (BB), left atrium (LA) and pulmonary vein area (PVA). CV vectors were constructed to calculate median CV in addition to total activation times (TAT) and unipolar voltages. Biatrial median CV did not differ between patients with and without AF (90 ± 8 cm/s vs. 92 ± 6 cm/s, p = 0.56); only BB showed a CV reduction in the AF group (79 ± 12 cm/s vs. 88 ± 11 cm/s, p = 0.02). In patients without AF, there was no predilection site for the lowest CV (P5) (RA: 12%; BB: 29%; LA: 29%; PVA: 29%). In patients with AF, lowest CV was most often measured at BB (53%) and ranged between 15 to 22 cm/s (median: 20 cm/s). Lowest CVs were also measured at the LA (18%) and PVA (29%), but not at the RA. AF was associated with a prolonged TAT (p = 0.03) and decreased voltages (P5) at BB (p = 0.02). BB was a predilection site for slowing of conduction in patients with AF. Prolonged TAT and decreased voltages were also found at this site. The next step will be to determine the relevance of a reduced CV at BB in relation to AF development and maintenance.

The Electrophysiology of Atrial Fibrillation: From Basic Mechanisms to Catheter Ablation.

The electrophysiology of atrial fibrillation (AF) has always been a deep mystery in understanding this complex arrhythmia. The pathophysiological mechanisms of AF are complex and often remain unclear despite extensive research. Therefore, the implementation of basic science knowledge to clinical practice is challenging. After more than 20 years, pulmonary vein isolation (PVI) remains the cornerstone ablation strategy for maintaining the sinus rhythm (SR). However, there is no doubt that, in many cases, especially in persistent and long-standing persistent AF, PVI is not enough, and eventually, the restoration of SR occurs after additional intervention in the rest of the atrial myocardium. Substrate mapping is a modern challenge as it can reveal focal sources or rotational activities that may be responsible for maintaining AF. Whether these areas are actually the cause of the AF maintenance is unknown. If this really happens, then the targeted ablation may be the solution; otherwise, more rough techniques such as atrial compartmentalization may prove to be more effective. In this article, we attempt a broad review of the known pathophysiological mechanisms of AF, and we present the recent efforts of advanced technology initially to reveal the electrical impulse during AF and then to intervene effectively with ablation.

Why is neuromodulation effect of pulmonary vein isolation not same in all cases?

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardiac ganglionated plexi (GPs) of the autonomic system are primarily located in major epicardial fat pads adjacent to the left atrium and pulmonary vein junctions. These structures may play a central role in both the initiation and maintenance of atrial fibrillation (AF). Previous studies reported modification of GPs during pulmonary vein isolation (PVI) may increase rate of sinus node and AF-free survival. However, a deficiency certainly existed why is modification of GPs observed in some patients during PVI but not in others? Purpose We aimed to evaluate ratio of ablation points within classical antral circumferential ablation lines for PVI and distribution of 4 major atrial ganglionated plexus. Methods Thirty-eight consecutive patients undergoing ablation of GP for vagally mediated bradyarrhythmias were evaluated. All GP sites were detected by using previously defined fragmented electrogram based strategy which is a validated tool when compared with a combination of spectral analysis and high frequency stimulation to detect GPs. Estimated ablation lines for antral circumferential ablation was defined as a circumferential isolation line performed ≥1 cm away from the pulmonary vein ostium as identified by 3D electroanatomical reconstruction (Figure 1). The total number of ablation points in each GP sites and ratio of ablation points within estimated antral circumferential ablation lines were recorded. Results The great majority of ablation points were detected at the insertion of the right pulmonary veins. Number of ablation points in each GP site in descending order is as follows: (1) the right superior GP = 13.6 ± 6; (2) the left superior GP = 10.5 ± 5; (3) the right inferior GP = 5.9 ± 4; and (4) the left inferior GP = 2.5 ± 3. The ratio of ablation points within estimated antral circumferential ablation lines was higher in right-sided GPs (50.5%±24 for the right superior GP and 30.2%±31 for the right inferior GP vs 18.3%±24 for the left superior GP and 11.6%±26 for the left inferior GP. Figure 2 demonstrates total number of ablation points and the ratio of ablation points within estimated antral circumferential ablation lines in each GP site. Conclusions The present study shows that individual variability of distribution of GPs and how antral ablation was done during PVI might be the main contributors of neuromodulation effect. Further randomized, controlled and multicenter studies should be performed to confirm these findings. Abstract Figure 1

Insights into electrophysiological mechanisms of atrial fibrillation propagation using simultaneous bi-atrial mapping

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Oxford Biomedical Research Centre Introduction Early evidence of pulmonary vein triggers initiating AF has led to focus on the left atrium (LA). Little work has been done to characterise the role of the right atrium (RA) in AF maintenance. Purpose To characterise the relative roles of the LA and RA in maintenance of atrial fibrillation and explore mechanisms of AF propagation. Methods Simultaneous bi-atrial mapping was carried out in patients undergoing first time catheter ablation using 2 linked non-contact charge density mapping systems to obtain 30-second recordings during AF. The predominant channel of communication between chambers was identified and the time difference across this channel measured (see figure). The proportion of signals earlier in each chamber was calculated and a dominant chamber identified if preceding the opposite chamber for ≥60% of the recording. AF was characterised in each chamber according to frequency of specific propagation patterns (localised rotational activation (LRA) and focal firing (FF)). The difference in AF characteristics in the LA and RA according to acute procedural outcome (termination with ablation vs. DCCV) was measured using 2-way ANOVA and predictors of AF termination identified using binomial logistic regression. Results Twenty-one patients were included (16 persistent AF, 5 paroxysmal AF, 11 in sinus rhythm at baseline) with 41 maps obtained prior to ablation. A dominant chamber was identified in 11 maps (in 9 patients). Of these, 5 maps (in 4 patients) were LA dominant, and 6 maps (in 5 patients) were RA dominant. The remainder showed balanced interatrial propagation. For patients with persistent AF, in the RA, those needing DCCV had more LRA than those with termination with ablation (79 activations, (95% CI 65-93) vs. 51 (30-71); p = 0.025). There was no difference in the LA in the two groups (77 vs 59, p = 0.541). There were fewer FFs in the RA vs LA in patients needing DCCV (123 (106-140) vs. 155 (137-172), p = 0.012)(see panel F). No differences in distribution of LIA were observed. The frequency of LRA (p = 0.003) and FF (p = 0.004) in the RA, and RA AFCL (p = 0.041), were predictors of acute procedural outcome. Conclusions Our novel approach of simultaneous bi-atrial mapping revealed that mechanisms responsible for AF maintenance were evenly distributed between atria whilst acute AF termination with left atrial ablation was dependent on the contribution of right atrial substrate. Strategies incorporating right atrial mechanisms may result in improved outcomes from AF ablation. Abstract Figure.

Application of recurrence plot analysis to characterise whole chamber propagation of atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Oxford Biomedical Research Centre Introduction Non-contact charge density mapping allows visualisation of whole chamber propagation during atrial fibrillation (AF). The identification of regions with repetitive or, conversely, more complex patterns of wavefront propagation may provide clues to mechanisms responsible for AF maintenance and lead to improved outcomes from catheter ablation. Our novel mapping approach based on signal recurrence plots has never been applied to whole chamber, bi-atrial recording of atrial fibrillation. Purpose To apply recurrence analysis to characterise whole chamber bi-atrial AF propagation. Methods Non-contact dipole signals from left and right atrial maps were obtained during simultaneous bi-atrial charge density mapping of AF. Signals were converted to phase and mean phase coherence calculated for the generation of recurrence distance matrices for the whole chamber and each anatomical region (6x LA and 4x RA) over the 30-second recording duration, where a value of 1 (purple, see figure panel A) represents uniform repetitive conduction, and 0 (red), irregular, non-repetitive activity. Whole chamber and regional mean recurrence values were calculated and correlated with the frequency of wavefronts of localised irregular activation patterns. Results Maps were obtained prior to ablation in 21 patients (5 paroxysmal (pAF), 16 persistent AF (persAF)) undergoing de-novo catheter ablation procedures. Whole chamber recurrence was higher in patients with pAF (0.40 ± 0.08) than persAF (0.34 ± 0.05), p &amp;lt; 0.0005. There was an inverse correlation between regional recurrence values and the number of localised irregular activations detected (-0.7021, p &amp;lt; 0.0005, figure panel B) with the lateral LA and anterior RA demonstrating the highest recurrence values in each chamber (figure panel C). Conclusion Use of recurrence distance matrices characterises global AF propagation phenotypes. Regional values are inversely correlated with the frequency of localised irregular activation patterns identified demonstrating an anatomic dependence in the level of AF propagation complexity, greatest in the anterior LA and septal RA. Comparison of strategies targeting regions with maximal vs. minimal values during catheter ablation may define an optimal approach to treatment of persistent AF. Abstract Figure. Recurrence abstract figure

Updates on epicardial adipose tissue mechanisms on atrial fibrillation.

Obesity is a well-known risk factor for atrial fibrillation (AF). Local epi-myocardial or intra-myocardial adiposity caused by aging, obesity, or cardiovascular disease (CVD) is considered to be a better predictor of the risk of AF than general adiposity. Some of the described mechanisms suggest that epicardial adipose tissue (EAT) participates in structural remodeling owing to its endocrine activity or its infiltration between cardiomyocytes. Epicardial fat also wraps up the ganglionated plexi that reach the myocardium. Although the increment of volume/thickness and activity of EAT might modify autonomic activity, autonomic system dysfunction might also change the endocrine activity of epicardial fat in a feedback response. As a result, new preventive therapeutic strategies are focused on reducing adiposity and weight loss before AF ablation or inhibiting autonomic neurotransmitter secretion on fat pads during open-heart surgery to reduce the recurrence or postoperative risk of AF. In this manuscript, we review some of the novel findings regarding the pathophysiology and associated risk factors of AF, with special emphasis on the role of EAT in the electrical, structural, and molecular mechanisms of AF initiation and maintenance. In addition, we have included a brief note provided on epicardial fat preclinical models that could be useful for identifying new therapeutic targets.

Rotor Drivers in Induction and Maintenance of Atrial Fibrillation

Atrial fibrillation is the most common arrhythmia in clinical practice. It is associated with an increased risk of stroke, chronic heart failure, and sudden cardiac death. Our options of restoring and maintaining sinus rhythm have a very limited effect, both in the case of antiarrhythmic and catheter treatment. Catheter ablation has proven to be a more effective approach than antiarrhythmic therapy. The success rate of the procedure reaches 70%. However, radiofrequency ablation is associated with a risk of complications, with 4.5% of patients likely to develop major complications, including tamponade (1.31%), femoral pseudoaneurysm (0.71%), and death (0.15%). Given the generally recognized dominant role of the pulmonary veins in the induction of atrial fibrillation, their electrical isolation has become the recommended tactic of the catheter approach. In the case of patients with paroxysmal form of atrial fibrillation, the success rate of the procedure reaches 87%. Unfortunately, in the case of persistent forms of atrial fibrillation, the effectiveness of the primary procedure decreases to 28% and reaches 51% with repeated interventions. In addition to the anatomically oriented isolation of the pulmonary veins, a number of strategies have been proposed to reach the secondary zones of atrial fibrillation induction. The results of recent studies on the effectiveness of strategies for ablation of rotor regions and their role in the induction and maintenance of AF may lead to the further development of catheter ablation techniques and an individual radiofrequency ablation approach in a particular patient.

Dynamic comparisons of epicardial electrograms between the left atrium and pulmonary veins in atrial fibrillation in goat model

Objective: To compare epicardial electrograms between the left atrium (LA) and pulmonary veins (PVs) dynamically at development of persistent atrial fibrillation(AF) in goats PVs. Methods: Ten female goats were instrumented with electrodes at the LA and left side PV. Sustained AF (＞24 h) was induced in the goat by rapid intermittent left atrial pacing for(9.5±2.3)days at a pacing interval of 20 ms for 1 s with a maximum output of 6.0 V, followed by a 2-s period without pacing. Characteristics of PVs and LA epicardial electrograms were analyzed in the development of AF. Results: With prolonged stimulation, the duration of AF was prolonged, complex fractionated atrial electrograms(CFAEs) in LA and was increased gradually, PVs had more CFAEs than LA all the time. When induced AF lasted for more than 24 h, CFAEs in PVs became sustained approximately (2.7%±3.6% vs 92.6%±6.4%, at onset of AF vs AF lasted for more than 24 h, P＜0.05), and the ratio of CFAEs in PVs was more than that in LA (92.6%±6.4% vs 72.8%±5.3%, P＜0.05). Conclusion: The epicardial CFAEs are in specific area, which increase along with electrical remodeling. The epicardial CFAEs may play an important role in the maintenance of AF in this model.

Computational models of atrial fibrillation: achievements, challenges, and perspectives for improving clinical care.

Despite significant advances in its detection, understanding and management, atrial fibrillation (AF) remains a highly prevalent cardiac arrhythmia with a major impact on morbidity and mortality of millions of patients. AF results from complex, dynamic interactions between risk factors and comorbidities that induce diverse atrial remodelling processes. Atrial remodelling increases AF vulnerability and persistence, while promoting disease progression. The variability in presentation and wide range of mechanisms involved in initiation, maintenance and progression of AF, as well as its associated adverse outcomes, make the early identification of causal factors modifiable with therapeutic interventions challenging, likely contributing to suboptimal efficacy of current AF management. Computational modelling facilitates the multilevel integration of multiple datasets and offers new opportunities for mechanistic understanding, risk prediction and personalized therapy. Mathematical simulations of cardiac electrophysiology have been around for 60 years and are being increasingly used to improve our understanding of AF mechanisms and guide AF therapy. This narrative review focuses on the emerging and future applications of computational modelling in AF management. We summarize clinical challenges that may benefit from computational modelling, provide an overview of the different in silico approaches that are available together with their notable achievements, and discuss the major limitations that hinder the routine clinical application of these approaches. Finally, future perspectives are addressed. With the rapid progress in electronic technologies including computing, clinical applications of computational modelling are advancing rapidly. We expect that their application will progressively increase in prominence, especially if their added value can be demonstrated in clinical trials.

Epiphenomenal Re-Entry and Spurious Focal Activation Detection by Atrial Fibrillation Mapping Algorithms.

The purpose of this study was to validate the ability of mapping algorithms to detect rotational activations (RoA) and focal activations (FoA) during fibrillatory conduction (FC) and atrial fibrillation (AF) and understand their mechanistic relevance. Mapping algorithms have been proposed to detect RoA and FoA to guide AF ablation. Rapid left atrial pacing created FC-fibrillatory electrograms-with and without AF induction in dogs (n=17). Activation maps were constructed using Topera (Abbott, St. Paul, Minnesota) or CARTOFINDER (Biosense Webster, Irvine,California) algorithms. Mapping strategies included: panoramic noncontact mapping with a basket catheter (CARTOFINDER n=6, Topera n=5); and sequential contact mapping using 8-spline OctaRay catheter (Biosense Webster) (n=6). Offline frequency and spectral analysis were also performed. Algorithm-detected RoA was manually verified. The right atrium (RA) consistently exhibited fibrillatory signals during FC. FC with and without AF hadsimilar left-to-right frequency gradients. Basket maps were either uninterpretable (847 of 990 Topera, 132 of 148 Cartofinder) or had unverifiable RoA. OctaRay contact mapping showed 4% RoA (n=30 of 679) and63% FoA (n=429 of 679). Verified RoA clustered at consistent sites, was more common in the RA than leftatrium (odds ratio: 3.5), and colocalized with sites of frequency breakdown in the crista terminalis and RA appendage. During pacing, spurious FoA sites were identified around the atria, but not at the actual pacing sites. RoA and FoA site distribution was similar during pacing with and without induction, and during induced AF. Mapping algorithms were unable to detect pacing sites as true drivers of FC, and detected epiphenomenal RoA and FoA sites unrelated to AF induction or maintenance. Algorithm-detected RoA and FoAdidnot identify true AF drivers.

Bioinformatic analysis for the identification of potential gene interactions and therapeutic targets in atrial fibrillation.

Atrial fibrillation (AF) is the most common type of tachycardia. The major injury caused by AF is a systemic embolism. Although AF therapies have evolved substantially, the success rate of sinus rhythm maintenance is relatively low. The reason is the incomplete understanding of the AF mechanisms. A Gene Expression Omnibus (GEO) dataset (GSE79768) was downloaded. Differentially expressed genes (DEGs) were identified by bioinformatic analysis. Enriched terms and pathways were identified by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A protein-protein interaction (PPI) network was constructed to determine regulatory genes. CytoHubba and the Molecular Complex Detection (MCODE) algorithm were used to identify potential hub genes and important modules. The Predicting Associated Transcription Factors From Annotated Affinities (PASTAA) method was used to predict transcription factors (TFs). Two hundred thirty-five upregulated DEGs and seventy-seven downregulated DEGs were identified. In the GO biological process, cellular component, and molecular function analyses, positive regulation of cell migration, anchoring junctions, and cell adhesion molecule binding were enriched significantly. The Hippo signalling pathway was the most significantly enriched pathway. In the PPI network analysis, we found that Class A/1 (rhodopsin-like receptors) may be the critical module. Ten hub genes were extracted, including 6 upregulated genes and 4 downregulated genes. CXCR2, TLR4, and CXCR4 may play critical roles in AF. In the TF prediction, we found that Irf-1 may be implicated in AF. We found that the CXCR4, TLR4, CXCR2 genes, the Hippo signalling pathway and the class A/1 (rhodopsin-like receptors) module may play critical roles in AF occurrence and maintenance, which may provide novel targets for AF treatment.