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Background: Reduced cardiorespiratory fitness (CRF) is an independent risk factor for the progression of atrial fibrillation (AF). We hypothesized that reduced CRF is associated with structural, functional, and electrical remodeling of the left atrium., Objectives: This study sought to correlate objectively assessed CRF with functional and electrical left atrial (LA) parameters using invasive and noninvasive assessments., Methods: Consecutive patients with symptomatic AF undergoing catheter ablation were recruited. CRF was objectively quantified pre-ablation by using cardiopulmonary exercise testing. Using peak oxygen consumption, participants were classified as preserved CRF (>20 mL/kg/min) or reduced CRF (<20 mL/kg/min). LA stiffness was assessed invasively with hemodynamic monitoring and imaging during high-volume LA saline infusion. LA stiffness was calculated as ΔLA diameter/ΔLA pressure over the course of the infusion. LA function was assessed with echocardiographic measures of LA emptying fraction and LA strain. Electrical remodeling was assessed by using high-density electroanatomical maps for LA voltage and conduction., Results: In total, 100 participants were recruited; 43 had reduced CRF and 57 had preserved CRF. Patients with reduced CRF displayed elevated LA stiffness (P = 0.004), reduced LA emptying fraction (P = 0.006), and reduced LA reservoir strain (P < 0.001). Reduced CRF was also associated with reduced LA voltage (P = 0.039) with greater heterogeneity (P = 0.027) and conduction slowing (P = 0.04) with greater conduction heterogeneity (P = 0.02). On multivariable analysis, peak oxygen consumption was independently associated with LA stiffness (P = 0.003) and LA conduction velocities (P = 0.04)., Conclusions: Reduced CRF in patients with AF is independently associated with worse LA disease involving functional and electrical changes. Improving CRF may be a target for restoring LA function in AF., Competing Interests: Funding Support and Author Disclosures This study was supported by the Center for Heart Rhythm Disorders at the University of Adelaide. Drs Ariyaratnam, Mishima, Kadhim, Emami, and Fitzgerald are supported by Postgraduate Scholarships from the University of Adelaide. Dr Elliott is supported by a Future Leader Fellowship from the National Heart Foundation of Australia. Dr Sanders is supported by an Investigator Grant from the National Health and Medical Research Council of Australia. Dr Emami reports that the University of Adelaide has received consulting fees on his behalf from Medtronic and Biosense Webster. Dr Sanders has served on the advisory board of Medtronic, Abbott Medical, Boston Scientific, PaceMate, and CathRx; and reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Boston Scientific, and Abbott Medical, and that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific, and MicroPort CRM. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. All rights reserved.)

Importance: Ablation of persistent atrial fibrillation (AF) remains a challenge. Left atrial fibrosis plays an important role in the pathophysiology of AF and has been associated with poor procedural outcomes., Objective: To investigate the efficacy and adverse events of targeting atrial fibrosis detected on magnetic resonance imaging (MRI) in reducing atrial arrhythmia recurrence in persistent AF., Design, Setting, and Participants: The Efficacy of Delayed Enhancement-MRI-Guided Fibrosis Ablation vs Conventional Catheter Ablation of Atrial Fibrillation trial was an investigator-initiated, multicenter, randomized clinical trial involving 44 academic and nonacademic centers in 10 countries. A total of 843 patients with symptomatic or asymptomatic persistent AF and undergoing AF ablation were enrolled from July 2016 to January 2020, with follow-up through February 19, 2021., Interventions: Patients with persistent AF were randomly assigned to pulmonary vein isolation (PVI) plus MRI-guided atrial fibrosis ablation (421 patients) or PVI alone (422 patients). Delayed-enhancement MRI was performed in both groups before the ablation procedure to assess baseline atrial fibrosis and at 3 months postablation to assess for ablation scar., Main Outcomes and Measures: The primary end point was time to first atrial arrhythmia recurrence after a 90-day blanking period postablation. The primary safety composite outcome was defined by the occurrence of 1 or more of the following events within 30 days postablation: stroke, PV stenosis, bleeding, heart failure, or death., Results: Among 843 patients who were randomized (mean age 62.7 years; 178 [21.1%] women), 815 (96.9%) completed the 90-day blanking period and contributed to the efficacy analyses. There was no significant difference in atrial arrhythmia recurrence between groups (fibrosis-guided ablation plus PVI patients, 175 [43.0%] vs PVI-only patients, 188 [46.1%]; hazard ratio [HR], 0.95 [95% CI, 0.77-1.17]; P = .63). Patients in the fibrosis-guided ablation plus PVI group experienced a higher rate of safety outcomes (9 [2.2%] vs 0 in PVI group; P = .001). Six patients (1.5%) in the fibrosis-guided ablation plus PVI group had an ischemic stroke compared with none in PVI-only group. Two deaths occurred in the fibrosis-guided ablation plus PVI group, and the first one was possibly related to the procedure., Conclusions and Relevance: Among patients with persistent AF, MRI-guided fibrosis ablation plus PVI, compared with PVI catheter ablation only, resulted in no significant difference in atrial arrhythmia recurrence. Findings do not support the use of MRI-guided fibrosis ablation for the treatment of persistent AF., Trial Registration: ClinicalTrials.gov Identifier: NCT02529319.

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age ( n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.

Aims: Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the 'NACHT, LRR, and PYD Domains-containing Protein 3' (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF., Methods and Results: Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3-/-) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3-/- mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3-/-) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice., Conclusion: These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: High night-to-night variability in obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways., Objective: We elucidated the effect of repeated exposure to transient OSA conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF substrate., Methods: INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS)., Results: INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0% ± 0.5% vs CTR 5.1% ± 0.3%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033)., Conclusion: Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF substrates and was associated with increased AF susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The goal of this study was to describe functional endocardial-epicardial dissociation (FEED), signal complexities, and three-dimensional activation dynamics of the human atrium with structural heart disease (SHD)., Background: SHD commonly predisposes to arrhythmias. Although progressive remodeling is implicated, direct demonstration of FEED in the human atrium has not been reported previously., Methods: Simultaneous intraoperative mapping of the endocardial and epicardial lateral right atrial wall was performed by using 2 high-density grid catheters during sinus rhythm, pacing drive (600 ms and 400 ms cycle length), and premature extrastimulation (PES). Unipolar electrograms (EGMs) were exported into custom-made software for activation and phase mapping. Difference of ≥20 ms between paired endocardial and epicardial electrodes defined dissociation. EGMs with ≥3 deflections were classified as fractionated., Results: Sixteen patients (mean age 60.5 ± 4.1 years; 18.7% with a history of atrial fibrillation) with SHD (43% ischemia, 57% valvular disease) were included. A total of 9,218 EGMs were analyzed. Compared with sinus rhythm, phase and activation analyses showed significant FEED during pacing at 600 ms and 400 ms (phase mapping 22.4% vs. 10% [p < 0.0001] and 25.8% vs. 10% [p < 0.0001], respectively; activation mapping 25.4% vs. 7.8% [p < 0.0001] and 27.7% vs. 7.8% [p < 0.0001]) and PES (phase mapping 34% vs. 10% [p < 0.0001]; activation mapping 29.5% vs. 7.8% [p < 0.0001]). Fractionated EGMs occurred significantly more during PES compared with sinus rhythm (50.2% vs. 39.5%; p < 0.0001). Activation patterns differed significantly during pacing drive and PES, with preferential epicardial exit during the latter (15.9% vs. 13.8%; p = 0.046)., Conclusions: Simultaneous endocardial-epicardial mapping revealed significant FEED with signal fractionation and preferential epicardial breakthroughs with PES. Such complex three-dimensional interaction in electrical activation provides mechanistic insights into atrial arrhythmogenesis with SHD., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to determine the impact of rate and direction on left atrial (LA) substrate., Background: The extent to which substrate mapped in sinus rhythm varies according to cycle length and direction of wave front propagation is unknown., Methods: A total of 73 consecutive patients with atrial fibrillation (AF) underwent electroanatomic LA mapping before pulmonary vein isolation using multipolar catheter during distal coronary sinus (CS) pacing at 600 ms and 300 ms. Additional maps were created during left superior pulmonary vein pacing at 300 ms. Bipolar voltage, conduction velocity (CV), and complex signals were determined., Results: Mean age was 61 ± 9 years, 67% were men, and 53% had persistent AF. Global mean voltage was lower with CS pacing at 300 ms compared with 600 ms (1.56 ± 0.47 mV vs. 1.74 ± 0.48 mV; p < 0.001). This was seen in all LA segments. Global CV was reduced (30.4 ± 13.0 cm/s vs. 38.6 ± 14.0 cm/s; p < 0.001) with greater complex signals at 300 ms (8.9% vs. 5.3%; p < 0.005). Compared with CS pacing, left superior pulmonary vein pacing demonstrated highly regional changes with decreased voltage (1.04 ± 0.43 mV vs. 1.47 ± 0.53 mV; p = 0.01) and CV (24.4 ± 13.0 cm/s vs. 39.9 ± 16.6 cm/s; p = 0.008), and greater complex signals posteriorly. Longer AF duration in paroxysmal AF (p = 0.02) and shorter duration in persistent AF (p = 0.015) and left ventricular ejection fraction (p = 0.016) were independent predictors of voltage change., Conclusions: In patients with AF, variation in cycle length and direction of wave front activation produce both generalized and regional changes in voltage, CV, and complex fractionation, resulting in significant changes in substrate maps. This study highlights the potential limitations of static low-voltage maps to identify the AF ablation target zone., (Copyright © 2019. Published by Elsevier Inc.)

Background: Atrial fibrillation (AF) is common after pacemaker implantation. However, the impact of pacemaker algorithms in AF prevention is not well understood., Objective: The purpose of this study was to evaluate the role of pacing algorithms in preventing AF progression., Methods: A systematic search of articles using the PubMed and Embase databases resulted in a total of 754 references. After exclusions, 21 randomized controlled trials (8336 patients) were analyzed, comprising studies reporting ventricular pacing percentage (VP%) (AAI vs DDD, n = 1; reducing ventricular pacing [RedVP] algorithms, n = 2); and atrial pacing therapies (atrial preference pacing [APP], n = 14; atrial antitachycardia pacing [aATP]+APP, n = 3; RedVP+APP+aATP, n = 1)., Results: Low VP% (<10%) lead to a nonsignificant reduction in the progression of AF (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.57-1.13; P = .21; I 2 = 67%) compared to high VP% (>10%). APP algorithm reduced premature atrial complexes (PAC) burden (mean difference [MD] -1117.74; 95% CI -1852.36 to -383.11; P = .003; I 2 = 67%) but did not decrease AF burden (MD 8.20; 95% CI -5.39 to 21.80; P = .24; I 2 = 17%) or AF episodes (MD 0.00; 95% CI -0.24 to 0.25; P = .98; I 2 = 0%). Similarly, aATP+APP programming showed no significant difference in AF progression (odds ratio 0.65; 95% CI 0.36-1.14; P = .13; I 2 = 61%). No serious adverse events related to algorithm were reported., Conclusion: This meta-analysis of randomized controlled trials demonstrated that algorithms to reduce VP% can be considered safe. Low burden VP% did not significantly suppress AF progression. The atrial pacing therapy algorithms could suppress PAC burden but did not prevent AF progression., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Background: The posterior left atrium is an arrhythmogenic substrate that contributes to the initiation and maintenance of atrial fibrillation (AF); however, the feasibility, safety, and efficacy of posterior wall isolation (PWI) as an AF ablation strategy has not been widely reported., Methods: We undertook a systematic review and meta-analysis of studies performing PWI to assess (1) acute procedural success including the ability to achieve PWI and the number of procedure-related complications, (2) Long-term, clinical success including rates of arrhythmia recurrence and posterior wall reconnection, and (3) The efficacy of PWI compared with pulmonary vein isolation on preventing arrhythmia recurrence. MEDLINE, EMBASE, and Web of Science databases were searched in May 2018 to retrieve relevant studies. Results were pooled using a random effects model., Results: Seventeen studies (13 box isolation, 3 single ring isolation, and 1 debulking ablation) comprising 1643 patients (31.3% paroxysmal AF, left atrial diameter 41±3.1 mm) were included in the final analysis. In studies focusing specifically on PWI, the acute procedural success rate for achieving PWI was 94.1% (95% CI, 87.2%-99.3%). Single-procedure 12-month freedom from atrial arrhythmia was 65.3% (95% CI, 57.7%-73.9%) overall and 61.9% (54.2%-70.8%) for persistent AF. Randomized control trials comparing PWI to pulmonary vein isolation (3 studies, 444 patients) yielded conflicting results and could not confirm an incremental benefit to PWI. Fifteen major complications (0.1%), including 2 atrio-esophageal fistulas, were reported., Conclusions: PWI as an end point of AF ablation can be achieved in a large proportion of cases with good rates of 12-month freedom from atrial arrhythmia. Although the procedure-related complication rate is low, it did not eliminate the risk of atrio-esophageal fistula. Registration: URL: http://www.crd.york.ac.uk/prospero. PROSPERO registration number: CRD42018107212.

Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity and mortality. The autonomic nervous system has a significant role in the milieu predisposing to the triggers, perpetuators and substrate for atrial fibrillation. It has direct electrophysiological effects and causes alterations in atrial structure. In a significant portion of patients with atrial fibrillation, the autonomic nervous system activity is likely a composite of reflex excitation due to atrial fibrillation itself and contribution of concomitant risk factors such as hypertension, obesity and sleep-disordered breathing. We review the role of autonomic nervous system activation, with focus on changes in reflex control during atrial fibrillation and the role of combined sympatho-vagal activation for atrial fibrillation initiation, maintenance and progression. Finally, we discuss the potential impact of combined aggressive risk factor management as a strategy to modify the autonomic nervous system in patients with atrial fibrillation and to reverse the arrhythmogenic substrate., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Due to barriers to accessing timely elective electrical cardioversion (CV) for persistent AF (PeAF), we adopted a policy of instructing patients to present directly to the Emergency Department (ED) for CV., Objective: We compare a strategy of Emergency CV (ED-CV) versus Elective CV (EL-CV) for treatment of symptomatic PeAF., Methods: Between 2014 and 7, we evaluated 150 patients undergoing CV for PeAF. ED-CV patients were provided an AF action plan for recurrent symptoms and advised to present to ED within 36 h. EL-CV patients followed standard care, including cardiologist referral and placement on an elective hospital waiting list. Follow-up was 12 months., Results: We included 75 consecutive ED-CV patients and 75 consecutive EL-CV patients. ED-CV patients had a significantly shorter median AF duration prior to CV (1 day vs 3 months; p < 0.01) and less overall AF-related symptoms at 12 months (modified EHRA symptom score ≥ 2a in 44% vs 72%; p = 0.005). Time to next AF recurrence was longer in the ED-CV group (295 ± 15 vs 245 ± 15 days; logrank p = 0.001), as was time to AF ablation referral (314 ± 13 vs 276 ± 15 days; logrank p = 0.01). Baseline LA area was similar (ED-CV 27 ± 4 cm 2 vs EL-CV 28 ± 11 cm 2 ; p = 0.67), however EL-CV had larger atria at follow-up (31 ± 8 vs 26 ± 6 cm 2 ; p = 0.01). There were no complications in either group., Conclusion: ED-CV is an acceptable strategy for symptomatic PeAF. In addition to reduced time spent in AF and improved symptom scores, this strategy may also slow progression of atrial substrate & delay onset of next AF episode., (Copyright © 2018. Published by Elsevier B.V.)

Atrial fibrillation (AF) and heart failure (HF) pose international health care challenges that contribute significantly to hospitalizations, morbidity, mortality, and significant health care costs. Both AF and HF contribute to the development of each other and both are associated with a worsened prognosis when they occur together. Assessment of systolic function via transthoracic echocardiography is essential in the investigation of the AF patient. Clinical and echocardiographic assessment may classify AF patients with HF into HF with reduced ejection fraction (HF-rEF) and HF with preserved ejection fraction (HF-pEF). Such classification can assist in numerous important management decisions in AF., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Aims: Atrio-oesophageal fistula (AOF) is a potentially lethal complication of atrial fibrillation (AF) ablation. Many studies have evaluated the presence and prevention of endoscopically-detected oesophageal lesions (EDOL) as a proxy measure for risk of AOF. This systematic review and meta-analysis sought to determine the prevalence of EDOL and effectiveness of general preventive measures during AF ablation., Methods and Results: We searched electronic databases for studies reporting prevalence or prevention of EDOL post-AF ablation. Pooled prevalence were reported with 95% confidence intervals (CI) while studies evaluating preventive measures including oesophageal temperature monitoring (OTM), esophageal manipulation and type of anaesthesia were analyzed descriptively or by random-effects modeling. Twenty-five studies were included in the analysis. Any and ulcerated EDOL pooled prevalence was 11% (95%CI, 6-15%) and 5% (95%CI, 3-7%), respectively. In six studies, there was no difference in EDOL with or without OTM (pooled OR 1.65, 95%CI, 0.22-12.55). There was no difference using a multi-sensor versus single-sensor OTM (one study) nor when using a deflectable probe (two studies). Oesophageal displacement was associated with significant instrumentation injury in one study. Two studies evaluating Oesophageal cooling showed conflicting results. General anaesthesia was associated with more EDOL than conscious sedation in two studies., Conclusion: The pooled prevalence of any and ulcerated EDOL post-ablation was 11% and 5%, but varied between studies. Techniques such as OTM and oesophageal displacement or cooling have not conclusively demonstrated a reduction in EDEL, while general anaesthesia may be associated with higher EDOL risk. Further randomized data are critically needed to validate and develop measures to prevent EDOL and AOF.

Introduction: Atrioesophageal fistula (AEF) is a dire complication of atrial fibrillation ablation. The diagnostic yield of computed tomography (CT) chest, the role and timing of repeat testing, and the value of other investigations in the diagnosis of AEF is uncertain., Methods: We systematically reviewed published AEF cases to evaluate radiological, bedside, and biochemical investigations for AEF (registered on PROSPERO [CRD42017077493])., Results: Eighty-seven articles with 126 patients (median age, 59 years; male, 71%) were included in the analysis. CT chest was performed in 88% (111/126) and was abnormal in 87%. A clear diagnosis of AEF (fistula/perforation) was only detected in 35% (34/97). Other major findings included free air in mediastinum (26%), left atrium (LA), or LA wall (24%). In 11 patients with normal/nonspecific initial CT chest, major abnormalities were detected in 91% (10/11) of repeat CT chest performed 6 days (median; range, 4-22) after initial scan. Initial CT head was normal in 51%; diffuse air emboli was identified in 79% (22/28). Initial transthoracic echocardiography was normal in 61% of cases. The spectrum of radiological abnormalities included Air (mediastinum/LA), Effusion (pleural/pericardial), Fistula/Perforation, and Thickening (esophagus/LA) - "AEF-Tests." Esophagram demonstrated contrast extravasation in 87% (13/15). Blood culture was consistently positive (100%; 28/28), particularly for streptococcus species (93%; 26/28)., Conclusion: The diagnosis of AEF remains challenging. Clinicians should be aware of the limitations in the yield of CT chest, the variety of major abnormalities reported, the need for repeat testing, unique brain imaging findings, and the importance of positive blood cultures and raised inflammatory markers., (© 2018 Wiley Periodicals, Inc.)

Background: Current phase mapping systems for atrial fibrillation create 2-dimensional (2D) maps. This process may affect the accurate detection of rotors. We developed a 3-dimensional (3D) phase mapping technique that uses the 3D locations of basket electrodes to project phase onto patient-specific left atrial 3D surface anatomy., Objective: We sought to determine whether rotors detected in 2D phase maps were present at the corresponding time segments and anatomical locations in 3D phase maps., Methods: One-minute left atrial atrial fibrillation recordings were obtained in 14 patients using the basket catheter and analyzed off-line. Using the same phase values, 2D and 3D phase maps were created. Analysis involved determining the dominant propagation patterns in 2D phase maps and evaluating the presence of rotors detected in 2D phase maps in the corresponding 3D phase maps., Results: Using 2D phase mapping, the dominant propagation pattern was single wavefront (36.6%) followed by focal activation (34.0%), disorganized activity (23.7%), rotors (3.3%), and multiple wavefronts (2.4%). Ten transient rotors were observed in 9 of 14 patients (64%). The mean rotor duration was 1.1 ± 0.7 seconds. None of the 10 rotors observed in 2D phase maps were seen at the corresponding time segments and anatomical locations in 3D phase maps; 4 of 10 corresponded with single wavefronts in 3D phase maps, 2 of 10 with 2 simultaneous wavefronts, 1 of 10 with disorganized activity, and in 3 of 10 there was no coverage by the basket catheter at the corresponding 3D anatomical location., Conclusion: Rotors detected in 2D phase maps were not observed in the corresponding 3D phase maps. These findings may have implications for current systems that use 2D phase mapping., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: This study sought to evaluate the spatial relationships of focal electrical sources (FSs) to complex fractionated atrial electrograms (CFAE) and continuous electrical activity (CEA)., Background: Fractionated atrial electrograms have been associated with atrial fibrillation (AF) drivers in computational studies and represent ablation targets in the management of persistent AF., Methods: We included a subset of 66 patients (age: 63 [56, 67] years, 69% persistent AF) with electroanatomic data from the SELECT AF (Selective complex fractionated atrial electrograms targeting for atrial fibrillation) randomized control trial that compared the efficacy of CFAE with CEA ablation in AF patients undergoing pulmonary vein antral ablation. Focal sources were identified based on bipolar electrogram periodicity and QS unipolar electrogram morphology., Results: A total of 77 FSs (median: 1 [1st quartile, 3rd quartile: 1, 2] per patient) were identified most commonly in the pulmonary vein antrum and left atrial appendage. The proportions of FSs inside CFAE and CEA regions were similar (13% vs. 1.3%, respectively; p = 0.13). Focal sources were more likely to be on the border zone of CFAEs than in CEAs (49% vs. 7.8%, respectively; p = 0.012). Following ablation, 53% of patients had ≥1 unablated extrapulmonary vein FS. The median number of unablated FS was higher in patients with AF recurrence post ablation than in patients without (median: 1 [0, 1] vs. 0 [0, 1], respectively; p = 0.026)., Conclusions: One-half of the FSs detected during AF localized to the border of CFAE areas, whereas most of the FSs were found outside CEA areas. CFAE or CEA ablation leaves a number of FS unablated, which is associated with AF recurrence. These findings suggest that many CFAEs may arise from passive wave propagation, remote from FS, which may limit their therapeutic efficacy in AF substrate modification., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: With the recent advent of high-density (HD) 3-dimensional (3D) mapping, the utility of entrainment is uncertain. However, the limitations of visual representation and interpretation of these high-resolution 3D maps are unclear., Objective: The purpose of this study was to determine the strengths and limitations of both HD 3D mapping and entrainment mapping during mapping of right atrial macroreentry., Methods: Fifteen patients were studied. The number and type of circuits accounting for ≥90% of the tachycardia cycle length using HD 3D mapping were verified using systematic entrainment mapping. Entrainment sites with an unexpectedly long postpacing interval despite proximity to the active circuit were evaluated., Results: Based on HD 3D mapping, 27 circuits were observed: 12 peritricuspid, 2 upper loop reentry, 10 lower loop reentry, and 3 lateral wall circuits. With entrainment, 17 of the 27 circuits were active: all 12 peritricuspid and 2 upper loop reentry. However, lower loop reentry was confirmed in only 3 of 10, and none of the 3 lateral wall circuits were present. Mean percentage of tachycardia cycle length covered by active circuits was 98% ± 1% vs 97% ± 2% for passive circuits (P = .09). None of the 345 entrainment runs terminated tachycardia or changed tachycardia mechanism. In 8 of 15 patients, 13 examples of unexpectedly long postpacing interval were observed at entrainment sites located distal to localized zones of slow conduction seen on HD 3D mapping., Conclusion: Using HD 3D mapping, "visual reentry" may be due to passive circuitous propagation rather than a critical reentrant circuit. HD 3D mapping provides new insights into regional conduction and helps explain unusual entrainment phenomena., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Besides hypertension, obesity and the metabolic syndrome have recently emerged as risk factors for atrial fibrillation. This study sought to delineate the development of an arrhythmogenic substrate for atrial fibrillation in hypertension with and without concomitant obesity and metabolic syndrome., Methods and Results: We compared obese spontaneously hypertensive rats (SHR-obese, n=7-10) with lean hypertensive controls (SHR-lean, n=7-10) and normotensive rats (n=7-10). Left atrial emptying function (MRI) and electrophysiological parameters were characterized before the hearts were harvested for histological and biochemical analyses. At the age of 38 weeks, SHR-obese, but not SHR-lean, showed increased body weight and impaired glucose tolerance together with dyslipidemia compared with normotensive rats. Mean blood pressure was similarly increased in SHR-lean and SHR-obese when compared with normotensive rats (178±9 and 180±8 mm Hg [not significant] versus 118±5 mm Hg, P <0.01 for both), but left ventricular end-diastolic pressure was more increased in SHR-obese than in SHR-lean. Impairment of left atrial emptying function, increase in total atrial activation time, and conduction heterogeneity, as well as prolongation of inducible atrial fibrillation durations, were more pronounced in SHR-obese as compared with SHR-lean. Histological and biochemical examinations revealed enhanced triglycerides and more pronounced fibrosis in the left atrium of SHR-obese. Besides increased expression of profibrotic markers in SHR-lean and SHR-obese, the profibrotic extracellular matrix protein osteopontin was highly upregulated only in SHR-obese., Conclusions: In addition to hypertension alone, concomitant obesity and metabolic syndrome add to the atrial arrhythmogenic phenotype by impaired left atrial emptying function, local conduction abnormalities, interstitial atrial fibrosis formation, and increased propensity for atrial fibrillation., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Recent advances in our understanding of the mechanisms underlying atrial fibrillation (AF) have further underscored the complex pathophysiological basis of the arrhythmia. It has become apparent that the current clinical classification of AF does not reflect the severity of the underlying atrial disease. Atrial fibrosis has been identified as the key structural change in different substrates that are responsible for the perpetuation of AF. Three-dimensional electroanatomical mapping and late gadolinium-enhanced magnetic resonance imaging are novel modalities that can be used to facilitate identification and quantitation of atrial fibrosis for improved delineation of the AF substrate. Advances in AF mapping technology using endocardial 'panaromic' basket-type catheter and non-invasive body surface electrodes have facilitated the identification of two major arrhythmic mechanisms of interest, namely rotational ('rotors') and ectopic focal activations ('foci'). Ongoing research on these potential drivers of AF may provide guidance to more mechanistic based therapies to improve outcomes for this complex arrhythmia in the future. Here, we aim to review the differences in AF substrate in those with paroxysmal and more persistent forms of the arrhythmia by evaluating fibrosis, rotors and foci, towards improved AF substrate classification and individualised substrate based therapies., (Copyright © 2017. Published by Elsevier B.V.)

Exercise has substantial health benefits with pleomorphic vascular, metabolic, psychological and anti-neoplastic actions resulting in improved quality of life and longevity. Despite these many benefits, numerous studies have shown that endurance athletes are more likely to develop atrial fibrillation (AF) than non-athletes. The type, intensity and amount of sport appears to influence the risk of developing AF. Several endurance sport activities have been shown to increase the risk of developing AF but an excess in AF has not been shown in non-endurance sports. Furthermore, lifetime hours of participation appear to increase the risk of developing AF. Intriguingly, women appear relatively protected and an association between endurance sport and AF has not been clearly demonstrated amongst female endurance athletes. The mechanisms by which endurance sport promotes the development of AF are unclear. There are, however, a number of pathophysiological mechanisms which are known to increase the risk of AF in non-athletes which have correlates in athletes. These include structural remodelling of the left atrium, elevated left atrial pressure, inflammation, myocardial fibrosis, vagal tone, sinus bradycardia and genetic predisposition. In this article, we explore how some of these mechanisms may contribute to the development of AF in endurance athletes., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Evidence for epicardial-endocardial breakthrough (EEB) is derived from mapping inferences in patients with atrial fibrillation who may also have focal activations., Objective: The purpose of this study was to investigate whether EEB could be discerned during stable right atrial (RA) macroreentry using high-density high-spatial resolution 3-dimensional mapping., Methods: Macroreentry was diagnosed using 3-dimensional mapping and entrainment. Bipolar maps were reviewed for EEB defined as (1) presence of focal endocardial activation with radial spread unaccounted for by an endocardial wavefront and (2) present with the same timing on every tachycardia cycle. The EEB site was always in proximity to a line of endocardial conduction slowing or block. Distance and conduction velocity from the line of block to the EEB site was calculated. Electrograms at EEB sites were individually analyzed for morphology and to confirm direction of activation. Entrainment was performed at EEB sites., Results: Twenty-six patients were studied. Fourteen examples of EEB were seen: 11 at the posterior RA (4 at the superior portion of the posterior wall and 7 at the inferior section) and 1 each at the cavotricuspid isthmus postablation, RA septum, and inferolateral RA. The mean area of the EEB site was 0.6 ± 0.2 cm 2 . A mean of 79.5% ± 18.6% of unipolar electrograms at the EEB site demonstrated an rS morphology. The mean distance and conduction velocity from the line of endocardial block to the EEB site at the posterior RA was 13.6 ± 2.3 mm and 59.3 ± 12.3 cm/s, respectively. In 4 patients, entrainment demonstrated that EEB sites were within the circuit and in 1 of these patients critical to arrhythmia maintenance. Activation maps during tachycardia and coronary sinus pacing demonstrated EEB at the same anatomic site., Conclusion: EEB sites were demonstrated in stable atrial macroreentry supported by systematic entrainment confirmation and demonstration of the same phenomenon during pacing., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: Recent research has unravelled an increasing list of cardiac conditions and risk factors that may be responsible for the abnormal underlying atrial substrate that predisposes to atrial fibrillation (AF). Atrial fibrosis has been demonstrated as the pivotal structural abnormality underpinning conduction disturbances that promote AF in different disease models. Despite the advancement in our discoveries of the molecular mechanisms involved in the profibrotic milieu, targeted therapeutics against atrial fibrosis remain lacking. Areas covered: This review is focused on detailing the key molecular signalling pathways that contribute to atrial fibrosis including: angiotensin II, transforming growth factor (TGF- ß1), connective tissue growth factor (CTGF) and endothelin-1. We also discussed the potential therapeutic options that may be useful in modulating the abnormal atrial substrate. In addition, we examined the new paradigm of AF care in lifestyle and risk factor management that has been shown to arrest and reverse the atrial remodelling process leading to improved AF outcomes. Expert commentary: The future of AF care is likely to require an integrated approach consisting of aggressive risk factor management in addition to the established paradigm of rate and rhythm management and anticoagulation. Translational studies on molecular therapeutics to combat atrial fibrosis is urgently needed.

We describe a novel approach for simultaneously determining regional differences in action potential (AP) morphology and tissue electrophysiological properties in isolated atria. The epicardial surface of rat atrial preparations was placed in contact with a multi-electrode array (9 × 10 silver chloride electrodes, 0.1 mm diameter and 0.1 mm pitch). A glass microelectrode (100 MΩ) was simultaneously inserted into the endocardial surface to record intracellular AP from either of 2 regions (A, B) during pacing from 2 opposite corners of the tissue. AP duration at 80% of repolarisation and its restitution curve was significantly different only in region A (p < 0.01) when AP was initiated at different stimulation sites. Alternans in AP duration and AP amplitude, and in conduction velocity were observed during 2 separate arrhythmic episodes. This approach of combining microelectrode array and intracellular membrane potential recording may provide new insights into arrhythmogenic mechanisms in animal models of cardiovascular disease.

Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac disorder with diverse clinical outcomes including sudden death, heart failure, and stroke. Depressed heart rate variability (HRV), a measure of cardiac autonomic regulation, has been shown to predict mortality in patients with cardiovascular disease. Cardiac autonomic remodelling in animal models of HCM are not well characterised. This study analysed Gly203Ser cardiac troponin-I transgenic (TG) male mice previously demonstrated to develop hallmarks of HCM by age 21 weeks. 33 mice aged 30 and 50 weeks underwent continuous electrocardiogram (ECG) recording for 30 min under anaesthesia. TG mice demonstrated prolonged P-wave duration (P < 0.001) and PR intervals (P < 0.001) compared to controls. Additionally, TG mice demonstrated depressed standard deviation of RR intervals (SDRR; P < 0.01), coefficient of variation of RR intervals (CVRR; P < 0.001) and standard deviation of heart rate (SDHR; P < 0.001) compared to controls. Additionally, total power was significantly reduced in TG mice (P < 0.05). No significant age-related difference in either strain was observed in ECG or HRV parameters. Mice with HCM developed slowed atrial and atrioventricular conduction and depressed HRV. These changes were conserved with increasing age. This finding may be indicative of atrial and ventricular hypertrophy or dysfunction, and perhaps an indication of worse clinical outcome in heart failure progression in HCM patients., (© 2015 Wiley Publishing Asia Pty Ltd.)

Background: Temporal dynamics of electrical wave propagation during AF is unknown. There are reports of transient linking of atrial activation. We aim to characterize temporal dynamics of wave propagation patterns during AF in an established chronically remodeled substrate., Methods: Bi-atrial epicardial mapping of AF (mean duration 62±61s) was performed in 13 sheep with induced hypertension using custom-designed plaques. Wave propagation patterns were classified into periods of repetitive activity termed modes., Results: In total, we identified 9241 distinct depolarization events which were classified as: passing wave (69% occurrence, 68.6% of total time), point source (20.4%, 13.1%), wave collision (4%, 2.8%), re-entrant wave (0.7%, 6.3%), half-rotation (2.9%, 4.4%), wave splitting (2.7%, 4.3%), conduction block (0.05%, 0.03%) and figure of eight reentry (0.05%, 0.05%). Episodes of re-entrant activity had mean length 701±1012ms. A total of 435 modes of distinct periods of repetitive activity were detected (121 in LA and 314 in RA). Looking at temporal changes between modes, we found a preferential transition: change between train of waves propagating from direction of coronary sinus and reentrant activity. High density mapping of the hypertensive fibrillating atria observed 20% point sources and 0.7% of reentrant activation which may have served as drivers of AF. Remaining activations were peripheral waves. Majority of the activation was organized into events of transient linking with existence of preferential types of transitions., Conclusions: These findings support the importance of substrate based regions of anatomically or functionally determined preferential conduction in the maintenance of AF., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Macroreentrant atrial tachycardia is a common complication following surgery for congenital heart disease (CHD), and is often highly symptomatic with potentially significant hamodynamic consequences. Medical management is often unsuccessful, requiring the use of invasive procedures. Cavotricuspid isthmus dependent flutter is the most common circuit but atypical circuits also exist, involving sites of surgical intervention or areas of scar related to abnormal hemodynamics. Ablation can be technically challenging, due to complex anatomy, and difficulty with catheter stability. A thorough assessment of the patients status and pre-catheter ablation planning is critical to successfully managing these patients.

Background: The pulmonary vein-left atrial (PV-LA) junction is key in pathogenesis of AF, and acute stretch is an important stimulus to AF. We aimed to characterize the response of the junction to acute stretch, hypothesizing that stretch would result in electrophysiological changes predisposing to re-entry., Methods and Results: Fifteen participants undergoing cardiac surgery underwent evaluation of the right superior PV-LA junction using an epicardial mapping plaque. In 10, this was performed before and after atrial stretch imposed by rapid volume expansion, and in 5, it was performed with an intervening observation period. Activation was characterized by conduction slowing and electrogram fractionation transversely across the PV-LA junction, with lines of block also demonstrated perpendicular to the junction. Conduction was decremental (plaque activation time 135.8 ± 46.8 ms with programmed extra stimuli at 10 ms above effective refractory period versus 66.1 ± 22.9 ms with pacing at 400 ms; P<0.001) and percentage fractionation was greater with programmed extra stimuli at 10 ms above (33.5%± 15.3% versus 20.7%± 14.0%, P=0.001). Right atrial pressure increased by 2.5 ± 1.8 mm Hg (P=0.002) with volume expansion. Stretch resulted in conduction slowing across the PV-LA junction (increase in activation time 10.9 ± 14.6 ms in acute stretch group versus -0.1 ± 4.5 ms in control group; P=0.002). Conduction slowing was more marked with programmed extra stimuli at 10 ms above effective refractory period than with stable pacing (13.4 ± 16.5 ms versus 1.7 ± 5.4 ms; P=0.003). Stretch resulted in a significant increase in fractionated electrograms (7.9%± 7.0% versus -0.4 ± 3.3; P=0.004)., Conclusions: Acute stretch results in conduction slowing across the PV-LA junction, with a greater degree of signal complexity. This substrate may be important in AF initiation and maintenance by promoting re-entry., (© 2014 American Heart Association, Inc.)

Atrial fibrillation (AF) is the most frequent cardiac arrhythmia in clinical practice. AF is often associated with profound functional and structural alterations of the atrial myocardium that compose its substrate. Recently, a relationship between the thickness of epicardial adipose tissue (EAT) and the incidence and severity of AF has been reported. Adipose tissue is a biologically active organ regulating the metabolism of neighbouring organs. It is also a major source of cytokines. In the heart, EAT is contiguous with the myocardium without fascia boundaries resulting in paracrine effects through the release of adipokines. Indeed, Activin A, which is produced in abundance by EAT during heart failure or diabetes, shows a marked fibrotic effect on the atrial myocardium. The infiltration of adipocytes into the atrial myocardium could also disorganize the depolarization wave front favouring micro re-entry circuits and local conduction block. Finally, EAT contains progenitor cells in abundance and therefore could be a source of myofibroblasts producing extracellular matrix. The study on the role played by adipose tissue in the pathogenesis of AF is just starting and is highly likely to uncover new biomarkers and therapeutic targets for AF.

Background: Recently pericardial adipose tissue (PAT) has been shown to be an independent predictor of atrial fibrillation (AF). Atrial PAT may influence underlying atrial musculature creating a substrate for AF. This study sought to validate the assessment of total and atrial PAT by standard cardiovascular magnetic resonance (CMR) measures and describe and validate a three dimensional atrial PAT model., Methods: 10 merino cross sheep underwent CMR using a 1.5 Tesla system (Siemens, Sonata, Erlangen, Germany). Atrial and ventricular short axis (SA) images were acquired, using ECG -gated steady state free precession sequences. In order to quantify total volume of adipose tissue, a three dimensional model was constructed from consecutive end-diastolic images using semi-automated software. Regions of adipose tissue were marked in each slice followed by linear interpolation of pixel intensities in spaces between consecutive image slices. Total volume of adipose tissue was calculated as a total volume of the three dimensional model and the mass estimated from volume measurements. The sheep were euthanized and pericardial adipose tissue was removed and weighed for comparison to the corresponding CMR measurements., Results: All CMR adipose tissue estimates significantly correlated with autopsy measurements (ICC > 0.80; p < 0.03). Intra- observer reliability in CMR measures was high, with 95% levels of agreement within 5.5% (ICC = 0.995) for total fat mass and its individual atrial (95% CI ± 8.3%, ICC = 0.993) and ventricular components (95% CI ± 6.6%, ICC = 0.989). Inter- observer 95% limits of agreement were within ± 10.7% (ICC = 0.979), 7.4% (ICC = 0.991) and 7.2% (ICC = 0.991) for atrial, ventricular and total pericardial adipose tissue, respectively., Conclusion: This study validates the use of a semi-automated three dimensional atrial PAT model utilizing standard (clinical) CMR sequences for accurate and reproducible assessment of atrial PAT. The measurement of local cardiac fat stores via this methodology could provide a sensitive tool to examine the regional effect of fat deposition on atrial substrate which potentially may influence AF ablation strategies in obese patients.

Objectives: We sought to assess the effect of atrial fibrillation (AF) on atrial thrombogenesis in humans by determining the impact of rate and rhythm., Background: Although AF is known to increase the risk of thromboembolic stroke from the left atrium (LA), the exact mechanisms remain poorly understood., Methods: We studied 55 patients with AF who underwent catheter ablation while in sinus rhythm; 20 patients were induced into AF, 20 patients were atrial paced at 150 beats/min, and 15 were control patients. Blood samples were taken from the LA, right atrium, and femoral vein at baseline and at 15 min in all 3 groups. Platelet activation (P-selectin) was measured by flow cytometry. Thrombin generation (thrombin-antithrombin [TAT] complex), endothelial dysfunction (asymmetric dimethylarginine [ADMA]), and platelet-derived inflammation (soluble CD40 ligand [sCD40L]) were measured using enzyme-linked immunosorbent assay., Results: Platelet activation increased significantly in both the AF (p < 0.001) and pacing (p < 0.05) groups, but decreased in control patients (p < 0.001). Thrombin generation increased specifically in the LA compared with the periphery in both the AF (p < 0.01) and pacing (p < 0.01) groups, but decreased in control patients (p < 0.001). With AF, ADMA (p < 0.01) and sCD40L (p < 0.001) levels increased significantly at all sites, but were unchanged with pacing (ADMA, p = 0.5; sCD40L, p = 0.8) or in control patients (ADMA, p = 0.6; sCD40L, p = 0.9)., Conclusions: Rapid atrial rates and AF in humans both result in increased platelet activation and thrombin generation. Prothrombotic activation occurs to a greater extent in the human LA compared with systemic circulation. AF additionally induces endothelial dysfunction and inflammation. These findings suggest that although rapid atrial rates increase the thrombogenic risk, AF may further potentiate this risk., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Obesity is associated with atrial fibrillation (AF); however, the mechanisms by which it induces AF are unknown., Objective: To examine the effect of progressive weight gain on the substrate for AF., Methods: Thirty sheep were studied at baseline, 4 months, and 8 months, following a high-calorie diet. Ten sheep were sampled at each time point for cardiac magnetic resonance imaging and hemodynamic studies. High-density multisite biatrial epicardial mapping was used to quantify effective refractory period, conduction velocity, and conduction heterogeneity index at 4 pacing cycle lengths and AF inducibility. Histology was performed for atrial fibrosis, inflammation, and intramyocardial lipidosis, and molecular analysis was performed for endothelin-A and -B receptors, endothelin-1 peptide, platelet-derived growth factor, transforming growth factor β1, and connective tissue growth factor., Results: Increasing weight was associated with increasing left atrial volume (P = .01), fibrosis (P = .02), inflammatory infiltrates (P = .01), and lipidosis (P = .02). While there was no change in the effective refractory period (P = .2), there was a decrease in conduction velocity (P<.001), increase in conduction heterogeneity index (P<.001), and increase in inducible (P = .001) and spontaneous (P = .001) AF. There was an increase in atrial cardiomyocyte endothelin-A and -B receptors (P = .001) and endothelin-1 (P = .03) with an increase in adiposity. In association, there was a significant increase in atrial interstitial and cytoplasmic transforming growth factor β1 (P = .02) and platelet-derived growth factor (P = .02) levels., Conclusions: Obesity is associated with atrial electrostructural remodeling. With progressive obesity, there were changes in atrial size, conduction, histology, and expression of profibrotic mediators. These changes were associated with spontaneous and more persistent AF., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background: Atrial premature contractions (APCs) are well described to precede the initiation of paroxysmal atrial fibrillation (pAF). However, whether APC characteristics alter with progression of the arrhythmia is unknown., Objective: To determine the APC characteristics in terms of burden and relative coupling interval with progression of the AF disease process., Methods: Fifty consecutive patients with pAF, 50 consecutive patients with persistent AF (perAF), and 25 age-matched controls underwent clinical review, transthoracic echocardiography, and ambulatory electrocardiogram monitoring. After excluding 29 patients who had AF for the entire recording (n = 24) or unreliable recordings (n = 5), we analyzed data from 49 patients with pAF, 24 patients with perAF, and 23 healthy controls. All normal morphology R-R intervals with a >25% decrease in R-R coupling compared with the previous R-R interval (coupling interval index) were deemed APCs (n = 95,873)., Results: The median APC burden was higher in patients with pAF (2 [1-22] APCs/h; P = .004) and perAF (3 [1-6] APCs/h; P = .04) than in controls (1 [0-1] APCs/h) but was not different (P = .66) between the AF subgroups. Patients with pAF had a distinct increase in ectopy burden after 7 PM and elevation throughout the night (P = .002) in comparison with a blunted and complementary temporal response in the perAF cohort (P = .01). Patients with pAF demonstrated a greater proportion of shortly coupled APCs (29% [13-45]; P = .04) compared with persistent arrhythmia (17% [5-29])., Conclusions: "Real-life" atrial trigger statistics of APC burden, timing, and diurnal rhythms track the transition from a trigger-based, autonomically sensitive paroxysmal arrhythmia to a more substrate-based persistent disease., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Aims: There is increasing evidence of the role direction-dependent conduction plays in the arrhythmogenic interaction between ectopic triggers and abnormal atrial substrates. We thus sought to characterize direction-dependent conduction in chronically stretched atria., Methods and Results: Twenty-four patients with chronic atrial stretch due to mitral stenosis and 24 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium, crista terminalis, and coronary sinus (CS) characterized direction-dependent conduction along linear catheters and across the crista terminalis. Bi-atrial electroanatomic maps were created in both sinus rhythm and an alternative wavefront direction by pacing from the distal CS. This allowed an assessment of conduction velocities, electrogram, and voltage characteristics during wavefronts propagating in different directions.  While differing wavefront directions caused changes in both chronic atrial stretch and reference patients (P< 0.001 for all), these direction-dependent changes were greater in chronic atrial stretch compared with reference patients, who exhibited greater slowing in conduction velocities (P= 0.09), prolongation of bi-atrial activation time (P= 0.04), increase in number (P< 0.001) and length (P< 0.001) of lines of conduction block, increase in fractionated electrograms (P< 0.001), and decrease in voltage (P= 0.08) during left-to-right compared with right-to-left atrial activation. These direction-dependent changes were associated with a greater propensity for chronically stretched atria to develop atrial fibrillation (P= 0.02)., Conclusions: Atrial remodelling in chronic atrial stretch exacerbates physiological direction-dependent conduction characteristics. Our data suggest that the greater direction-dependent conduction seen in patients with chronic atrial stretch may promote arrhythmogenesis due to ectopic triggers from the left atrium.

Background: Whether curative ablation can prevent progression of the atrial electroanatomic remodeling associated with atrial fibrillation (AF) is not known., Objective: The purpose of this study was to determine whether successful radiofrequency ablation (RFA) of AF can prevent progression of the atrial substrate associated with AF., Methods: Detailed right atrial electroanatomic maps from 11 patients without apparent structural heart disease undergoing RFA of AF at baseline and ≥6 months following successful RFA were compared to 11 control patients undergoing electrophysiologic evaluation of supraventricular tachycardia. Bipolar voltage, conduction, effective refractory periods (ERPs), and signal complexity were assessed., Results: At baseline compared with the control group, the AF group demonstrated (1) lower voltage (P <.001); (2) slowed conduction (P = .005); (3) more prevalent complex signals (P <.001); (4) prolonged regional refractoriness (P <.05), and (5) left atrial dilation (P = .01). At 10 ± 13 month follow-up, the AF group demonstrated the following compared to baseline: (1) lower voltage (P <.05); (2) either no improvement or further slowing of conduction; (3) further prolongation of regional refractoriness (P <.05); and (4) reversal of left atrial dilation (P <.05)., Conclusion: Patients with lone AF demonstrate evidence of an abnormal atrial substrate at baseline compared to control patients without AF. This substrate does not appear to reverse even after successful catheter ablation. These findings may have implications for long-term outcomes of ablation and for timing of ablative intervention., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: There is a known association between obstructive sleep apnea (OSA) and atrial fibrillation (AF); however, how OSA affects the atrial myocardium is not well described., Objective: To determine whether patients with OSA have an abnormal atrial substrate., Methods: Forty patients undergoing ablation of paroxysmal AF and in sinus rhythm (20 with OSA [apnea-hypopnea index ≥ 15] and 20 reference patients with no OSA [apnea-hypopnea index < 15] by polysomnography) were studied. Multipolar catheters were positioned at the lateral right atrium (RA), coronary sinus, crista terminalis, and RA septum to determine the effective refractory period at 5 sites, conduction time along linear catheters at the RA and the coronary sinus, conduction at the crista terminalis, and sinus node function (corrected sinus node recovery time). Biatrial electroanatomic maps were created to determine the voltage, conduction, and distribution of complex electrograms (duration ≥ 50 ms)., Results: The groups had no differences in the prevalence of established risk factors for AF. Patients with OSA had the following compared with those without OSA: no difference in effective refractory period (P = .9), prolonged conduction times along the coronary sinus and RA (P = .02), greater number (P = .003) and duration (P = .03) of complex electrograms along the crista terminalis, longer P-wave duration (P = .01), longer corrected sinus node recovery time (P = .02), lower atrial voltage (RA, P <.001; left atrium, P <.001), slower atrial conduction velocity (RA, P = .001; left atrium, P = .02), and more widespread complex electrograms in both atria (RA, P = .02; left atrium, P = .01)., Conclusion: OSA is associated with significant atrial remodeling characterized by atrial enlargement, reduction in voltage, site-specific and widespread conduction abnormalities, and longer sinus node recovery. These features may in part explain the association between OSA and AF., (Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Background: The pulmonary veins (PVs) and the PV-LA (left atrium) junction are established sources of triggers initiating atrial fibrillation. In addition, they have been implicated in the maintenance of arrhythmia., Objective: To undertake high-density electrophysiological characterization of the right superior PV-LA junction in humans., Methods: Mapping was performed in 18 patients without a history of atrial fibrillation undergoing cardiac surgery. A high-density epicardial plaque was positioned at the anterior right superior pulmonary vein covering 3 regions: LA, PV-LA junction, and the PV. Isochronal maps were created during (1) sinus rhythm (SR); (2) LA pacing (LA-Pace); (3) PV pacing (PV-Pace); (4) LA programmed electrical stimulation (LA-PES); and (5) PV programmed electrical stimulation (PV-PES). Regional differences in conduction slowing/conduction block (CS/CB) and the prevalence of fractionated signals (FS) and double potentials (DPs) were assessed., Results: A region of isochronal crowding representing CS/CB developed at the PV-LA junction in 84% of the maps. Three distinct activation patterns were seen. Pattern 1: Uniform SR activation without CS/CB. LA-Pace and PES caused 1 to 2 lines of isochronal crowding (CS/CB) at the PV-LA junction. Pattern 2: CS/CB occurred at the PV-LA junction in SR. LA/PV-Pace and LA/PV-PES caused an increase in CS/CB at the PV-LA junction with widely split DPs and FS. Pattern 3: A single incomplete line of CS at the PV-LA junction in SR. With LA/PV pacing and LA/PV-PES, multiple lines (≥3) of CS/CB developed at the PV-LA junction with evidence of circuitous activation and a marked increase in DPs and FS., Conclusion: High-density epicardial mapping of the right superior pulmonary vein demonstrates marked functional conduction delay and circuitous activation patterns at the PV-LA junction, creating the substrate for reentry., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Percutaneous transseptal left atrial (LA) access is increasingly becoming a routine procedure in the electrophysiology and cardiac catheterisation laboratories. Our aim was to review an unselected large series of this procedure performed over a period of five years. We clinically characterised difficult cases and presented a method of safe and expeditious LA access. Overall, 543 transseptal punctures were performed. Of those, 10 were classified as difficult, with failure to access the LA in three or more attempts. In all 10 cases, surgical electrocautery was successfully used to facilitate needle puncture of the septum. All patients subsequently underwent an uncomplicated procedure. In conclusion, we describe a method to trouble-shoot the difficult transseptal access procedure, outlining the clinical characteristics, echocardiographic features and special precautions that need to be considered when utilising this method., (Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.)

Aims: Mapping of atrial fibrillation (AF) involves identification of low-voltage regions associated with complex fractionated electrograms (CFE) which theoretically represent abnormal substrate and targets for ablation. Whether low-voltage CFE areas also identify abnormal substrate during paced rhythm is unknown., Methods and Results: Twelve patients with persistent AF undergoing ablation of AF had high-density three-dimensional electroanatomic maps created during AF and paced rhythm (24 maps) and the mean voltage during AF and paced rhythm was compared for eight segments of the left atrium (LA). The following were correlated during AF and paced rhythm: regional mean voltage; %low voltage (defined as <0.5 mV); and extent of CFE. In addition, the relationship between the extent of CFE in AF: (i) %low voltage and (ii) conduction during paced rhythm were determined. Mean voltage was lower during AF than paced rhythm for all regions and globally (0.7 ± 0.2 mV vs. 2.1 ± 0.6 mV, P < 0.001). The regional and overall %low voltage of the LA was greater during AF than paced rhythm (53 ± 19% vs. 9 ± 2%, P < 0.001). There was no correlation between mean voltage or %low voltage during AF and paced rhythm. Complex fractionated electrograms were prevalent throughout all regions during AF, but did not correlate with %low voltage, fractionation, or slowed conduction during paced rhythm., Conclusion: Areas of CFE and low voltage recorded during AF frequently demonstrate normal atrial myocardial characteristics (normal conduction, electrograms, and voltage) during sinus rhythm. Therefore, AF CFE sites do not necessarily identify regions of an abnormal atrial substrate. However, this does not exclude the possibility that CFE might identify a focal driver or source occurring in a region of normal atrial myocardium.

Background: It has been suggested that omega-3 polyunsaturated fatty acids (n-3 PUFAs) may prevent the development of atrial fibrillation (AF)., Objective: The purpose of this study was to evaluate the impact of these agents on development of the AF substrate in heart failure (HF)., Methods: In this study, HF was induced by intracoronary doxorubicin infusions. Twenty-one sheep [7 with n-3 PUFAs treated HF (HF-PUFA), 7 with olive oil-treated HF controls (HF-CTL), 7 controls (CTL)] were studied. Open chest electrophysiologic study was performed with assessment of biatrial effective refractory period (ERP) and conduction. Cardiac function was monitored by magnetic resonance imaging. Atrial n-3 PUFAs levels were quantified using chromatography. Structural analysis was also performed., Results: Atrial n-3 PUFAs levels were twofold to threefold higher in the HF-PUFA group. n-3 PUFAs prevented the development of HF-related left atrial enlargement (P = .001) but not left ventricular/atrial dysfunction. Atrial ERP was significantly lower in the HF-PUFA group (P <.001), but ERP heterogeneity was unchanged. In addition, n-3 PUFAs suppressed atrial conduction abnormalities seen in HF of prolonged P-wave duration (P = .01) and slowed (P <.001) and heterogeneous (P <.05) conduction. The duration of induced AF episodes in HF-PUFA was shorter (P = .02), although AF inducibility was unaltered (P = NS). A 20% reduction of atrial interstitial fibrosis was seen in the HF-PUFA group (P <.05)., Conclusion: In this ovine HF study, chronic n-3 PUFAs use protected against adverse atrial remodeling by preventing atrial enlargement, fibrosis, and conduction abnormalities leading to shorter AF episodes despite lower ERP., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Introduction: All preclinical studies of atrial remodeling in heart failure (HF) have been confined to a single model of rapid ventricular pacing. To evaluate whether the atrial changes were specific to the model or represented an end result of HF, this study aimed to characterize atrial remodeling in an ovine model of doxorubicin-induced cardiomyopathy., Methods and Results: Fourteen sheep, 7 with cardiomyopathy induced by repeated intracoronary doxorubicin infusions and 7 controls, were studied. The development of HF was monitored by cardiac imaging and hemodynamic parameters. Open chest electrophysiological study was performed using custom-made 128-electrode epicardial plaque assessing effective refractory period (ERP) and conduction velocity. Atrial tissues were harvested for structural analysis. The HF group had demonstrable moderate global HF (left ventricular ejection fraction [LVEF]: 37.1 vs 46.4%; P = 0.003) and showed the following compared to controls: left atrial dilatation (P = 0.02) and dysfunction (P = 0.005); longer P-wave duration (P < 0.05); higher ERP at all cycle lengths (P ≤ 0.002) and locations (P < 0.001); slower conduction velocity (P < 0.001); increased conduction heterogeneity index (P < 0.001); increased atrial fibrosis (right atrial [RA]: 5.9 ± 2.6 vs 2.8 ± 0.9%; P < 0.0001, left atrial [LA]: 3.7 ± 2.2 vs 2.4 ± 1.1%; P = 0.002), and longer induced atrial fibrillation (AF) episodes (16 ± 22 vs 2 ± 3 seconds; P = 0.04)., Conclusion: In this model of HF, there was significant atrial remodeling characterized by atrial enlargement/dysfunction, increased fibrosis, slowed/heterogeneous conduction, and increased refractoriness associated with more sustained AF. These findings appear the "same sort" to previous models of HF implicating a final common substrate leading to the development of AF in HF., (© 2010 Wiley Periodicals, Inc.)

1. High-density cardiac electrophysiological study (EPS) of small animal atria has been limited to optical mapping techniques, which require complex and expensive equipment setup. We aim to evaluate the feasibility of carrying out EPS in isolated atrial tissues using a custom made high-density multiple-electrode array (MEA). 2. Isolated rat atrial preparations were studied. The MEA (4 × 5 mm) consisted of 90 silver chloride coated electrodes (0.1 mm diameter, 0.5 mm pitch) and was connected to a conventional EP system yielding 80 bipolar signals. Atrial tissues were placed over the MEA in a dish bubbled with 100% oxygen and superfused with modified HEPES solution at pH 7.35 and 37°C. Then, 1 mmol of 2,3-butanedione monoxime was added to suppress motion artifacts from muscle contractions. Custom plaque analysis software was used for offline conduction analysis. 3. Isolated atrial tissues showed good viability of > 30 min, allowing ample time for complete EPS. High quality electrograms with excellent signal to noise ratio were obtained. All electrophysiological parameters showed good reproducibility: effective refractory period, conduction velocity and heterogeneity index. Tachycardia was also inducible in these normal atria. 4. The present study shows the feasibility of performing high-density EPS of small isolated atrial tissues with a conventional electrode-based technique. The MEA system is compatible with standard electrophysiology recording systems and provides a novel, inexpensive option for detailed EPS in small animal models. In particular, it presents new research avenues to further explore the mechanisms of atrial arrhythmias in various transgenic and knockout rodent models., (© 2010 The Authors. Clinical and Experimental Pharmacology and Physiology © 2010 Blackwell Publishing Asia Pty Ltd.)

Background: Patients with lone atrial fibrillation (AF) have an abnormal atrial substrate., Objective: The purpose of this study was to determine the role of direction-dependent conduction in patients with lone AF., Methods: Twenty-four patients with paroxysmal lone AF and 24 reference patients with left-sided accessory pathways were studied. Multipolar catheters placed at the lateral right atrium, crista terminalis, coronary sinus (CS), and left atrial roof were used to determine direction-dependent conduction characteristics. Biatrial electroanatomic maps were created during sinus rhythm and with distal CS pacing to characterize direction-dependent differences in conduction velocities, electrogram complexity, and voltage., Results: Differing wavefront directions caused changes in conduction velocity (P <.001), biatrial activation times (P <.001), electrogram fragmentation (P <.001), site-specific conduction delays (P <.001), and voltage (P <.001) in both lone AF and reference patients. These direction-dependent abnormalities were amplified in lone AF patients compared to reference patients, who exhibited greater slowing in conduction velocities (P = .02), prolongation of biatrial activation time (P = .04), increase in number (P <.001) and length (P <.001) of lines of conduction block, increase in proportion of fractionated electrograms (P <.001), and decrease in voltage (P = .03) during distal CS pacing compared to sinus rhythm., Conclusion: This study demonstrates the marked direction-dependent conduction abnormalities present in patients with lone AF. These results provide further insights into the critical interplay between the underlying abnormal substrate and differing wavefront directions. The study suggests that direction-dependent conduction abnormalities may explain in part the greater arrhythmogenicity of ectopic triggers from the left atrium rather than the right atrium., (Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.)

Background: Hypertension accounts for more atrial fibrillation (AF) than any other predisposing factor., Objective: The purpose of this study was to characterize the time course, extent, and electrostructural correlation of atrial remodeling in chronic hypertension., Methods: Thirty-two sheep were studied: 21 with induced "one-kidney, one-clip" hypertension and 11 controls. Sequential closed-chest electrophysiologic studies were performed in 12 conscious animals (6 hypertensive, 6 controls) to evaluate progressive remodeling over 15 weeks. Additional atrial structural/functional analyses were performed in 5 controls and at 5, 10, and 15 weeks of hypertension (five per time point) via histology/cardiac magnetic resonance imaging to correlate with open-chest electrophysiologic parameters., Results: The hypertensive group developed a progressive increase in mean arterial pressure (P <.001). Mean effective refractory periods were uniformly higher at all time points (P <.001). Progressive biatrial hypertrophy (P = .003), left atrial dysfunction (P <.05) and greater AF inducibility were seen early with increased inflammation from 5 weeks of hypertension. In contrast, significant conduction slowing (P <.001) with increased heterogeneity (P <.001) along with increased interstitial fibrosis resulted in longer and more fractionated AF episodes only from 10 weeks of hypertension. Significant electrostructural correlation was seen in conduction abnormalities and AF inducibility with both atrial inflammation and fibrosis., Conclusion: Hypertension is associated with early and progressive changes in atrial remodeling. Atrial remodeling occurs at different time domains in chronic hypertension with significant electrostructural correlation of the remodeling cascade. Early institution of antihypertensive treatment may prevent formation of substrate capable of maintaining AF., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Chronic pulmonary disease and sleep apnea have been associated with the development of atrial fibrillation (AF)., Objective: The purpose of this study was to characterize the atrial electrical changes that occur with hypercapnia and hypoxemia and to determine their role in AF development., Methods: Seventeen sheep (6 control, 5 hypercapnia, 6 hypoxemia) underwent open chest electrophysiologic evaluation under autonomic blockade. A 64-electrode endocardial basket catheter was positioned in the right atrium, and 2 x 128 electrode epicardial plaques were sutured to the right atrial and left atrial appendages to determine atrial refractoriness (effective refractory period [ERP]) at 9 sites and 5 cycle lengths, conduction time to fixed points on each plaque, and AF vulnerability., Results: Hypercapnia was associated with a 152% lengthening of ERP from baseline and increased conduction time. ERPs rapidly returned to baseline, but recovery of conduction was delayed at least 117 +/- 24 minutes following resolution of hypercapnia. AF vulnerability was reduced during hypercapnia (with increased ERP) but increased significantly with subsequent return to eucapnia (when ERP normalized but conduction time remained prolonged). No significant changes in ERP, atrial conduction time, or AF vulnerability occurred in hypoxemic or control groups., Conclusion: Differential recovery of ERP and conduction that occurs following hypercapnia might account for the increased vulnerability to AF observed in the phase after return to eucapnia. This may explain in part the increased prevalence of AF in pulmonary disease and sleep apnea., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) is associated with an increased risk of thrombus formation in the left but not the right atrium. The mechanisms underlying this differential effect on the atria are unknown., Objective: The purpose of this study was to examine whether atrial-specific differences in platelet activation are present in patients with AF., Methods: Nineteen patients (13 men and 6 women; age 60 +/- 2 years) with AF undergoing ablation in sinus rhythm were studied. Blood samples from the left atrium, right atrium, and femoral vein were obtained at the start of the procedure and analyzed by whole-blood flow cytometry for expression of platelet P-selectin (CD62P), vitronectin receptor (CD51/61), and active glycoprotein IIb/IIIa receptor (PAC-1). Platelet aggregation was evaluated using adenosine diphosphate (ADP)-induced whole-blood impedance aggregometry. Seven patients with left-sided accessory pathway also were studies as a reference group for the effect of transseptal puncture on platelet reactivity., Results: Platelet P-selectin levels were significantly elevated in the left atrium compared to the right atrium (10.2% +/- 2.5% vs 8.6% +/- 2.3%, P <.05). CD51/61 and PAC-1 levels did not differ between sampling sites. ADP-induced platelet aggregation was significantly higher in the left atrium compared to the right atrium and femoral vein (P <.05 for both). Platelet P-selectin levels and ADP-induced platelet aggregation did not differ between sampling site in the reference group., Conclusion: In patients with AF, left atrial platelet reactivity is increased compared to the right atria and peripheral circulation. The study data suggest that the presence of chamber-specific platelet activation may explain, in part, the propensity for left atrial thrombus formation in patients with AF., (Copyright 2010 Heart Rhythm Society. All rights reserved.)