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Background: Clinical studies have reported that epicardial adipose tissue (EpAT) accumulation associates with the progression of atrial fibrillation (AF) pathology and adversely affects AF management. The role of local cardiac EpAT deposition in disease progression is unclear, and the electrophysiological, cellular, and molecular mechanisms involved remain poorly defined., Objectives: The purpose of this study was to identify the underlying mechanisms by which EpAT influences the atrial substrate for AF., Methods: Patients without AF undergoing coronary artery bypass surgery were recruited. Computed tomography and high-density epicardial electrophysiological mapping of the anterior right atrium were utilized to quantify EpAT volumes and to assess association with the electrophysiological substrate in situ. Excised right atrial appendages were analyzed histologically to characterize EpAT infiltration, fibrosis, and gap junction localization. Co-culture experiments were used to evaluate the paracrine effects of EpAT on cardiomyocyte electrophysiology. Proteomic analyses were applied to identify molecular mediators of cellular electrophysiological disturbance., Results: Higher local EpAT volume clinically correlated with slowed conduction, greater electrogram fractionation, increased fibrosis, and lateralization of cardiomyocyte connexin-40. In addition, atrial conduction heterogeneity was increased with more extensive myocardial EpAT infiltration. Cardiomyocyte culture studies using multielectrode arrays showed that cardiac adipose tissue-secreted factors slowed conduction velocity and contained proteins with capacity to disrupt intermyocyte electromechanical integrity., Conclusions: These findings indicate that atrial pathophysiology is critically dependent on local EpAT accumulation and infiltration. In addition to myocardial architecture disruption, this effect can be attributed to an EpAT-cardiomyocyte paracrine axis. The focal adhesion group proteins are identified as new disease candidates potentially contributing to arrhythmogenic atrial substrate., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) and left ventricular systolic dysfunction (LVSD) frequently co-exist despite adequate rate control. Existing randomized studies of AF and LVSD of varying etiologies have reported modest benefits with a rhythm control strategy., Objectives: The goal of this study was to determine whether catheter ablation (CA) for AF could improve LVSD compared with medical rate control (MRC) where the etiology of the LVSD was unexplained, apart from the presence of AF., Methods: This multicenter, randomized clinical trial enrolled patients with persistent AF and idiopathic cardiomyopathy (left ventricular ejection fraction [LVEF] ≤45%). After optimization of rate control, patients underwent cardiac magnetic resonance (CMR) to assess LVEF and late gadolinium enhancement, indicative of ventricular fibrosis, before randomization to either CA or ongoing MRC. CA included pulmonary vein isolation and posterior wall isolation. AF burden post-CA was assessed by using an implanted loop recorder, and adequacy of MRC was assessed by using serial Holter monitoring. The primary endpoint was change in LVEF on repeat CMR at 6 months., Results: A total of 301 patients were screened; 68 patients were enrolled between November 2013 and October 2016 and randomized with 33 in each arm (accounting for 2 dropouts). The average AF burden post-CA was 1.6 ± 5.0% at 6 months. In the intention-to-treat analysis, absolute LVEF improved by 18 ± 13% in the CA group compared with 4.4 ± 13% in the MRC group (p < 0.0001) and normalized (LVEF ≥50%) in 58% versus 9% (p = 0.0002). In those undergoing CA, the absence of late gadolinium enhancement predicted greater improvements in absolute LVEF (10.7%; p = 0.0069) and normalization at 6 months (73% vs. 29%; p = 0.0093)., Conclusions: AF is an underappreciated reversible cause of LVSD in this population despite adequate rate control. The restoration of sinus rhythm with CA results in significant improvements in ventricular function, particularly in the absence of ventricular fibrosis on CMR. This outcome challenges the current treatment paradigm that rate control is the appropriate strategy in patients with AF and LVSD. (Catheter Ablation Versus Medical Rate Control in Atrial Fibrillation and Systolic Dysfunction [CAMERA-MRI]; ACTRN12613000880741)., (Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Alcohol is popular in Western culture, supported by a perception that modest intake is cardioprotective. However, excessive drinking has detrimental implications for cardiovascular disease. Atrial fibrillation (AF) following an alcohol binge or the "holiday heart syndrome" is well characterized. However, more modest levels of alcohol intake on a regular basis may also increase the risk of AF. The pathophysiological mechanisms responsible for the relationship between alcohol and AF may include direct toxicity and alcohol's contribution to obesity, sleep-disordered breathing, and hypertension. We aim to provide a comprehensive review of the epidemiology and pathophysiology by which alcohol may be responsible for AF and determine whether alcohol abstinence is required for patients with AF., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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.)

Objectives: The purpose of this study was to evaluate diffuse myocardial fibrosis of the left ventricle (LV) in patients with atrial fibrillation (AF)., Background: Diffuse myocardial fibrosis is a hallmark of cardiomyopathy. Unlike replacement fibrosis, it is not visualized on delayed-enhancement cardiac magnetic resonance (CMR) imaging, but may be quantified with contrast-enhanced T(1) mapping methods. In atrial fibrillation (AF), it may be induced by arrhythmia or reflect pre-existing cardiomyopathy., Methods: Ninety subjects underwent CMR using a clinical 1.5-T scanner: 23 controls, 40 paroxysmal AF patients, and 27 persistent AF patients. Cardiac morphology and function was evaluated from CMR cine imaging. A histologically validated T(1) mapping sequence was used to calculate post-contrast T(1) relaxation time (T(1) time) of the LV myocardium as an index of diffuse myocardial fibrosis., Results: Age was similar across controls, paroxysmal AF patients, and persistent AF patients (54 ± 12 years, 58 ± 9 years, and 56 ± 10 years, p = NS). Persistent AF patients had larger indexed left atrium volume (55 ± 18 ml vs. 41 ± 12 ml and 47 ± 14 ml) and lower ejection fraction (54 ± 10% vs. 65 ± 6% and 61 ± 8%) than controls and paroxysmal AF patients (p < 0.05). Post-contrast ventricular T(1) time differed across all groups (controls, 535 ± 86 ms; paroxysmal AF, 427 ± 95 ms; persistent AF, 360 ± 84 ms; p < 0.001). Univariate predictors of post-contrast ventricular T(1) time included age, sex, AF category, ejection fraction, LV mass, congestive heart failure, and body mass index. After multivariate analysis, age, AF category, and ejection fraction remained independent predictors., Conclusions: Post-contrast ventricular T(1) mapping identifies diffuse LV fibrosis in patients with AF and provides new insights into the association between AF and adverse ventricular remodeling., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to evaluate the association between regional myocardial fibrosis and ventricular arrhythmias in patients with cardiomyopathy., Background: Patients with heart failure are at risk of sudden cardiac death (SCD). Current guidelines recommend implantable cardioverter-defibrillator (ICD) devices for a subgroup based on impaired left ventricular function. A significant proportion of devices never discharge, hence a more accurate method for targeting those at risk is desirable., Methods: We prospectively enrolled 103 patients meeting criteria for ICD implantation for primary prevention of SCD. Cardiac magnetic resonance imaging was performed before device implantation. Regional fibrosis was identified with late gadolinium enhancement (LGE)., Results: Median follow-up was 573 days (interquartile range: 379 to 863 days). The LGE identified regional fibrosis in 31 of 61 (51%) patients with nonischemic cardiomyopathy (NICM) and in all 42 patients with ischemic cardiomyopathy (ICM). There was a 29% (9 of 31) discharge rate in the NICM group with LGE compared with a 14% (6 of 42) discharge rate in the ICM group (p = NS). There were no ICD discharges in the NICM group without LGE, which was significantly lower than the rate observed in both the ICM patients (p = 0.04) and the NICM patients with LGE (p < 0.01). Left ventricular ejection fraction was similar in patients with and without device therapy (24 ± 12% vs. 26 ± 8%, p = NS) and those with or without LGE (25 ± 9% vs. 26 ± 9%, p = NS)., Conclusions: Patients with advanced cardiomyopathy and myocardial fibrosis demonstrated by LGE on cardiac magnetic resonance imaging have a high likelihood of appropriate ICD therapy. Correspondingly, absence of LGE may indicate a lower risk for malignant ventricular arrhythmias., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study aimed to characterize the incidence, clinical and electrophysiologic features, and long-term outcomes of patients with tachycardia-mediated cardiomyopathy (TCM) secondary to focal atrial tachycardia (AT)., Background: TCM is known to complicate atrial tachyarrhythmias. Little is known of the patient and tachycardia characteristics associated with the development of left ventricular (LV) dysfunction and the long-term outcomes after cure of tachycardia., Methods: A total of 345 patients with focal AT underwent radiofrequency ablation between January 1997 and July 2008. A retrospective analysis was performed to identify patients with LV dysfunction, defined as an ejection fraction <50% on echocardiography. Patients with pre-existing structural heart disease (n = 14) were excluded. Patients with TCM (n = 30) and without TCM (n = 301) were compared. Recovery of LV function was also assessed., Results: The incidence of TCM was 10%. Incessant or very frequent paroxysmal tachycardia was strongly associated with TCM, compared to patients without TCM (100% vs. 20%, p < 0.001). Patients in the TCM group were younger (mean age 39 +/- 22 years vs. 51 +/- 17 years, p = 0.0006) and more frequently male (60% vs. 38%, p < 0.001). Patients with TCM had a longer mean tachycardia cycle length (502 +/- 131 ms vs. 402 +/- 105 ms, p < 0.0001) and slower ventricular rate (117 +/- 21 beats/min vs. 141 +/- 33 beats/min, p = 0.0007) during tachycardia compared with patients who did not have TCM. Appendage sites are associated with a high incidence of incessant tachycardia (84%) and LV dysfunction (42%). After successful ablation, LV function was restored in 97% of patients at a mean of 3 months., Conclusions: Cardiomyopathy occurs in 10% of patients with focal AT. A slower incessant tachycardia is more frequently complicated by cardiomyopathy. Long-term restoration of LV function can be achieved after successful catheter ablation of the tachycardia focus.

Objectives: This study sought to characterize the conduction properties of the posterior left atrium (PLA) in patients with different forms of structural heart disease undergoing cardiac surgery., Background: The PLA plays an important role in the initiation and maintenance of atrial fibrillation., Methods: This study included 34 patients having elective cardiac surgery. There were 4 groups of patients: normal left ventricular (LV) function (coronary artery bypass grafting [CABG]); severe LV dysfunction (LVF/CABG); severe mitral regurgitation (MR); severe aortic stenosis (AS). Epicardial mapping of the PLA was performed in sinus rhythm and during differential pacing. Activation patterns, regional conduction velocity (CV), conduction heterogeneity, anisotropy, and total plaque activation time (TAT) were assessed., Results: Left atrial size in patients with LVF/CABG (47 +/- 7 mm) and MR (54 +/- 6 mm) was larger than patients with CABG (39 +/- 7 mm) and AS (42 +/- 6 mm; p < 0.05). During pacing, all patients developed a vertical line of conduction delay running between the pulmonary veins. The extent of this conduction delay was greater in patients with LVF/CABG and MR than patients with AS and CABG (p < 0.05). Conduction heterogeneity, anisotropy, and TAT were greater in patients with LVF/CABG and MR than patients with CABG (p < 0.05). These changes resulted in circuitous wave front propagation., Conclusions: There is a line of functional conduction delay in a consistent anatomical location in the PLA in patients with structural heart disease. This is most marked in conditions associated with significant chronic atrial enlargement and leads to circuitous wave front propagation, suggesting a potential role in arrhythmogenesis.

Objectives: The purpose of this study was to perform a detailed analysis of the P-wave morphology (PWM) in focal atrial tachycardia (AT) and construct and prospectively evaluate an algorithm for identification of the anatomic site of origin., Background: Although smaller studies have described the PWM from particular anatomic locations, a detailed algorithm characterizing the likely location of a tachycardia associated with a P-wave of unknown origin has been lacking., Methods: The PWMs for 126 consecutive patients undergoing successful radiofrequency ablation of 130 ATs are reported. P waves were included only when the onset was preceded by a discernible isoelectric segment. P waves were classified as positive (+), negative (-), isoelectric, or biphasic. Sensitivity, specificity, and predictive values were calculated. On the basis of these results, an algorithm was constructed and prospectively evaluated in 30 new consecutive ATs., Results: The distribution of ATs was right atrial (RA) in 82 of 130 (63%) and left atrial (LA) in 48 of 130 (37%). Right atrial sites included crista (n = 28), tricuspid annulus (n = 29), coronary sinus (CS) ostium (n = 14), perinodal (n = 7), right septum (n = 1), and RA appendage (n= 3). Left atrial sites included pulmonary veins (n = 32), mitral annulus (n = 8), CS body (n= 3), left septum (n = 3), and LA appendage (n = 2). In electrocardiographic lead V1, a negative or +/- P-wave demonstrated a specificity of 100% for a RA focus, and a + or -/+ P-wave demonstrated a sensitivity of 100% for a LA focus. A characteristic PWM was associated with high sensitivity and specificity at common atrial sites for tachycardia foci. A P-wave algorithm correctly identified the focus in 93%., Conclusions: Characteristic PWMs corresponding to known anatomic sites for focal AT are associated with high specificity and sensitivity. A P-wave algorithm correctly identified the site of tachycardia origin in 93%.

Objectives: We sought to describe the electrophysiological features and long-term outcome after radiofrequency catheter ablation (RFCA) of atrial tachycardia (AT) arising from the coronary sinus (CS) musculature., Background: Atrial tachycardia requiring RFCA deep within the CS has been described in isolated case reports. However, the mechanism and exact site of origin of this tachycardia have not been well elucidated., Methods: The study included 8 patients (5 men) of a consecutive series of 283 patients undergoing RFCA for focal AT., Results: In sinus rhythm, a discrete potential (P) was noted after the CS atrial electrogram and during tachycardia, the CS (P) preceded the surface P-wave by 30 to 50 ms. The CS (P) always preceded the earliest electrogram in the left atrium (LA). Three-dimensional electroanatomical mapping was available in four patients, and in one case it showed earliest activation in the CS with rapid spread to the proximal CS and then to the LA. Ablation of the AT initially attempted from the earliest site in the LA in three patients was unsuccessful. In all patients the tachycardia was safely and successfully ablated at a site 3.6 cm within the CS. There has been no recurrence over a follow-up of 37 +/- 13 months., Conclusions: Focal AT emanating deep within the CS musculature can be recognized by a discrete potential associated with the CS atrial signal both during sinus rhythm and tachycardia. Long-term success without complications can be accomplished by ablating within the CS in close proximity to the CS (P).

Objectives: The goal of this study was to characterize the electrocardiographic and electrophysiologic features and frequency of focal atrial tachycardia (AT) originating from the coronary sinus ostium (CS)., Background: The ostium of the coronary sinus has been described as a site of origin of AT, but detailed characterization of these tachycardias is limited., Methods: Thirteen patients (6.7%) of 193 undergoing radiofrequency ablation (RFA) for focal AT are reported. Endocardial activation maps (EAM) were recorded from catheters at the CS (10 pole), crista terminalis (20 pole), and His positions. The P waves were classified negative, positive, isoelectric, or biphasic., Results: The mean age was 41 +/- 6 years, seven female patients, with symptoms for 8 +/- 3 years. Tachycardia was induced by programmed extra-stimuli in eight patients, was spontaneous in three patients, and in response to isoproterenol in two patients. These foci had a characteristic P-wave morphology. At the CS ostium, the P-wave was deeply negative in all inferior leads, negative or isoelectric becoming positive in lead V(1), then progressively negative across the precordium. Lead aVL was positive in all patients. Earliest EAM activity occurred at the proximal CS at 20 +/- 3 ms ahead of P-wave. Mean activation time at the successful RFA site = -36 +/- 8 ms; RFA was acutely successful in 11 of 13 patients. Long-term success was achieved in 11 of 11 over a median follow-up of 25 +/- 4 months., Conclusions: The CS ostium is an uncommon site of origin for focal AT (6.7%). It can be suspected as a potential anatomic site of AT origin from the characteristic P-wave and activation timing. Long-term success was achieved with focal ablation in the majority of patients.

Objectives: The purpose of this study was to characterize the pattern of atrial remodeling seen with human aging., Background: Atrial fibrillation (AF) occurs in 3% to 4% of the population over 65 years of age. It is associated with thromboembolic complications, worsening heart failure, and increased mortality, yet the electrical and structural remodeling that occurs with human aging remains unknown., Methods: Thirteen patients (66.4 +/- 1.7 years) > or =60 years (group A), 13 patients (50 +/- 2.1 years) age 31 to 59 years (group B), and 15 patients (24.7 +/- 1.0 years) < or =30 years (group C) underwent conventional electrophysiologic studies and electroanatomic mapping. We measured atrial refractoriness (ERP) at the distal coronary sinus (CS); low and high lateral right atrium (LRA) and the high septal right atrium at 600, 500, and 400 ms; maximum corrected sinus node recovery time (CSNRT); P-wave duration (PWD); conduction time (CT) along the CS and LRA; and discrete double potentials (DP) along the crista., Results: Aging was associated with an increase in atrial ERP, prolonged CT along the CS, increased PWD and CSNRT. There was no significant change in dispersion of refractoriness or rate adaptation. Electroanatomic mapping revealed diffuse areas of low voltage with regional conduction slowing. Both techniques demonstrated a greater number of DPs and fractionated signals along the crista terminalis with aging., Conclusions: Aging is associated with regional conduction slowing, anatomically determined conduction delay at the crista, and structural changes that include areas of low voltage. In addition, impairment of sinus node function and an increase in atrial ERP occurred with aging. This electrical and structural remodeling may explain the increased propensity to AF with aging.

Objectives: The study was done to characterize the electrocardiographic and electrophysiologic features of focal atrial tachycardia originating at the mitral annulus (MA)., Background: Though the majority of left atrial tachycardias originate around the ostia of the pulmonary veins, only isolated reports have described focal tachycardia originating from the MA., Methods: Seven patients of a consecutive series of 172 patients undergoing radiofrequency ablation for focal atrial tachycardia are reported. Electrophysiologic study involved catheters positioned along the coronary sinus (CS), crista terminalis (CT), His bundle, and a mapping/ablation catheter., Results: All seven patients had tachycardia foci originating from the superior region of the MA in close proximity to the left fibrous trigone and mitral-aortic continuity. These foci demonstrated a characteristic P-wave morphology and endocardial activation pattern. The P-wave morphology in the precordial leads typically showed a biphasic pattern, with an inverted component followed by an upright component. The P-wave was consistently of low amplitude in the limb leads. Earliest endocardial activity occurred at the His bundle region in all seven patients. In general, CS activation was proximal to distal, and mid-CT activation was earlier than high or low CT. Ablation was successful at the superior aspect of the MA in all patients., Conclusions: The MA is an unusual but important site of origin for focal atrial tachycardia, with a propensity to be localized to the superior aspect. It can be suspected as a potential anatomic site of tachycardia origin from analysis of P-wave morphology and the atrial endocardial activation sequence map. Using mapping targeted to anatomic structures achieved a high success rate for ablation.