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Obstructive sleep apnea, which involves chronic intermittent hypoxia (CIH), is a major risk factor for developing atrial fibrillation (AF). Whether or not CIH alone alters cardiac mechanisms to support AF is unknown. This study investigated the effects of CIH on atrial electrophysiology and arrhythmia vulnerability and evaluated the role of autonomics in CIH promotion of AF. Adult male Sprague-Dawley rats were exposed to 8 h/day of CIH or normoxia for 7 days. After exposure, rats were anesthetized for intracardiac electrophysiological experiments. Atrial effective refractory periods (AERPs) and AF inducibility were determined using programmed electrical stimulation and burst pacing in the absence and presence of autonomic receptor agonists and antagonists. Western blot analysis measured atrial protein expression of muscarinic M2, M3, and β 1 -adrenergic receptors. Compared with normoxia-exposed control rats, CIH-exposed rats had enhanced AF vulnerability using both programmed electrical stimulation and burst pacing, accompanied by greater AERP responses to carbachol and propranolol, lesser responses to isoproterenol, and higher atrial M2 receptor protein levels. Enhanced atrial vulnerability was accentuated by carbachol and abolished by atropine, indicating that the AF-promoting effects of CIH depended principally on parasympathetic activation. Enhancement of atrial vulnerability and AERP shortening with cholinergic agonists in CIH-exposed rats is consistent with sensitivity to parasympathetic activation. Higher responses to adrenergic receptor blockade in CIH-exposed rats is consistent with sympathetic potentiation. These findings implicate CIH as an important mediator of enhanced AF susceptibility in obstructive sleep apnea and provide novel insights into the underlying mechanisms. NEW & NOTEWORTHY Our study demonstrates, for the first time, that chronic intermittent hypoxia alone enhances vulnerability to atrial arrhythmia induction, which depends principally on parasympathetic activation. Enhanced atrial vulnerability was accompanied by heightened electrophysiological responses of the atrial myocardium to carbachol and isoproterenol, dampened responses to propranolol, and increased atrial M2 receptor protein levels.

Atrial fibrillation is a side effect of ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase used for treatment of B-cell lymphoproliferative disorders. We determined if single (2 or 10 mg/kg), or chronic (14 days) oral ibrutinib followed by 24-hour washout conferred susceptibility to electrically induced arrhythmias in 1-month-old male C57BL/6 mice. A single higher dose of ibrutinib increased arrhythmia inducibility. There was no inducibility difference after chronic dosing with washout. This suggests that high serum drug levels might be responsible for the proarrhythmic effect of ibrutinib and that an altered dosing strategy might mitigate the side effects., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, increased vagal tone, slowed conduction velocity, prolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atria, without corresponding alterations in the ventricles. Microarray results suggest the involvement of the inflammatory cytokine, TNFα, in exercised-induced atrial remodelling. Accordingly, exercise induces TNFα-dependent activation of both NFκB and p38MAPK, while TNFα inhibition (with etanercept), TNFα gene ablation, or p38 inhibition, prevents atrial structural remodelling and AF vulnerability in response to exercise, without affecting the beneficial physiological changes. Our results identify TNFα as a key factor in the pathology of intense exercise-induced AF.

This discussion paper re-examines the conduction-activation of the atria, based on observations, with respect to the complexity of the heart as an organ with a brain, and its evolution from a peristaltic tube. The atria do not require a specialized conduction system because they use the subendocardial layer to produce centripetal transmural activation fronts, regardless of the anatomical and histological organization of the transmural atrial wall. This has been described as "two-layer" physiology which provides robust transmission of activation from the sinus to the AV node via a centripetal transmural activation front. New productive insights can come from re-examining the physiology, not only during sinus rhythm but also during atrial tachycardias, in particular atrial flutter and atrial fibrillation (AF). During common flutter, the areas of slow conduction, in the isthmus and following trabeculations, particularly the subendocardial layer confines conduction through the trabeculations which supports re-entry. During experimental or postoperative flutter, the circular 2D activation around the obstacle follows the physiological transmural activation. Understanding this physiology offers insights into AF. During acute or protracted AF, the presence of stationary or drifting rotors is characteristic and consistent with normal physiological 2D atrial activation, suggesting that suppressing physiological transmural activation of AF will permanently restore normal sinus node atrial activation. In contrast, during permanent AF, normal 2D activation is abolished; the presence of transmural, serpentine, and chaotic atrial activation suggests that the normal physiological activation pattern has been replaced by a new, irreversible variety of atrial conduction that is a new physiology, which is consistent with evolution of complex systems.

Introduction: Direct catheter ablation for atrial fibrillation does not yield reproducible permanent control as for other atrial arrhythmias. Therefore, there is a need for an alternative intervention, i.e., left atrial exclusion, based on elective ablation of the interatrial connecting bundles., Methods and Results: We describe the "operative anatomy" of the three major interatrial connections: the Bachmann bundle, the coronary sinus bundle, and the left atrial-atrioventricular node connection, based on macroscopic dissections of human and porcine hearts and our previous experience. We identified the three right atrial attachments, with the coronary sinus (CS) and left atrial (LA)-atrioventricular (AV) nodal connection being most problematic for safe ablation., Conclusions: To obtain a complete isolation of the left from the right atrium, all three connections must be ablated. The CS connection must be ablated distal to the ostium. If present, the LA-AV nodal connection can be safely ablated from the left atrium.

Atrial fibrillation (AF), the most common cardiac arrhythmia seen in general practice, can be promoted by conduction slowing. Cardiac impulse conduction depends on gap junction channels, which are composed of connexins (Cxs). While atrial Cx40 and Cx43 are equally expressed, AF studies have primarily focused on Cx40 reductions. The G60S Cx43 mutant (Cx43(G60S/+)) mouse model of Oculodentodigital dysplasia has a 60% reduction in Cx43 in the atria. Cx43(G60S/+) mice were compared with Cx40-deficient (Cx40(-/-)) mice to determine the role of Cxs in atrial tachycardia/fibrillation (AT/F). Intracardiac electrophysiological studies were done in 6-mo-old male C57BL/6 Cx43(G60S/+) mutant, littermate (Cx43(+/+)), Cx40(-/-), and C57BL/6 wild-type (WT) mice. AT/F induction used an extra stimulus during sinus rhythm, programmed electrical stimulation, or burst pacing (1-ms pulses, 50-Hz, 400-ms train) in the absence and presence of carbachol (CCh). Atrial effective refractory periods did not differ between strains. Cx43(G60S/+) mice were more susceptible to induction of sustained AT/F (duration >2 min, 9 of 12; maximum >35 min) compared with Cx43(+/+) mice (3 of 11; χ(2) = 5.24; P = 0.02). CCh enhanced sustained AT/F susceptibility in WT (from 1 of 12 without, to 7 of 10 with CCh; χ(2) = 8.98; P < 0.01) but not in Cx40(-/-) mice (1 of 13 without vs. 2 of 9 with CCh; χ(2) = 0.95; P = NS). The pattern of epicardial recordings during AT/F in Cx43(G60S/+) mice was left preceding right, with left atrial fractionated activation patterns consistent with clinical observations of AF. In conclusions, while Cx43(G60S/+) mice had severe AT/F, Cx40(-/-) mice were resistant to CCh-induced AT/F.

Background: Atrial fibrillation (AF) is the most common sustained arrhythmia observed in otherwise healthy individuals. Most lone AF cases are nonfamilial, leading to the assumption that a primary genetic origin is unlikely. In this study, we provide data supporting a novel paradigm that atrial tissue-specific genetic defects may be associated with sporadic cases of lone AF., Methods and Results: We sequenced the entire coding region of the connexin 43 (Cx43) gene (GJA1) from atrial tissue and lymphocytes of 10 unrelated subjects with nonfamilial, lone AF who had undergone surgical pulmonary vein isolation. In the atrial tissue of 1 patient, we identified a novel frameshift mutation caused by a single nucleotide deletion (c.932delC) that predicted 36 aberrant amino acids followed by a premature stop codon, leading to truncation of the C-terminal domain of Cx43. The mutation was absent from the lymphocyte DNA of the patient, indicating genetic mosaicism. Protein trafficking studies demonstrated intracellular retention of the mutant protein and a dominant-negative effect on gap junction formation of both wild-type Cx43 and Cx40. Electrophysiological studies revealed no electrical coupling of cells expressing the mutant protein alone and significant reductions in coupling when coexpressed with wild-type connexins., Conclusions: This study reports atrial tissue genetic mosaicism of a novel loss-of-function Cx43 mutation associated with lone AF. These findings implicate somatic genetic defects of Cx43 as a potential cause of AF and support the paradigm that sporadic, nonfamilial cases of lone AF may arise from genetic mosaicism that creates heterogeneous coupling patterns, predisposing the tissue to reentrant arrhythmias.

Atrial fibrillation (AF) is the most common arrhythmia seen in general practice. Muscarinic ACh receptors (M2R, M3R) are involved in vagally induced AF. M2R and M3R activate the heterotrimeric G proteins, G(i) and G(q), respectively, by promoting GTP binding, and these in turn activate distinct K(+) channels. Signaling is terminated by GTP hydrolysis, a process accelerated by regulator of G protein signaling (RGS) proteins. RGS2 is selective for G(q) and thus may regulate atrial M3R signaling. We hypothesized that knockout of RGS2 (RGS2(-/-)) would render the atria more susceptible to electrically induced AF. One-month-old male RGS2(-/-) and C57BL/6 wild-type (WT) mice were instrumented for intracardiac electrophysiology. Atrial effective refractory periods (AERPs) were also determined in the absence and presence of carbachol, atropine, and/or the selective M3R antagonist darifenacin. Susceptibility to electrically induced AF used burst pacing and programmed electrical stimulation with one extrastimulus. Real-time RT-PCR measured atrial and ventricular content of RGS2, RGS4, M2R, M3R, and M4R mRNA. AERP was lower in RGS2(-/-) compared with WT mice in both the high right atrium (HRA) (30 +/- 1 vs. 34 +/- 1 ms, P < 0.05) and mid right atrium (MRA) (21 +/- 1 vs. 24 +/- 1 ms, P < 0.05). Darifenacin eliminated this difference (HRA: 37 +/- 2 vs. 39 +/- 2 ms, and MRA: 30 +/- 2 vs. 30 +/- 1, P > 0.4). RGS2(-/-) were more susceptible than WT mice to atrial tachycardia/fibrillation (AT/F) induction (11/22 vs. 1/25, respectively, P < 0.05). Muscarinic receptor expression did not differ between strains, whereas M2R expression was 70-fold higher than M3R (P < 0.01). These results suggest that RGS2 is an important cholinergic regulator in the atrium and that RGS2(-/-) mice have enhanced susceptibility to AT/F via enhanced M3 muscarinic receptor activity.

Electrophysiological cardiac data mapping is an essential tool for the study of cardiac rhythm disorders, such as atrial fibrillation. Over the past decade, various advanced cardiac mapping systems have been developed to create detailed cardiac maps and assist physicians in diagnosis and therapy guidance. While these systems have increased the ability to study and treat cardiac arrhythmias, inherent limitations exist. The objective of this paper is to describe and evaluate a system that extends current approaches to cardiac mapping, to create a dynamic cardiac map, using patient-specific cardiac models. This paper details novel approaches to collecting a stream of electrophysiological cardiac data, registering the data with patient-specific dynamic cardiac models, and displaying the data directly on the dynamic model surface, giving a more accurate and comprehensive visualization environment when compared to current systems. To validate the system, a series of laboratory and in vivo experiments were conducted. In the laboratory studies, the system was used to test the user's ability to accurately locate a landmark in physical space, as well as their ability to accurately navigate to a virtual location. In the in vivo studies the overall system performance was compared to an existing electrophysiological recording system, where right atrial cardiac maps were created during sinus and paced cardiac rhythms. The results showed that the new dynamic cardiac mapping system was able to maintain high accuracy in locating physical and virtual landmarks, while being able to create a dynamic cardiac map displayed on a dynamic cardiac surface model.

We previously published encircling endocardial cryo-isolation of the pulmonary vein (PV) region. This study documented mechanisms of isolation failure using CARTO mapping. Cryo-isolation used a modified Surgifrost introduced via a Universal Cardiac Introducer on the left atrial appendage. Of five pigs, two had incomplete isolation and repeat mapping: Activation was over Bachmann's bundle (BB) in one and the coronary sinus (CS) in the other. Repeat cryoablation failed to eliminate gaps. Histologically, the BB gap had nonlesioned sub-epicardial fibres and thick fat covering the cryolesioned BB: fat protecting the epicardium from cryoablation. The inferior gap had a large CS, and a thick myocardium bridging the isthmus: myocardial thickness and CS thermal sink preventing transmural cryolesions. CARTO mapping localized gaps. Although the CS is known to cause failure, its protective mechanism is not well documented. The BB gap is novel. These findings have important clinical implications for isolation of the PV region.

Background: Atrial fibrillation is the most common type of cardiac arrhythmia and a leading cause of cardiovascular morbidity, particularly stroke. The cardiac gap-junction protein connexin 40 is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria. We hypothesized that idiopathic atrial fibrillation has a genetic basis and that tissue-specific mutations in GJA5, the gene encoding connexin 40, may predispose the atria to fibrillation., Methods: We sequenced GJA5 from genomic DNA isolated from resected cardiac tissue and peripheral lymphocytes from 15 patients with idiopathic atrial fibrillation. Identified GJA5 mutations were transfected into a gap-junction-deficient cell line to assess their functional effects on protein transport and intercellular electrical coupling., Results: Four novel heterozygous missense mutations were identified in 4 of the 15 patients. In three patients, the mutations were found in the cardiac-tissue specimens but not in the lymphocytes, indicating a somatic source of the genetic defects. In the fourth patient, the sequence variant was detected in both cardiac tissue and lymphocytes, suggesting a germ-line origin. Analysis of the expression of mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling., Conclusions: Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling. Our data suggest that common diseases traditionally considered to be idiopathic may have a genetic basis, with mutations confined to the diseased tissue., (Copyright 2006 Massachusetts Medical Society.)

Background: Off-pump, closed, beating heart, minimally-invasive surgery in patients with lone atrial fibrillation (AF) must be effective to become the preferred alternative to catheter ablation. Because of the inherent anatomical limitations of the epicardial access, we explored the feasibility of an intracardiac approach., Methods: We report an acute study of en bloc, cryo-exclusion of the pulmonary vein region in 7 pigs. The left atrial appendage (LAA) was approached via a left thoracotomy. Electrodes were attached to the posterior wall of the left atrium (LPA) and right atrial appendage (RAA) for pacing and electrophysiological monitoring. A modified Surgifrost probe was introduced via the LAA and positioned using transesophageal (TEE) and intracardiac (ICE) echocardiographic guidance to generate encircling cryolesions (3 minutes, -105 degrees C) of the pulmonary vein region., Results: A complete two-way block was achieved in 6 pigs and an incomplete block in 1. The excluded segment had very slow idiosyncratic rhythm or was electrically silent. In all pigs before isolation, sustained AF was inducible with the most rapid rhythms and fractionated electrograms recorded from the LA. While sustained AF was induced before exclusion, it was not after isolation in either the exclude or non-excluded segments. All tissue samples taken along the encircling cryolesions had transmural cryolesions on pathological examination., Conclusions: We conclude that off-pump, closed heart, beating, intracardiac AF surgery is feasible, reliable and can duplicate the accuracy and precision of the open-heart approach. However, further developments are needed to make this novel approach an alternative to current approaches for catheter ablation.

Introduction: Catheter‐tissue contact force is a determinant of radiofrequency (RF) ablation lesion effectiveness. However, ablation on a beating heart is subject to force variability, making it difficult to optimally deliver consistently durable and transmural lesions. This work evaluates improvements in contact force stability and lesion reproducibility by using a catheter contact‐force controller (CFC) during lesion delivery in vitro and in vivo. Methods and Results: Using a sheath and force‐sensing catheter, an experienced operator attempted to maintain a constant force of 20 g at targets within the atria and left ventricle of a pig manually and using the CFC; the average force and contact‐force variation (CFV) achieved using each approach were compared. Ablation lesions (20 W, 30 seconds, 17 mL/min irrigation) were created in bovine tissue samples mounted on a platform programmed to reproduce clinically relevant motion. CFC‐assisted lesions were delivered to stationary and moving tissue with forces of 5 to 35  g. Mimicking manual intervention, lesions were also delivered to moving tissue while the CFC was disabled. Resultant lesion volumes were compared using two‐way analysis of variance. When using the CFC, the average force was within 1 g of the set level, with a CFV less than 5 g, during both in vitro and in vivo experiments. Reproducible and statistically identical (P = .82) lesion volumes proportional to the set force were achieved in both stationary and moving tissue when the CFC was used. Conclusions: CFC assistance maintains constant force in vivo and removes effect of motion on lesion volume during RF lesion delivery. [ABSTRACT FROM AUTHOR]

The heart receives sympathetic and parasympathetic efferent innervation as well as the ability to process information internally via an intrinsic cardiac autonomic nervous system (ICANS). For over a century, the role of the parasympathetics via vagal acetylcholine release was related to controlling primarily heart rate. Although in the late 1800s shown to play a role in atrial arrhythmia, the myocardium took precedence from the mid-1950s until in the last decade a resurgence of interest in the autonomics along with signaling cascades, regulators, and ion channels. Originally ignored as being benign and thus untreated, recent emphasis has focused on atrial arrhythmia as atrial fibrillation (AF) is the most common arrhythmia seen by the general practitioner. It is now recognized to have significant mortality and morbidity due to resultant stroke and heart failure.With the aging population, there will be an unprecedented increased burden on health care resources. Although it has been known for more than half a century that cholinergic stimulation can initiate AF, the classical concept focused on the M2 receptor and its signaling cascade including RGS4, as these had been shown to have predominant effects on nodal function (heart rate and conduction block) aswell as contractility. However, recent evidence suggests that the M3 receptor may also playa role in initiation and perpetuation of AF and thus RGS2, a putative regulator of the M3 receptor, may be a target for therapeutic intervention. Mice lacking RGS2 (RGS2-/-), were found to have significantly altered electrophysiological atrial responses and were more susceptible to electrically induced AF. Vagally induced or programmed stimulationinduced AF could be blocked by the selective M3R antagonist, darifenacin. These results suggest a potential surgical target (ICANS) and pharmacological targets (M3R, RGS2) for the management of AF. [ABSTRACT FROM AUTHOR]

. Experimental evidence suggests that spinal cord stimulation (SCS) can cause augmentation of parasympathetic influences on the heart via enhanced vagus nerve (VgN) activity. Herein, we investigated whether this might lead to enhanced inducibility of vagally mediated atrial tachyarrhythmias (AT) and whether such actions depend on intact autonomic neural connections with central neurons. Epidural SCS electrodes were implanted at T1-T4 in anesthetized canines. Sinus cycle length prolongation, atrial repolarization changes (191 epicardial electrode sites), and AT inducibility in response to right VgN stimuli applied at the cervical level were determined before and during SCS. VgN-induced sinus cycle length prolongation was potentiated during SCS among the animals with intact neural connections or bilateral vagotomy proximal to the stimulation site, whereas such prolongation was unaffected by SCS among animals with bilateral decentralization of stellate ganglia. Likewise, the atrial surface area in which VgN-induced repolarization wave form changes were identified was significantly augmented during SCS among the former but not among the latter. AT facilitation occurred during SCS in the majority of animals with intact neural connections, particularly among those displaying relatively greater potentiation of vagally mediated sinus cycle length prolongation. The data indicate that SCS may cause potentiation of parasympathetic influences on the atria in response to cervical VgN stimulation. Such SCS effects appear to be mediated via decreased tonic inhibitory sympathetic influences in the presence of intact stellate ganglion connections to central neurons. (J Cardiovasc Electrophysiol, Vol. 22, pp. 440-447) [ABSTRACT FROM AUTHOR]