No description available.

Atrial arrhythmias are very common clinically relevant conditions that are strongly associated with aging and parasympathetic tone. Additionally, ATP-sensitive K+ (KATP) channel activation has been reported to facilitate the development of re-entrant atrial arrhythmias. Since KATP channels are direct effectors of Gαi/o and RGS4 is an inhibitor of Gαi/o-signaling, we here investigate whether KATP channel activity is increased under decreased RGS4 activity in a manner that enhances susceptibility to AF. We show that loss of RGS4 facilitates the induction of atrial arrhythmias under parasympathetic challenge both in whole animals and isolated atrial tissues. Furthermore, using both genetic disruption (Kir6.2 ablation) and pharmacologic blockade (tolbutamide), we show that loss of functional KATP channels decreases the incidence of pacing-induced re-entry and prolongs repolarization in RGS4-deficient atria. Our findings are consistent with the conclusion that enhanced KATP channel activity may contribute to pacing-induced re-entrant rotors in the RGS4-deficient mouse model.

Atrial arrhythmias are very common clinically relevant conditions that are strongly associated with aging and parasympathetic tone. Additionally, ATP-sensitive K+ (KATP) channel activation has been reported to facilitate the development of re-entrant atrial arrhythmias. Since KATP channels are direct effectors of Gαi/o and RGS4 is an inhibitor of Gαi/o-signaling, we here investigate whether KATP channel activity is increased under decreased RGS4 activity in a manner that enhances susceptibility to AF. We show that loss of RGS4 facilitates the induction of atrial arrhythmias under parasympathetic challenge both in whole animals and isolated atrial tissues. Furthermore, using both genetic disruption (Kir6.2 ablation) and pharmacologic blockade (tolbutamide), we show that loss of functional KATP channels decreases the incidence of pacing-induced re-entry and prolongs repolarization in RGS4-deficient atria. Our findings are consistent with the conclusion that enhanced KATP channel activity may contribute to pacing-induced re-entrant rotors in the RGS4-deficient mouse model.

In patients with normal hearts, increased vagal tone is associated with the onset of paroxysmal atrial fibrillation (AF). Vagal denervation of the atria renders AF less inducible. Circumferential pulmonary vein ablation (CPVA), with or without isolation (CPVI), is effective for treating paroxysmal AF, and has been shown to impact HRV indices, in turn reflecting vagal denervation. We examined the impact of CPVI on HRV indices over time, and evaluated the relationship between vagal modification and rate of recurrence of AF. High resolution ECG recordings were collected from 64 patients (49 male, 15 female, mean age 57.1±9.7) undergoing CPVI for paroxysmal (n=46) or persistent (n=18) AF. Recordings were made pre-procedure, and at intervals up to 12 months. Success was defined as no recurrence. After CPVI, 27 patients presented recurrence. Pre-procedure HRV variables did not differ from controls in patients with a subsequent successful procedure. However, patients with recurrence demonstrated significantly-reduced pre-procedure HRV compared both with controls, and with patients having successful procedures (39.6±23.4 & 33.7±19.2 vs 21.8±11.8, P =0.01 & P=0.04). Following the procedure, HRV was reduced vs pre-procedure in patients with successful procedures (33.7±19.2 vs 18.6±15.8, P=0.01), and did not differ from unsuccessful procedures over a 12 month FU. Both groups were reduced compared with a control value. There was no significant difference in HRV between patients who experienced recurring AF (n=9), and those who experienced AT or flutter (n=18). Our data suggests that patients experiencing recurrence after one procedure have reduced HRV that is not changed by CPVI; whereas patients with a successful single procedure experience a change in HRV variables that is sustained over a long period, but is no different post-procedure from patients experiencing recurrence. These data suggest that denervation associated with CPVI may benefit patients with normal vagal tone prior to the procedure, but that sustained denervation is not a critical factor in successful outcome after CPVI. / Thesis (Master, Computing) -- Queen's University, 2010-12-07 08:32:15.066

Cardiac conduction abnormalities can often lead to heart failure, stroke and sudden cardiac death. Heart disease stands as the leading cause of mortality and morbidity in the United States, accounting for 30% of all deaths. Early detection of malfunctions such as arrhythmias and systolic heart failure, the two heart conditions studied in this dissertation, would definitely help reduce the burden cardiovascular diseases have on public health and overcome the current clinical challenges. The imaging techniques currently available to doctors for cardiac activation sequence mapping are invasive, ionizing, time-consuming and costly. Thus, there is an undeniable urgent need for a non-invasive and reliable imaging tool, which could play a crucial role in the early diagnosis of conduction diseases and allow physicians to choose the best course of action. The 12-lead electrocardiogram (ECG) is the current non-invasive clinical tool routinely used to diagnose and localize cardiac arrhythmias prior to intracardiac catheter ablation. However, it has limited accuracy and can be subject to operator bias. Besides, QRS complex narrowing on the clinical ECG after pacing device implantation is also used for response assessment in patients undergoing Cardiac Resynchronization Therapy (CRT). The latter is an established treatment for systolic heart failure patients who have Left Bundle Branch Block as well as a reduced ejection fraction and prolonged QRS duration. Yet, it is still not well understood why 30 to 40 % of CRT recipients do not respond. Echocardiography, due to its portability and ease-of-use, is the most frequently used imaging modality in clinical cardiology. In this dissertation, we assess the clinical performance of Electromechanical Wave Imaging (EWI) as a high frame rate ultrasound-based functional modality that can non-invasively map the electromechanical activation of the heart, i.e., the transient deformations immediately following the electrical activation. The objective of this dissertation is to demonstrate the potential clinical value of EWI for both arrhythmia detection and CRT characterization applications. The first step in translating EWI to the clinic was ensuring that the technique could reli- ably and reproducibly measure the electromechanical activation sequence independently of the probe angle and imaging view in healthy human volunteers (n=7). This dissertation then demonstrated the accuracy of EWI for localizing a variety of ventricular and atrial arrhythmias (accessory pathways in Wolff-Parkinson-White (WPW) syndrome, premature ventricular contractions, focal atrial tachycardia and macro-reentrant atrial flutter) in pediatric (n=14) and adult (n=55) patients prior to catheter ablation more accurately than 12-lead ECG predictions, as validated against electroanatomical mapping. Additionally, 3D-rendered EWI isochrones were illustrated to be capable of significantly distinguishing different biventricular pacing conditions (p≤0.05) with the RWAT and LWAT metrics, assessing the ventricular dyssynchrony change in heart failure patients (n=16) undergoing CRT, and visualizing it in 3D. EWI also provided quantification of %𝘙𝘔𝘓𝘝 in CRT patients (n=38): the amount of left-ventricular resynchronized myocardium, which was found to be a reliable response predictor at 3-, 6-, or 9-month clinical follow-up through its post-CRT values by significantly identifying super-responders from non-responders within 24 hours of implantation (p≤0.05). Furthermore, 3D-rendered isochrones successfully characterized the ventricular activation resulting from His Bundle pacing for the first time (n=4), which was undistinguishable from true physiological activation in sinus rhythm healthy volunteers with the EWI-based activation time distribution dispersion metric. The dispersion was, however, reported to significantly discriminate novel His pacing from other more conventional biventricular pacing schemes (p≤0.01). Finally, we developed and optimized a fully automated zero-crossing algorithm towards a faster, more robust and less observer dependent EWI isochrone generation process. The support vector machine (SVM) and Random Forest machine learning models were both shown capable of successfully identifying the accessory pathway in WPW patients and the pacing electrode location in paced canines. Nevertheless, the best performing algorithm was hereby proven to be the Random Forest classifier with n=200 trees with a precision rising to 97%, and a predictivity that was not impacted by the type of testing dataset it was applied to (human or canine). Overall, in this dissertation, we established the clinical potential of EWI as a viable assisting visual feedback tool, that could not only be used for diagnosis and treatment planning prior to surgical procedures, but also for monitoring during, and assessing long-term resolution of arrhythmia after catheter ablation or heart failure after a CRT implant.

Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2007 Sep 12

Atrial arrhythmias are the most prevalent sustained cardiac arrhythmias. Rates of hospitalisation and costs incurred to healthcare organisations are increasing in epidemic proportions. Despite this, the mechanisms of the transition from sinus rhythm to arrhythmic states are not well understood. The high level of regional electrical heterogeneity observed in the atria is thought to contribute towards the high prevalence of atrial arrhythmias. However, current computer models of the intact human atria only account for a small degree of this regional electrical heterogeneity, and do not include descriptions of the pacemaker regions of the sinoatrial node and the atrioventricular node. In this project, a new computational model of the intact 3D human atria is developed. First, a new single cell model to simulate the electrical action potential of the human atrial myocyte is developed. This model more accurately simulated the experimentally observed properties of human atrial action potentials than previous models. A family of electrically heterogeneous models describing the major regions within the atria is then developed, including those of the sinoatrial- and atrioventricular- nodes. This set of regional cell models represents the most expansive and complete set currently available. It is demonstrated that the large range of different electrical properties results in a large range of action potential morphology and duration within the atria. Models of the effect of sympathetic and parasympathetic regulation on the electrical AP of the models of the atrial working myocardium and the pacemaker regions were also incorporated. This demonstrated that sympathetic regulation can increase the pacing rate of the sinoatrial node and the atrio-ventricular node, and has a complex dose dependent effect on the atrial working myocardium. Four distinct models of the effects of atrial fibrillation induced remodelling on the atrial working myocardium are developed. These characterised the effect of remodelling of IKur on the overall changes in action potential morphology and duration observed. It is shown that the presence or absence of remodelling of this channel accounts for two distinct observed morphologies. A previous 3D anatomical model of the human atria is improved. First, detailed anatomical models for the sinoatrial node and the atrioventricular node are incorporated into the model. Second, it is further segmented to include regions for the pulmonary veins, atrio-ventricular ring, atrial septum and sinoatrial node block zone. This model is used to investigate the effects of sympathetic and parasympathetic regulation in the 3D atria. Finally, a detailed investigation of the underlying mechanisms of atrial fibrillation in the 3D atria, and the effect of electrical remodelling on the behaviour of atrial fibrillation, is performed using the detailed 3D model. This work represents a significant advance in 3D human atrial modelling. The anatomical model incorporates a greater level of complexity than previous models, and for the first time allowed investigation of the pacemaking mechanisms in the 3D intact human atria. The atrial fibrillation protocols are more physiologically relevant than previous models and have elucidated the roles that electrophysiological remodelling, electrical heterogeneity and structural anisotropy play in the development and maintenance of atrial fibrillation.

Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)- sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P ˂ 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory.

No description available.

La fibrillation auriculaire est le trouble du rythme le plus fréquent chez l'homme. Elle conduit souvent à de graves complications telles que l'insuffisance cardiaque et les accidents vasculaires cérébraux. Un mécanisme neurogène de la fibrillation auriculaire mis en évidence. L'induction de tachyarythmie par stimulation du nerf médiastinal a été proposée comme modèle pour étudier la fibrillation auriculaire neurogène. Dans cette thèse, nous avons étudié l'activité des neurones cardiaques intrinsèques et leurs interactions à l'intérieur des plexus ganglionnaires de l'oreillette droite dans un modèle canin de la fibrillation auriculaire neurogène. Ces activités ont été enregistrées par un réseau multicanal de microélectrodes empalé dans le plexus ganglionnaire de l'oreillette droite. L'enregistrement de l'activité neuronale a été effectué continument sur une période de près de 4 heures comprenant différentes interventions vasculaires (occlusion de l'aorte, de la veine cave inférieure, puis de l'artère coronaire descendante antérieure gauche), des stimuli mécaniques (toucher de l'oreillette ou du ventricule) et électriques (stimulation du nerf vague ou des ganglions stellaires) ainsi que des épisodes induits de fibrillation auriculaire. L'identification et la classification neuronale ont été effectuées en utilisant l'analyse en composantes principales et le partitionnement de données (cluster analysis) dans le logiciel Spike2. Une nouvelle méthode basée sur l'analyse en composante principale est proposée pour annuler l'activité auriculaire superposée sur le signal neuronal et ainsi augmenter la précision de l'identification de la réponse neuronale et de la classification. En se basant sur la réponse neuronale, nous avons défini des sous-types de neurones (afférent, efférent et les neurones des circuits locaux). Leur activité liée à différents facteurs de stress nous ont permis de fournir une description plus détaillée du système nerveux cardiaque intrinsèque. La majorité des neurones enregistrés ont réagi à des épisodes de fibrillation auriculaire en devenant plus actifs. Cette hyperactivité des neurones cardiaques intrinsèques suggère que le contrôle de cette activité pourrait aider à prévenir la fibrillation auriculaire neurogène. Puisque la stimulation à basse intensité du nerf vague affaiblit l'activité neuronale cardiaque intrinsèque (en particulier pour les neurones afférents et convergents des circuits locaux), nous avons examiné si cette intervention pouvait être appliquée comme thérapie pour la fibrillation auriculaire. Nos résultats montrent que la stimulation du nerf vague droit a été en mesure d'atténuer la fibrillation auriculaire dans 12 des 16 cas malgré un effet pro-arythmique défavorable dans 1 des 16 cas. L'action protective a diminué au fil du temps et est devenue inefficace après ~ 40 minutes après 3 minutes de stimulation du nerf vague. / Atrial fibrillation is the most frequent sustained rhythm disorder in humans and often leads to severe complications such as heart failure and stroke. A neurogenic mechanism of atrial fibrillation has been hypothesized. Tachyarrhythmia induction by mediastinal nerve stimulation has been proposed as a model to study neurogenic atrial fibrillation. In this thesis, we studied the activity of intrinsic cardiac neurons and their interactions inside the right atrium ganglionated plexus in a canine model of neurogenic atrial fibrillation. These activities were recorded by a multichannel microelectrode array that was paled into the right atrium ganglionated plexus. The recording was done for up to 4 hours and it covered the neuronal activity during different interventions such as vascular (aorta occlusion, inferior vena cava occlusion, left anterior descending coronary artery occlusion), mechanical (touching atrium and ventricle) and electrical (stimulating of vagus nerve or stellate ganglion) stimuli as well as atrial fibrillation induction. Neuronal identification and classification were done using the principal component analysis and cluster on measurements analysis in Spike2 software. New method based on principal component analysis was proposed to cancel superimposed atrial activity on neuronal signal to increase the accuracy of the neuronal response identification and classification. Based on the neuronal response, we defined subtypes of neurons (afferent, efferent and local circuit neurons) and their related activity to different stressors which provided a more detailed description of the intrinsic cardiac nervous system. The majority of recorded neurons reacted to episodes of atrial fibrillation by becoming more active. This hyperactivity of intrinsic cardiac neurons during atrial fibrillation suggested that controlling that activity might help preventing neurogenic atrial fibrillation. Since low-level vagus nerve stimulation obtunds the intrinsic cardiac neuronal activity (especially for afferent and convergent local circuit neurons), we investigated whether this intervention could be applied as a therapy for atrial fibrillation. Our results showed that right vagus nerve stimulation was able to mitigate atrial fibrillation in 12 of 16 cases and showed an adverse pro-arrhythmic effect in 1 of 16 cases. The protective action however decreased over time and became ineffective after ~40 minutes for 3 minutes vagus nerve stimulation.