名古屋大学博士学位論文 学位の種類 : 博士(医学)(課程) 学位授与年月日:平成24年3月26日 櫛山泰規氏の博士論文として提出された

Atrial fibrillation is the most common sustained arrhythmia; however, its mechanism is not well understood. Several conditions such as valvular disease, heart failure, and hypertension predispose to atrial fibrillation. Identifying the electrophysiological substrate in these clinical conditions would yield insight into the mechanism of atrial fibrillation and aid in developing strategies to prevent or cure it. Rheumatic mitral stenosis is associated with high prevalence of atrial fibrillation. While atrial stretch itself may be adequate to explain the occurrence of atrial fibrillation in this population, it is not known if the disease process would remodel the atria so as to increase its propensity. Chapters 2 and 3 present the results of the studies evaluating the substrate for atrial fibrillation in both the left and right atria in rheumatic mitral stenosis. These studies have demonstrated extensive conduction abnormalities both regional and site specific associated with low voltage area and scar. Despite the prolonged atrial refractoriness, the propensity for atrial fibrillation was increased; lending support to the theory that structural remodelling associated with conduction abnormalities plays a greater role in the substrate predisposing to atrial fibrillation. Chapters 4 and 5 present the results of the studies evaluating the immediate effects of chronic atrial stretch reversal on the atrial electrical remodelling. These studies demonstrated that immediately after percutaneous mitral commissurotomy there was decrease in P wave duration, improvement in site specific conduction delay and conduction velocity associated with increase in the voltage. However, there was no change in atrial refractoriness. Chapter 6 studies the substrate long-term after reduction of stretch. There was further increase in conduction velocity and voltage associated with decrease in atrial refractoriness and conduction delay across the crista terminalis. These observations suggest that strategies aimed at reducing atrial stretch in different disease conditions would potentially decrease the burden or prevent atrial fibrillation. There is mounting evidence of the effect of stretch on the atria; however, the effect of stretch on the triggers of atrial fibrillation has not been evaluated before. Chapter 7 and 8 present the results of the study examining the effect of acute and chronic stretch on human pulmonary veins. Simultaneous pacing of the right ventricle and pulmonary vein induced acute stretch. The effect of chronic stretch was evaluated in patients with mitral stenosis. The atrial refractoriness was abbreviated in acute stretch while it was prolonged in the chronic form. Nevertheless, both resulted in marked pulmonary vein conduction abnormalities that were pronounced with chronic stretch and extra-stimuli. Additionally, structural remodelling was seen with chronic stretch. These abnormalities implicate stretch in the milieu for re-entry and pulmonary vein arrhythmogenesis in conditions predisposed to atrial fibrillation. In summary, this thesis has evaluated the effects of stretch on the substrate and triggers of atrial fibrillation. It provides evidence for the importance of structural changes and the associated abnormalities in conduction in predisposing to atrial fibrillation. These observations may be important in the development of tools to treat, cure and prevent atrial fibrillation. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Einleitung: Die zirkumferentielle Pulmonalvenenablation (CPVA) hat sich in den letzten Jahren als effektive Therapie bei Vorhofflimmern etabliert. Die Initiierung eines CPVA-Programms bleibt jedoch aufgrund der Komplexität der Prozedur und des Risikos lebensgefährlicher Komplikationen eine Herausforderung. Das Ziel dieser prospektiven Studie war es, die Effizienz und Sicherheit eines neuetablierten CPVA-Programms an einem medizinischen Zentrum mit zuvor wenig erfahrenen Untersuchern zu evaluieren.  Methoden und Ergebnisse: Zwischen 2006 und 2011 wurden 331 Patienten mit paroxysmalem und persistierendem Vorhofflimmern konsekutiv der zirkumferentiellen Pulmonalvenenablation zugeführt und unterzogen sich insgesamt 500 Prozeduren. Das mittlere Follow-Up betrug 648 ± 315 Tage. Die zunehmende Ablationspraxis führte neben der Prozessoptimierung zu einer deutlichen Reduzierung schwerwiegender Komplikationen. Prozedurdauer und Komplikationsrate erreichten nach 100 Ablationen ein stabiles und im Lichte der internationalen Literatur adäquates Niveau. Die Inzidenz schwerwiegender Komplikationen verringerte sich auf 1,3 - 1,9%. Insgesamt betrug der Anteil schwerwiegender Komplikationen 4%. Der Tod trat nicht auf. Keine der aufgetretenen Komplikationen führte zu einer permanenten Gesundheitsbeeinträchtigung der Patienten. Die Erfolgsraten waren seit Beginn des Programms auf einem konstanten Niveau und vergleichbar mit in der Literatur beschriebenen Werten.  Schlussfolgerung: Die vorliegende Studie zeigt, dass es gelingt, ein CPVA-Programm mit zuvor wenig erfahrenen Untersuchern effizient zu etablieren. Die Daten zeigen jedoch auch, dass mit einer erhöhten Komplikationsrate in der frühen Etablierungsphase zu rechnen ist. Nach 1,6 ± 0,7 Ablationen und einer Nachbeobachtung von einem Jahr waren 81,3% (266 / 327) der Patienten frei von symptomatischem Vorhofflimmern. Die Reablation ist eine wichtige Maßnahme, um die Erfolgsrate nachhaltig zu verbessern. Die Studie identifizierte Frührezidive innerhalb der Blanking-Periode und einen vergrößerten linken Vorhof als unabhängige Prädiktoren für die Rekurrenz von symptomatischem Vorhofflimmern.  Vor dem Hintergrund des steigenden Bedarfs an effektiven Therapien zur Behandlung von Vorhofflimmern sind die Ergebnisse dieser Studie hilfreich, um weitere CPVA-Programme zu planen und zu etablieren.

La fibrillation auriculaire (FA) est la forme la plus fréquente d'arythmie cardiaque chez l’Homme. L'isolement des veines pulmonaires (VP) par radiofréquence (RF) est le traitement de référence pour les patients atteints de fibrillation auriculaire paroxystique (FAP) réfractaire symptomatique malgré le traitement médicamenteux. L’isolation des VP fonctionne très bien pour traiter les FA paroxystiques mais elle a un rôle limité dans le traitement des patients atteints de FA persistante (FAPs). La FA persistante est en effet plus complexe, en raison du développement dans l'oreillette gauche (OG) d’un substrat arythmogène résultant d’un remodelage électrique et anatomique. Ce substrat maintient la FA et nécessite donc des ablations supplémentaires dans l’OG (en dehors des veines pulmonaires). Les récidives de fibrillation auriculaire sont principalement dues à la reconnexion électrique des veines pulmonaires. C’est un phénomène fréquent, qui limite le succès de la procédure à long terme. Certaines séries rapportent de 20 à 50% de récidive, avec un impact important pour le patient, et pour le système de santé puisque générant des hospitalisations et des procédures répétées. L'ablation point par point utilisant un cathéter d’ablation à électrode unique peut être techniquement complexe. De ce fait, les lésions transmurales, contiguës et pérennes sont parfois difficiles et longues à réaliser, expliquant pour une part les taux élevés de reconnexion. Par conséquent, de nouveaux types de cathéters d’ablation ont été développés. On citera par exemple : les cathéters ballons de cryoablation, les cathéters d’ablation circulaire à électrodes multiples (PVAC et nMARQ), sont maintenant disponibles et ont pour but la création de lésions complètes et continues. Cependant, le ballon de cryoablation a des limites, notamment dans sa capacité à s'adapter à la variabilité anatomique des VP et pour l'ablation des sites extra-veineux. La conséquence est qu’un cathéter d’ablation supplémentaire doit être utilisé pour l’ablation des sites extra-veineux ce qui rend la procédure plus complexe et coûteuse. L’absence d'irrigation du cathéter PVAC augmente sans doute le risque de complications thromboemboliques. Le cathéter nMARQ en revanche est un cathéter circulaire irrigué qui, en plus de son rôle dans l’isolation des VP, permet l'ablation de substrat en dehors des veines pulmonaires. Par ailleurs, les outils de cartographie et d'imagerie cardiaques sont de plus en plus couramment utilisés pour planifier et guider l'ablation de FA. On citera la cartographie électroanatomique invasive (Carto®3) et non invasive (ECVUETM), la tomodensitométrie (TDM) et l'imagerie par résonance magnétique (IRM). Nous avons émis l'hypothèse que différentes stratégies et technologies pourraient améliorer la procédure et les résultats de l’isolation des VP en produisant de meilleures lésions et en permettant une visualisation directe des lésions. Nous avons donc évalué le rôle du cathéter circulaire irriguée pour la cartographie et l’ablation (nMARQ) dans la FAP et la FAPs avec ou sans guidage non invasif par ECGi. Nous nous sommes également intéressés à l’analyse en IRM des lésions produites par ce cathéter lors de l’isolation des veines pulmonaires. À cette fin, les données de l’isolation des VP ont été obtenues et traitées de manière aiguë et à 3 mois. Le suivi clinique a été évalué à 1 an. La thèse se compose de 3 parties : Partie 1 : Comment améliorer l'isolation des veines pulmonaires chez les patients atteints de fibrillation auriculaire paroxystique ? Partie 2 : Cathéter circulaire multiélectrodes et ablation de fibrillation auriculaire persistante. Partie 3 : Rôle de l'imagerie par résonance magnétique dans l'évaluation de la reconnexion des veines pulmonaires après l'isolement des veines pulmonaires ? / Atrial fibrillation (AF) is the most common form of cardiac arrhythmia in Humans. Pulmonary vein isolation (PVI) by radiofrequency (RF) ablation is the mainstay treatment for patients with symptomatic and drug refractory paroxysmal atrial fibrillation (PAF) as ectopic beats (triggers) from pulmonary veins (PVs) initiate AF, however PVI alone had limited role in treating patients with persistent atrial fibrillation (PsAF), due to additional involvement in left atrium (LA) by electrical and anatomical remodeling, creating more complex substrate (fibrosis) that maintain AF and therefore necessitate non-PV sites ablation to modify the arhythmogenic substrate. Atrial fibrillation recurrence mainly due to pulmonary vein (PV) electrical reconnection is common and remains the current issue that limits long term procedural success and generates extra costs due to repeated hospital admissions and repeated procedures. Point by point ablation using single tip catheter can be challenging, complex and time consuming, enhancing electrical reconnection as stable lesions are difficult to achieve. To overcome these limitations, new type of catheters such as balloon (cryoablation) and multi-electrode circular ablation catheters like PVAC and nMARQ, are now available. However, cryoablation balloon is limited by inability to adapt to anatomic PV variability and to ablate non-PV sites. This means that an additional ablation catheter has to be used for non-PV targets, and it certainly adds to the costs. The PVAC catheter lacks of irrigation increases the risk of thromboembolic complications. On contrary, nMARQ is an irrigated circular ablation catheter which in addition to its role in PVI, allows for non-PV/LA substrate ablation. Cardiac mapping and imaging tools are now commonly used to plan and guide AF ablation, such as invasive (Carto 3) and noninvasive (ECVUE) electroanatomic mapping (EAM), computed tomography (CT) and magnetic resonance imaging (MRI), respectively. We hypothesized that different strategies and technologies could improve PVI procedure and outcome by producing better lesions and by allowing for direct visualization of lesions. We therefore, assessed the role of circular, irrigated mapping and ablation catheter (nMARQ) in PAF and PsAF with or without noninvasive ECGi guidance, and advanced imaging technologies (MRI) after PVI. For that purpose, PVI data were obtained and processed acutely and at 3 months. Clinical follow up was evaluated at 1 year. The thesis consists of 3 parts: Part 1: How to improve pulmonary vein isolation lesion formation in patients with paroxysmal atrial fibrillation? Part 2: Circular catheter and persistant atrial fibrillation ablation. Part 3: The role for magnetic resonance imaging in assessing pulmonary vein reconnection after pulmonary vein isolation?

No description available.

Background: The Framingham Study from 1991 showed a clear correlation between atrial fibrillation (AF) and ischemic stroke, where patients with AF had an almost fivefold increase in risk of stroke compared with patients without AF. Since then, several trials have evaluated different antithrombotic treatments to reduce the risk of stroke in patients with AF. Other trials have investigated factors that increase the risk of stroke in patients with AF and risk score systems have been developed to categorize patients into low or increased risk of stroke to help clinicians to decide which patients benefit from antithrombotic treatment and in whom it can be abstained, not to expose patients with low stroke risk to an increased risk of bleeding conferred by antithrombotic treatment. The aims of this thesis were: [1] to evaluate if a warfarin dosing algorithm can increase hit rate and decrease mean error compared with manually changed doses; [2] to assess the prevalence and net clinical benefit of aspirin as monotherapy for stroke prevention in AF; [3] to investigate the risk of thromboembolic and haemorrhagic complications within 30 days after electrical cardioversion (ECV) of AF in patients with and without oral anticoagulation (OAC) pre-treatment; and [4] to assess the proportion of patients discontinuing OAC after pulmonary vein isolation (PVI), identify factors predicting stroke after PVI and to investigate risk of complications after PVI with and without OAC. Materials and methods: All studies are retrospective and based on data from Swedish national quality registries. In paper I, data from Auricula was used to compare the resulting INR values after algorithmic warfarin dose suggestions and manually changed doses. In paper II data was extracted from the Swedish National Patient Register, the Dispensed Drugs Register and the Cause of Death Register. Patients with aspirin treatment were compared with patients without any antithrombotic treatment regarding risk of thromboembolic and haemorrhagic complications. In paper III data was collected from the Swedish National Patient Register and the Dispensed Drugs Register to examine risk of complications (thromboembolic and haemorrhagic events) within 30 days after cardioversion, comparing patients with and without oral anticoagulation pre-treatment. In paper IV data from six different Swedish national quality registries were used (Swedish Catheter Ablation Register, Auricula, Swedish National Patient Register, Dispensed Drugs Register, Cause of Death Register and Riksstroke). Patients undergoing pulmonary vein isolation (PVI) were investigated for adherence to guidelines regarding oral anticoagulation, predictors for stroke after PVI, as well as risk of ischemic stroke or intracranial haemorrhage after PVI in patients with and without treatment. Results: Paper I showed that a computerized dosing algorithm for warfarin in most cases perform as well or better compared with doses that have been changed manually, with a better hit-rate (0.72 vs. 0.67) and a lower mean error (0.44 vs. 0.48). Paper II showed that 32% of 182.678 patients with a diagnosis of AF were on monotherapy with aspirin for stroke prevention. A total of 115.185 patients were included, 58.671 with aspirin treatment and 56.514 without antithrombotic treatment at baseline. After stratification after CHA2DS2-VASc score and after multivariable adjustment, aspirin treatment did not confer a decrease in thromboembolic events. After propensity score mathcing, rate of ischemic stroke was 7.4%/year (95% CI 7.1-7.6) in aspirin treated patients and 6.6%/year (95% CI 6.4-6.9) in patients without antithrombotic treatment. In paper III 22.874 patients undergoing electrical cardioversion were included, 10.722 with and 12.152 without OAC pre-treatment. In patients with low stroke risk (CHA2DS2-VASc 0-1), no thromboembolic complication was seen within 30 days after cardioversion. In patients with CHA2DS2-VASc ≥2, the risk of thromboembolic complications was increased when no oral anticoagulation pre-treatment was used, results that remained after propensity score matching. No difference regarding haemorrhagic complications was seen. Paper IV included a total of 1585 patients undergoing PVI with a mean follow up of 2.6 years. Adherence to current guidelines regarding oral anticoagulation was good in patients with CHA2DS2-VASc ≥2. Previous ischemic stroke was a predictor for a new stroke after PVI. In patients with CHA2DS2-VASc ≥2 stroke risk was increased in patients discontinuing OAC compared to those continuing OAC (1,60%/year vs. 0.34%/year). Conclusion: Oral anticoagulation is still underutilized for prevention of stroke and systemic embolism in patients with atrial fibrillation. Patients with risk factors for stroke (CHA2DS2-VASc ≥2p) benefit from continuous oral anticoagulation treatment to prevent stroke, also in conjunction with electrical cardioversion and after pulmonary vein isolation. If warfarin is chosen, a computerised dosing algorithm can facilitate and standardize warfarin dosing and lead to better resulting INR values than manually changed doses. Aspirin should not be used for stroke prevention in patients with atrial fibrillation.

Real time spectrum analysis of signals obtained through lasso catheter during radiofrequency ablation of pulmonary vein was performed to determine the channel with dominant frequency. Threshold algorithm was used for signals which could be classified as type I and type II AF. Type III AF Signals which were highly fractionated or differentiated were evaluated for frequency content by performing Fast Fourier Transform. Data from Seven patients was collected and an episode of 180 ± 40 seconds was recorded and analyzed for each pulmonary vein that showed electrical activation. Frequency spectra for one second segment of signal for each channel were determined. The frequencies of channels were then compared to determine the channel with highest or dominant frequency. In most cases the frequency of a single channel varied erratically between 1 to 10 Hz for every subsequent one second segment which made DF detection among the channels unreliable and a single channel with dominant frequency could not be determined. A five second averaging for each channel did not produce a stable DF output and improvement was minimal. The erratic frequency behavior could be attributed to the spatial shift of micro- reentrant circuits or temporal variation in waveform over lap at the point of detection. To determine the DF more precisely either an increase in number of electrode or increase in time segment block for DF calculation is warranted. Increasing the time segment block will defeat the purpose of real time analysis thus an increase in number of electrode mapping the area of interest would be appropriate to resolve the issue.

The pulmonary vein (PV) constricts to hypoxia however little is known about the underlying mechanisms. Hypoxic PV constriction is proposed to recruit upstream capillary beds and optimise gas exchange in healthy humans and may play a role in high altitude pulmonary oedema. The PV is also intrinsic to disease states including pulmonary hypertension and pulmonary veno-occlusive disease. Blood vessel culture can be a powerful tool to enable assessment of the impact of environmental factors on vessel function and as a disease model. However culture conditions alone affect vessel contractility; the effect of culture conditions on PV function remained to be established. The aim of this project was to investigate hypoxic responses of porcine PVs including the impact of maintenance in culture. Maintenance of PVs in culture conditions for 24 hours increased contraction to hypoxia and inhibited hypoxic relaxation post-contraction. These changes to PV hypoxic responses were thought to result from endothelial dysfunction. However, the endothelial nitric oxide synthase inhibitor L-NAME inhibited PV hypoxic contraction and enhanced relaxation. The impact of K+ channel inhibitors on hypoxic contraction was also investigated. Penitrem A, 4AP, DPO-1, ZnCl2 and glyburide had no significant effect however TEA and BDM inhibited the hypoxic contraction. This suggested that TASK, KV1.5, BKCa and KATP do not play a role in the mechanism of hypoxic pulmonary venoconstriction however KV channels containing KV2.1 α subunits may modulate the response. Results with L-NAME suggested endothelial dysfunction may not fully account for the change in PV function after exposure to culture. Therefore the impact of PV maintenance in culture was further explored using an isolated PV smooth muscle cell (PVSMC) model. Maintenance of PVs in culture conditions had minimal impact on morphology and electrical properties of PVSMCs. Notably, resting membrane potential and hypoxia-induced depolarisation were not significantly different. Based on the findings of this study, the endothelium in PVs appears to a) play a major role in modulation of the hypoxic response b) be sensitive to short-term exposure to culture conditions. K+ channels appear to play a minor role in PV hypoxic contraction and SMCs isolated from PVs maintained in culture conditions have similar morphological and electrophysiological characteristics to freshly isolated PVSMCs. Taking all this into account, endothelial regulation of contractility should be a key focus for future PV research.

No description available.

Vorhofflimmern ist die häufigste Herzrhythmusstörung bei Erwachsenen und kann zu schwerwiegenden kardiovaskulären Komplikationen bei den betroffenen Patienten führen. Neben einer Einschränkung der Lebensqualität durch symptomatische Episoden u.a. mit Palpitationen, Schwindel, Dyspnoe und Synkopen kommt es zu einer deutlichen Steigerung des Schlaganfallrisikos. Oftmals liegen zusätzlich strukturelle Herzerkrankungen wie Klappenvitien, eine koronare Herzerkrankung oder eine linksventrikuläre Hypertrophie vor, die das Krankheitsbild weiter verschlechtern. Therapeutisch bieten sich neben der pharmakologischen antiarrhythmischen Behandlung auch invasive Methoden wie die Pulmonalvenenablation an. In dieser Arbeit wurden die Erfolge der unterschiedlichen Therapieoptionen bei Patienten mit Vorhofflimmern und der Indikation zur Pulmonalvenenablation anhand von zwei Patientengruppen verglichen. Während die erste Gruppe mit fünf von den ESC-Leitlinien für die Behandlung von Vorhofflimmern zugelassenen Medikamenten rein konservativ behandelt wurde, erhielten die Patienten in der zweiten Gruppe eine kombinierte Therapie aus Medikamenten und Pulmonalvenenablation. Die untersuchten Medikamente waren Betablocker, Klasse IC-Antiarrythmika, Sotalol, Amiodaron und Dronedaron.Insgesamt konnte ein hochsignifikanter Vorteil der kombinierten Therapie gegenüber der rein pharmakologischen Therapie festgestellt werden. Die besten Langzeitergebnisse zeigten sich bei Patienten, die im Falle eines Rezidivs weitere Ablationen erhielten. Beim Vergleich der Wirkung der unterschiedlichen Medikamente miteinander blieb die Überlegenheit eines der Medikamente über einen langfristigen Therapiezeitraum von zwölf Monaten im überwiegenden Teil der Untersuchungen aus. Signifikante Effektivitätsunterschiede konnten lediglich in der Untergruppe „vor Ablation“ festgestellt werden. Dabei war die Amiodarontherapie effektiver als Betablocker, Klasse IC-Antiarrhythmika und Dronedaron. Sotalol war zudem erfolgreicher als Dronedaron.Trotz des teils zufriedenstellenden Ansprechens der Patienten auf die pharmakologische Therapie ist diese durch das Auftreten von Nebenwirkungen beschränkt. Besonders Amiodaron und Dronedaron sind mit einer nicht zu vernachlässigenden Rate an Nebenwirkungen assoziiert. Mit der Pulmonalvenenablation steht eine effektive alternative Therapieoption zur Verfügung, die insbesondere im Rahmen eines kombinierten Therapieansatzes aus Medikamenten und invasiver Therapie inklusive Reablationen einen hochsignifikanten Vorteil gegenüber der rein konservativen Rhythmuskontrolle bietet.