There is a growing consensus that life-threatening cardiac arrhythmias like ventricular tachycardia (VT) or ventricular fibrillation (VF) arise because of the formation of spiral waves of electrical activation in cardiac tissue; unbroken spiral waves are associated with VT and broken ones with VF. Several experimental studies have shown that inhomogeneities in cardiac tissue can have dramatic effects on such spiral waves. In this thesis we try to understand these experimental results by carrying out detailed and systematic studies of the interaction of spiral waves with different types of inhomogeneities in mathematical models for cardiac tissue. In Chapter 1 we begin with a general introduction to cardiac arrhythmias, the cardiac conduction system, and the connection between electrical activation waves in cardiac tissue and cardiac arrhythmias. As we have noted above, VT and VF are believed to be associated with spiral waves of electrical activation on cardiac tissue; such spiral waves form because cardiac tissue is an excitable medium. Thus we give an overview of excitable media, in which sub-threshold perturbations decay but super-threshold perturbations lead to an action potential that consists of a rapid stage of depolarization of cardiac cells followed by a slow phase of repolarization. During this repolarization phase the cells are refractory. We then give an overview of earlier studies of the effects of inhomogeneities in cardiac tissue; and we end with a brief description of the principal problems we study here. Chapter 2 describes the models we use in our work. We start with a general introduction to the cable equation and then discuss the Hodgkin-Huxley-formalism for the transport of ions across a cell membrane through voltage-gated ion channels. We then describe in detail the three models that we use for cardiac tissue, which are, in order of increasing complexity, the Panfilov model, the Luo Rudy Phase I (LRI) model, and the reduced Priebe Beuckelmann (RPB)model. We then give the numerical schemes we use for solving these model equations and the initial conditions that lead to the formation of spiral waves. For all these models we give representative results from our simulations and compare the states with spiral turbulence. In Chapter 3 we investigate the effects of conduction inhomogeneities (obstacles) in the three models introduced in Chapter 2. We outline first the experimental results that have provided the motivation for our study. We then discuss how we introduce obstacles in our simulations of the Panffilov, LRI, and RPB models for cardiac tissue. Next we present the results of our numerical studies of the effects, on spiral-wave dynamics, of the sizes, shapes, and positions of the obstacles. Our Principal result is that spiral-wave dynamics in these models depends sensitively on the position of the obstacle. We find, in particular, that, merely by changing the position of a conduction inhomogeneity, we may convert spiral turbulence (the analogue in our models of VF) to a single rotating spiral (the analogue of VT) anchored to the obstacle or vice versa; even more exciting is the possibility that, at the boundary between these two types of behaviour, we find a quiescent state Q with no spiral waves. Thus our study obtains all the possible qualitative behaviours found in experiments, namely, (1) VF might persist even in the presence of an obstacle, (2) it might be suppressed partially and become VT, or (3) it might be eliminated completely. In Chapter 4 we extend our work on conduction inhomogeneities (Chapter 3) to ionic inhomogeneities. Unlike conduction inhomogeneities, ionic inhomogeneities allow the conduction of activation waves. We find, nevertheless, that they too can lead to the anchoring of spiral waves or even the complete elimination of spiral-wave turbulence. Since spiral waves can enter the region in which there is an ionic inhomogeneity, their behaviours in the presence of such an inhomogeneity are richer than those with conduction inhomogeneities. We find, in particular, that a single spiral wave anchored at an ionic inhomogeneity can show temporal evolution that may be periodic, quasiperiodic, or even chaotic. In the last case the spiral wave shows a chaotic pattern inside the ionic inhomogeneity and a regular one outside it. Defibrillation is the control of arrhythmias such as VF. Most often defibrillation is effected electrically by administering a shock, either externally or via an internally implanted defibrillator. The development of low-amplitude defibrillation schemes, which minimise the deleterious effects of the applied shock, is a major challenge in the treatment of cardiac arrhythmias. Numerical studies of models for cardiac tissue provide us with convenient means of studying the elimination of spiral-wave turbulence by the application of external electrical stimuli; this is the numerical analogue of defibrillation. Over the years some low-amplitude defibrillation schemes have been suggested on the basis of such numerical studies. In Chapter 5 we discuss two such schemes that have been shown to suppress spiral-wave turbulence in two-dimensional models for cardiac tissue and also scroll-wave turbulence in three-dimensional models. One of these schemes uses local electrical pacing, typically in the centre of the simulation domain; the other applies the external electrical stimuli over a mesh. We study the efficacy of these schemes in the presence of conduction inhomogeneities. We find, in particular, that the local-pacing scheme, though effective in a homogeneous simulation domain, fails to control spiral turbulence in the presence of an obstacle and, indeed, might even facilitate spiral-wave break up. By contrast, the second scheme, which uses a mesh, succeeds in eliminating spiral-wave turbulence even in the presence of an obstacle. We end with some concluding remarks about the possible experimental implications of our study in Chapter 6.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Introduction: Ventricular arrhythmias (VAs) are common after an acute coronary syndrome (ACS) and are associated with worse clinical outcomes. However, little is known about recent trends in their occurrence, their association with serum glucose levels, and their psychological impact in ACS setting. Methods: We examined 25-year (1986-2011) trends in the incidence rates (IRs) and hospital case-fatality rates (CFRs) of VAs, and the association between serum glucose levels and VAs in patients with an acute myocardial infarction (AMI) in the Worcester Heart Attack Study. Lastly, we examined the relationship between in-hospital occurrence of VAs and 12-month progression of depression and anxiety among hospital survivors of an ACS in the longitudinal TRACE-CORE study. Results: We found the IRs declined for several major VAs between 1986 and 2011while the hospital CFRs declined in both patients with and without VAs over this period. Elevated serum glucose levels at hospital admission were associated with a higher risk of developing in-hospital VAs. Occurrence of VAs, however, was not associated with worsening progression of symptoms of depression and/or anxiety over a 12-month follow-up period in patients discharged after an ACS. Conclusions: The burden and impact of VAs in patients with an AMI has declined over time. Elevated serum glucose levels at hospital admission may serve as a predictor for in-hospital occurrence of serious cardiac arrhythmias. In-hospital occurrence of VAs may not be associated with worsening progression of symptoms of depression and anxiety in patients with an ACS.

A la croisée des chemins entre médecine et physique des ultrasons, ce travail de thèse s’est intéressé à l’apport de solutions diagnostiques et de thérapeutiques novatrices dans le domaine de l’électrophysiologie cardiaque. Un système capable de délivrer des ultrasons focalisés dans le cœur par voie transoesophagienne sous guidage par ultrasons a été développé et testé in vivo chez 6 porcs. Les tirs HIFU ont été délivrés sur les oreillettes et les ventricules. Lors de l'autopsie, une analyse visuelle a démontré la présence de lésions thermiques dans les zones ciblées chez 3 animaux. Ces lésions ont été confirmées par analyse histologique (taille moyenne: 5,5 mm2 x 11 mm2). Aucune lésion thermique œsophagienne n'a été observée. Un animal a présenté une bradycardie due à un bloc auriculo-ventriculaire, ce qui a permis de confirmer une réelle interaction entre les tirs HIFU et le tissu nodal cardiaque. Nous avons cependant observé un manque de précision, principalement lié aux mouvements cardiaques ainsi qu’aux structures anatomiques situées entre les zones ciblées et le transducteur de thérapie. Ces difficultés ont été principalement reliées à l’anatomie du modèle porcin, loin de celle de l’être humain. La recherche d'un meilleur modèle a conduit à des tests d'imagerie concluants sur des babouins.Des expériences supplémentaires ont été conduites afin d'améliorer la cartographie des arythmies ventriculaires et le suivi de la formation de lésions pendant l'ablation.Des expériences ont été menées sur les ventricules gauches de quatre coeurs de porcs en mode travaillant. Le protocole visait à démontrer que différents modèles d'activation mécanique pouvaient être observés, que le ventricule soit en rythme sinusal, stimulé depuis l'épicarde ou l'endocarde. Des acquisitions d’imagerie de déformation électromécanique (EWI) ont été enregistrées sur les faces antérieures, latérales et postérieures du ventricule gauche. Les boucles ont été ensuite analysées à l’aveugle par deux lecteurs indépendants.Les interprétations des séquences EWI étaient correctes dans 89% des cas. Le taux de concordance globale entre les deux lecteurs était de 83%. Dans un ventricule stimulé, l'origine du front d'onde était focale et provenait de l'endocarde ou de l'épicarde stimulé. En rythme sinusal, le front d'onde était activé depuis tout l'endocarde, en direction de l'épicarde, à une vitesse de 1,7 ± 0,28 m.s-1. Les vitesses du front d'onde ont été mesurées respectivement lorsque l'endocarde ou l'épicarde étaient stimulés à une vitesse de 1,1 ± 0,35 m.s -1 et 1,3 ± 0,34 m.s-1 (p = NS). Nous avons aussi démontré sur des échantillons ex-vivo que l'imagerie trans oesophagienne par analyse des ondes de cisaillement (élastographie) pouvait cartographier l'étendue des lésions HIFU. Des tirs HIFU ont été réalisés à l'aide de la sonde trans oesophagienne sur des échantillons de blancs de poulet (n = 3), puis sur un modèle porcin ex vivo d'oreillette (gauche, n = 2) et de ventricule gauche (n = 1). L’élastographie a fourni des cartes de rigidité des tissus avant et après l'ablation. Les zones des lésions ont été obtenues par analyse et quantification des changements de couleur des tissus puis ont été comparées aux images par élastographie. Dans le blanc de poulet, la rigidité est passée en moyenne de 4.8±1.1 kPa à 20.5±10.0 kPa (ratio 5.0±3.2). Dans le ventricule gauche, la rigidité est passée en moyenne de 21.2±3.3kPa à 73.8±13.9kPa (ratio 3.7±1.2). Dans l’oreillette gauche, la rigidité est passée en moyenne de 12.2±4.3 kPa à 30.3±10.3 (ratio 3.2±2.0). En histologie, la taille des lésions variait de 0.1 à 1.5 cm2 dans la zone du plan d'imagerie. Les caractéristiques morphométriques étaient similaires entre histologie et élastographie / At the crossroads of medicine and physics, this work aimed to provide innovative diagnostic and therapeutic tools based on ultrasound, in the field of cardiac electrophysiology. A system capable of delivering HIFU into the heart by a transesophageal route using ultrasound (US) imaging guidance was developed and tested in vivo in six male pigs. HIFU exposures were performed on atria and ventricles. At the time of autopsy, visual inspection identified thermal lesions in the targeted areas in three of the animals. These lesions were confirmed by histologic analysis (mean size: 5.5 mm2 x 11mm2). No esophageal thermal injury was observed. One animal presented with bradycardia due to an atrio-ventricular block, which provides real-time confirmation of an interaction between HIFU and the electrical circuits of the heart. There was still a lack of accuracy, mainly related to cardiac motion, and to anatomical structures in between the targets and the transducer. It was mainly related to the in vivo model and its anatomy, far from the human’s. The search for a better model led to conclusive imaging tests on baboons. Additional experiments were conduced in order to improve the mapping of ventricular arrhythmias and the monitoring of lesion formation during ablation. First, experiments were conducted on left ventricles of four isolated working mode swine hearts. The protocol aimed at demonstrating that different patterns of mechanical activation could be observed whether the ventricle was in sinus rhythm, paced from the epicardium, or from the endocardium. Electromechanical wave imaging (EWI) acquisitions were recorded on the anterior, lateral, and posterior segments of the left ventricle. Loop records were blindly assigned to two readers. EWI sequences interpretations were correct in 89% of cases. The overall agreement rate between the two readers was 83%. When in a paced ventricle, the origin of the wave front was focal and originating from the endocardium or the epicardium. In sinus rhythm, wave front was global and activated within the entire endocardium towards the epicardium at a speed of 1.7±0.28 m.s-1. Wave front speeds were respectively measured when the endocardium or the epicardium were paced at a speed of 1.1 ± 0.35 m.s-1 vs 1.3±0.34 m.s-1 (p=NS). Lastly, we investigated the feasibility of a dual therapy and imaging approach with the same transoesophageal device. We demonstrated on ex-vivo samples that transoesophageal shear wave imaging (SWE) can map the extent of the HIFU lesions. HIFU ablation was performed with the transoesophageal probe on ex-vivo chicken breast samples (n=3), then atrium (left, n=2) and ventricle (left n=1, right n=1) of swine heart tissues. SWE provided stiffness maps of the tissues before and after ablation. Areas of the lesions were obtained by tissue color change with gross pathology and compared to SWE. Shear modulus of the ablated zones increased from 4.8±1.1 kPa to 20.5+/-10.0 kPa (ratio 5.0±3.2) in the chicken breast, from 12.2±4.3 kPa to 30.3±10.3 (ratio 3.2±2.0) in the atria and from 21.2±3.3kPa to 73.8±13.9kPa (ratio 3.7±1.2) in the ventricles. On gross pathology, the size of the lesions ranged from 0.1 to 1.5cm2 in the imaging plane area and morphometric characteristics were fitting with elasticity-estimated depths and widths of the lesions

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

Thèse en cotutelle avec Université de Nantes - Pays de La Loire - France (2005-2010) / Les maladies cardio-vasculaires sont la première cause de mortalité dans le monde. L’hypertrophie cardiaque est un processus de remodelage provoqué par une surcharge de travail du muscle cardiaque afin de mieux répondre à la demande de l’organisme. Bien que bénéfique à court terme, une hypertrophie trop accentuée conduira à long terme, à une insuffisance cardiaque. L’hypertrophie est associée à un remodelage électrique qui conduit généralement à un allongement du potentiel d’action, une des causes des arythmies ventriculaires et de la mort subite. Généralement, le mécanisme causal est la fibrillation ventriculaire, un trouble du rythme irréversible dont les mécanismes sont complexes et méconnus. Si les conséquences fonctionnelles in vitro des mutations génétiques ou du remodelage ionique sont relativement simples à étudier ou à prévoir, leur rôle dans les mécanismes des troubles du rythme in vivo sont plus difficiles à appréhender. Parmi les nombreux modèles animaux développés pour la recherche sur les troubles du rythme, la souris est de plus en plus utilisée en raison de notre capacité à muter, invalider ou sur-exprimer les gènes d'intérêt chez ces animaux. L'objectif de mon travail de thèse était de mieux comprendre le rôle des canaux ioniques en physiopathologie cardiaque, en particulier dans la survenue des troubles du rythme in vivo. Ces travaux ont permis d'améliorer notre connaissance du rôle des anomalies génétiques impliquant des canaux ioniques et du remodelage ionique dans la physiopathologie des troubles du rythme et pourrait ainsi ouvrir de nouvelles perspectives thérapeutiques dans le traitement anti-remodelage cardiaque et la prévention de la mort subite. / Cardiovascular disease is the leading cause of death in the world each year. If no action is taken to improve cardiovascular health and current trends continue, WHO estimates that 25% more healthy life years will be lost to cardiovascular disease globally by 2020. Cardiac hypertrophy is the consequence of an excessive workload of the heart muscle leading to cardiac remodeling process. As the workload increases, the ventricular walls grow thicker, lose elasticity and eventually may fail to pump with as much force as a healthy heart. Furthermore, hypertrophied myocardium is not physiologically normal and may confer a predisposition to potentially fatal arrhythmias. Generally, the causal mechanism is ventricular fibrillation, a cardiac rhythm disorder which is irreversible but the pathophysiological mechanisms are complex and poorly understood. The functional consequences of mutations or ionic remodeling are relatively simple to study in vitro, but their role in the pathophysiology of arrhythmias in vivo is more difficult to grasp. Among the different animal models developed in cardiac arrhythmias research, the mouse is increasingly used because of our ability to mutate, knock-out or over-express genes of interest. The objective of my thesis was to study the role of ion channels in physiology as well as cardiac pathophysiology, particularly in the involvement of the occurrence of cardiac arrhythmias in vivo. This thesis will improve our understanding of the role of genetic abnormalities involving ionic remodeling in the pathogenesis of the heart and may also open new therapeutic perspectives in the treatment of cardiac remodeling as well as sudden cardiac death.

Les maladies cardio-vasculaires sont la première cause de mortalité dans le monde. L’hypertrophie cardiaque est un processus de remodelage provoqué par une surcharge de travail du muscle cardiaque afin de mieux répondre à la demande de l’organisme. Bien que bénéfique à court terme, une hypertrophie trop accentuée conduira à long terme, à une insuffisance cardiaque. L’hypertrophie est associée à un remodelage électrique qui conduit généralement à un allongement du potentiel d’action, une des causes des arythmies ventriculaires et de la mort subite. Généralement, le mécanisme causal est la fibrillation ventriculaire, un trouble du rythme irréversible dont les mécanismes sont complexes et méconnus. Si les conséquences fonctionnelles in vitro des mutations génétiques ou du remodelage ionique sont relativement simples à étudier ou à prévoir, leur rôle dans les mécanismes des troubles du rythme in vivo sont plus difficiles à appréhender. Parmi les nombreux modèles animaux développés pour la recherche sur les troubles du rythme, la souris est de plus en plus utilisée en raison de notre capacité à muter, invalider ou sur-exprimer les gènes d'intérêt chez ces animaux. L'objectif de mon travail de thèse était de mieux comprendre le rôle des canaux ioniques en physiopathologie cardiaque, en particulier dans la survenue des troubles du rythme in vivo. Ces travaux ont permis d'améliorer notre connaissance du rôle des anomalies génétiques impliquant des canaux ioniques et du remodelage ionique dans la physiopathologie des troubles du rythme et pourrait ainsi ouvrir de nouvelles perspectives thérapeutiques dans le traitement anti-remodelage cardiaque et la prévention de la mort subite. / Cardiovascular disease is the leading cause of death in the world each year. If no action is taken to improve cardiovascular health and current trends continue, WHO estimates that 25% more healthy life years will be lost to cardiovascular disease globally by 2020. Cardiac hypertrophy is the consequence of an excessive workload of the heart muscle leading to cardiac remodeling process. As the workload increases, the ventricular walls grow thicker, lose elasticity and eventually may fail to pump with as much force as a healthy heart. Furthermore, hypertrophied myocardium is not physiologically normal and may confer a predisposition to potentially fatal arrhythmias. Generally, the causal mechanism is ventricular fibrillation, a cardiac rhythm disorder which is irreversible but the pathophysiological mechanisms are complex and poorly understood. The functional consequences of mutations or ionic remodeling are relatively simple to study in vitro, but their role in the pathophysiology of arrhythmias in vivo is more difficult to grasp. Among the different animal models developed in cardiac arrhythmias research, the mouse is increasingly used because of our ability to mutate, knock-out or over-express genes of interest. The objective of my thesis was to study the role of ion channels in physiology as well as cardiac pathophysiology, particularly in the involvement of the occurrence of cardiac arrhythmias in vivo. This thesis will improve our understanding of the role of genetic abnormalities involving ionic remodeling in the pathogenesis of the heart and may also open new therapeutic perspectives in the treatment of cardiac remodeling as well as sudden cardiac death. / Thèse en cotutelle avec Université de Nantes - Pays de La Loire - France (2005-2010)