京都大学 / 新制・課程博士 / 博士(医学) / 甲第23809号 / 医博第4855号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 渡邊 直樹, 教授 浅野 雅秀, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Cardiac time intervals (CTIs) are vital indicators of cardiac health and can be estimated using a combination of electrocardiography (ECG) and seismocardiography (SCG). This study investigates the impact of SCG sensor location across the sternum on CTI estimations and heart rate variability parameters. Signal processing algorithms were developed to detect the opening and closure of heart valves on SCG for CTI calculation. A novel ECG-independent method was also developed based on template matching to determine similar parameters solely based on SCG. Comparative analysis with gold-standard methods were conducted on the SCG fiducial points, evaluating accuracy and performance. Results indicate a high overall average F1 score and correlation for all fiducial point detections. The p values revealed significant differences in SCG-derived CTI estimations across the sensor locations, highlighting the importance of sensor placement for accurate assessments. This finding underscores a fundamental step toward precise evaluation of cardiac health.

Att överleva hjärtstopp utanför sjukhus är en allvarlig komplikation som kan leda till betydande fysiska och psykologiska utmaningar som kan påverka livskvalitén negativt. Den efterföljande vården, särskilt sjuksköterskans roll, är avgörande för att stödja återhämtningsprocessen och möta överlevarnas individuella behov. Denna litteraturöversikt syftade till att belysa erfarenheterna hos människor som har överlevt ett hjärtstopp utanför sjukhus. Genom att bearbeta åtta kvalitativa vetenskapliga artiklar identifierades tre huvudkategorier och sju underkategorier som sammanfattade överlevarnas erfarenheter. Resultatet visade på en komplex förändring av livssituationen för överlevarna, vilket inkluderar både fysiska och psykologiska begränsningar. Det framkom också en ökad existentiell medvetenhet och behovet av stöd från vården, familj och vänner. Bristen på vårdens stöd betonades och behovet av individuellt anpassat stöd och tydlig vägledning för att underlätta återhämtningsprocessen. I litteraturöversikten diskuterades även möjligheten att integrera patientens livskraft och religiösa övertygelser som resurs i vården för att främja återhämtningen. Sammanfattningsvis ger denna litteraturöversikt värdefull information om överlevarnas erfarenheter av att överleva ett hjärtstopp utanför sjukhus och betonar vikten av en helhetssyn i vården för att bemöta deras behov.

There is a growing consensus that life-threatening cardiac arrhythmias like ven- tricular 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 in homogeneities in cardiac tissue can have dramatic effects on such spiral waves. In this thesis we focus on spiral-wave dynamics in mathematical models of human ventricular tissue which contain (a) conduction in homogeneities, (b) ionic in- homogeneities, (c) fibroblasts, (d) Purkinje fibers. We also study the effect of a periodic deformation of the simulation domain on spiral wave-dynamics. Chapter 2 contains our study of “Spiral-Wave Dynamics and Its Control in the Presence of In homogeneities in Two Mathematical Models for Human Cardiac Tissue”; this chapter follows closely parts of a paper we have published [1]. Chapter 3 contains our study of “Spiral-wave dynamics in a Mathematical Model of Human Ventricular Tissue with Myocytes and Fibroblasts”; this chapter follows closely a paper that we have submitted for publication. Chapter 4 contains our study of “Spiral-wave Dynamics in Ionically Realistic Mathematical Models for Human Ventricular Tis- sue: The Effects of Periodic Deformation”; this chapter follows closely a paper that we have submitted for publication. Chapter 5 contains our study of “Spiral-wave dynamics in a Mathematical Model of Human Ventricular Tissue with Myocytes and Purkinje fibers”; this chapter follows closely a paper that we will submit for publication soon. In chapter 2, we study systematically the AP morphology in a state-of-the-art mathematical model of human ventricular tissue due to ten-Tusscher, Noble, Noble, and Panfilov (the TNNP04 model); we also look at the contribution of individual ionic currents to the AP by partially or completely blocking ion channels associated with the ionic currents. We then carry out systematic studies of plane- wave and circular-wave dynamics in the TNNP04 model for cardiac tissue model. We present a detailed and systematic study of spiral-wave turbulence and spa- tiotemporal chaos in two mathematical models for human cardiac tissue due to (a) ten-Tusscher and Panfilov (the TP06 model) and (b) ten-Tusscher, Noble, Noble, and Panfilov (the TNNP04 model). In particular, we use extensive numerical simulations to elucidate the interaction of spiral waves in these models with conduction and ionic in homogeneities. Our central qualitative result is that, in all these models, the dynamics of such spiral waves depends very sensitively on such in homogeneities. A major goal here is to develop low amplitude defibrillation schemes for the elimination of VT and VF, especially in the presence of in homogeneities that occur commonly in cardiac tissue. Therefore, we study a control scheme that has been suggested for the control of spiral turbulence, via low-amplitude current pulses, in such mathematical models for cardiac tissue; our investigations here are designed to examine the efficacy of such control scheme in the presence of in homogeneities in biophysical realistic models. We find that a scheme that uses control pulses on a spatially extended mesh is more successful in the elimination of spiral turbulence than other control schemes. We discuss the theoretical and experimental implications of our study that have a direct bearing on defibrillation, the control of life-threatening cardiac arrhythmias such as ventricular fibrillation. In chapter 3, we study the role of cardiac fibroblasts in ventricular tissue; we use the TNNP04 model for the myocyte cell, and the fibroblasts are modelled as passive cells. Cardiac fibroblasts, when coupled functionally with myocytes, can modulate their electrophysiological properties at both cellular and tissue levels. Therefore, it is important to study the effects of such fibroblasts when they are coupled with myocytes. Chapter 3 contains our detailed and systematic study of spiral-wave dynamics in the presence of fibroblasts in both homogeneous and inhomogeneous domains of the TNNP04 model for cardiac tissue. We carry out extensive numerical studies of such modulation of electrophysiological properties in mathematical models for (a) single myocyte fibroblast (MF) units and (b) two-dimensional (2D) arrays of such units; our models build on earlier ones and allow for no, one-way, or two-way MF couplings. Our studies of MF units elucidate the dependence of the action-potential (AP) morphology on parameters such as Ef , the fibroblast resting membrane potential, the fibroblast conductance Gf , and the MF gap-junctional coupling Ggap. Furthermore, we find that our MF composite can show autorhythmic and oscillatory behaviors in addition to an excitable response. Our 2D studies use (a) both homogeneous and inhomogeneous distributions of fibroblasts, (b) various ranges for parameters such as Ggap, Gf , and Ef , and (c) intercellular couplings that can be no, one-way, and two-way connections of fibroblasts with myocytes. We show, in particular, that the plane-wave conduction velocity CV decreases as a function of Ggap, for no and one-way couplings; however, for two-sided coupling, CV decreases initially and then increases as a function of Ggap, and, eventually, we observe that conduction failure occurs for low values of Ggap. In our homogeneous studies, we find that the rotation speed and stability of a spiral wave can be controlled either by controlling Ggap or Ef . Our studies with fibroblast inhomogeneities show that a spiral wave can get anchored to a local fibroblast inhomogeneity. We also study the efficacy of a low-amplitude control scheme, which has been suggested for the control of spiral-wave turbulence in mathematical models for cardiac tissue, in our MF model both with and without heterogeneities. In chapter 4, we carry out a detailed, systematic study of spiral-wave dynamics in the presence of periodic deformation (PD) in two state-of-the-art mathematical models of human ventricular tissue, namely, the TNNP04 model and the TP06 model. To the best of our knowledge, our work is the first, systematic study of the dynamics of spiral waves of electrical activation and their transitions, in the presence of PD, in such biophysically realistic mathematical models of cardiac tissue. In our studies, we use three types of initial conditions whose time evolutions lead to the following states in the absence of PD: (a) a single rotating spiral (RS), (b) a spiral-turbulence (ST) state, with a single meandering spiral, and (c) an ST state with multiple broken spirals for both these models. We then show that the imposition of PD in these three cases leads to a rich variety of spatiotemporal pat- terns in the transmembrane potential including states with (a) an RS state with n-cycle temporal evolution (here n is a positive integer), (b) rotating-spiral states with quasiperiodic (QP) temporal evolution, (c) a state with a single meandering spiral MS, which displays spatiotemporal chaos, (d) an ST state, with multiple bro- ken spirals, and (e) a quiescent state in which all spirals are absorbed (SA). For all three initial conditions, precisely which one of the states is obtained depends on the amplitudes and the frequencies of the PD in the x and y directions. We also suggest specific experiments that can test the results of our simulations. We also study, in the presence of PD, the efficacy of a low-amplitude control scheme that has been suggested, hitherto only without PD, for the control of spiral-wave turbulence, via low-amplitude current pulses applied on a square mesh, in mathematical models for cardiac tissue. We also develop line-mesh and rectangular-mesh variants of this control scheme. We find that square- and line-mesh-based, low-amplitude control schemes suppress spiral-wave turbulence in both the TP06 and TNNP04 models in the absence of PD; however, we show that the line-based scheme works with PD only if the PD is applied along one spatial direction. We then demonstrate that a minor modification of our line-based control scheme can suppress spiral-wave turbulence: in particular, we introduce a rectangular-mesh-based control scheme, in which we add a few control lines perpendicular to the parallel lines of the line- based control scheme; this rectangular-mesh scheme is a significant improvement over the square-mesh scheme because it uses fewer control lines than the one based on a square mesh. In chapter 5, we have carried out detailed numerical studies of (a) a single unit of an endocardial cell and Purkinje cell (EP) composite and (b) a two-dimensional bilayer, which contains such EP composites at each site. We have considered bio- physically realistic ionic models for human endocardial cells (Ecells) and Purkinje cells (Pcells) to model EP composites. Our study has been designed to elucidate the sensitive dependence, on parameters and initial conditions, of (a) the dynamics of EP composites and (b) the spatiotemporal evolution of spiral waves of electrical activation in EP-bilayer domains. We examine this dependence on myocyte parameters by using the three different parameter sets P1, P2, and P3; to elucidate the initial-condition dependence we vary the time at which we apply the S2 pulse in our S1-S2 protocol; we also investigate the dependence of the spatiotemporal dynamics of our system on the EP coupling Dgap, and on the number of Purkinje- ventricular junctions (PVJs), which are measured here by the ratio R, the ratio of the total number of sites to the number of PVJs in our simulation domain. Our studies on EP composites show that the frequency of autorhythmic activity of a P cell depends on the diffusive gap-junctional conductance Dgap. We perform a set of simulations to understand the source-sink relation between the E and P cells in an EP composite; such a source-sink relation is an important determinant of wave dynamics at the tissue level. Furthermore, we have studied the restitution properties of an isolated E cell and a composite EP unit to uncover this effect on wave dynamics in 2D, bilayers of EP composites. Autorhythmicity is an important property of Purkinje cell; it helps to carry electrical signals rapidly from bundle of His to the endocardium. Our investigation of an EP composite shows that the cycle length (CL) of autorhythmic activity decreases, compared to that of an uncoupled Purkinje cell. Furthermore, we find that the APD increases for an EP composite, compared to that of an uncoupled P cell. In our second set of simulations for an EP-composite unit, we have obtained the AP behaviors and the amount of flux that flows from the E to the P cell during the course of the AP. The direction of flow of this flux is an important quantity that identifies which one of these cells act as a source or a sink in this EP composite. We have found that the P cell in an EP composite acts as a stimulation-current source for the E cell in the depolarization phase of the AP, when the stimulus is applied to both cells or to the P cell only. However, the P cell behaves both as a source and a sink when the stimulus is applied to the E cell only. In our third set of simulations for an EP composite unit, we have calculated the restitution of the APD; this plays an important role in deciding the stability of spiral waves in mathematical models for cardiac tissue. Our simulation shows that, for the EP composite with high coupling (Dgap = Dmm~10), the APDR slope decreases, relative to its value for an isolated E cell, for parameter sets P1 and P2, and first increases (for 50 ≤ DI ≤ 100 ms) and then decreases for the parameter set P3 ; however, for low coupling (Dgap = Dmm~100), the variation of the AP D as function of DI, for an EP composite, shows biphasic behavior for all these three parameter sets. We found that the above dynamics in EP cable type domains, with EP composites, depends sensitively on R. We hope our in silico studies of spiral-wave dynamics in a variety of state-of-the- art ionic models for ventricular tissue will stimulate more experimental studies that examine such dynamics.

Cardiac arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), are among the leading causes of death in the industrialized world. There is growing consensus that these arrhythmias are associated with the formation of spiral and scroll waves of electrical activation in mammalian cardiac tissue; whereas single spiral and scroll waves are believed to be associated with VT, their turbulent analogs are associated with VF. Thus, the study of these waves is an important biophysical problem in-so-far-as to develop an understanding of the electrophysiological basis of VT and VF. In this thesis, we provide a brief overview of recent numerical studies of spiral- and scroll-wave dynamics in mathematical models of mammalian cardiac tissue. In addition to giving a description of how spiral and scroll waves can be initiated in such models, how they evolve, how they interact with conduction and ionic inhomogeneities, how their dynamics is influenced by the size and geometry of the heart, we also discuss how active Purkinje networks and passive fibroblast clusters modify the electrical activity of cardiomyocytes, and the relevance of such studies to defibrillation. In Chapter 2 we present a systematic study of the combined effects of muscle-fiber rotation and inhomogeneities on scroll-wave dynamics in the TNNP (ten Tusscher Noble Noble Panfilov) model for human cardiac tissue. In particular, we use the three-dimensional (3D) TNNP model with fiber rotation and consider both conduction and ionic inhomogeneities. We find that, in addition to displaying a sensitive dependence on the positions, sizes, and types of inhomogeneities, scroll-wave dynamics also depends delicately upon the degree of fiber rotation. We find that the tendency of scroll waves to anchor to cylindrical conduction inhomogeneities increases with the radius of the inho-mogeneity. Furthermore, the filament of the scroll wave can exhibit drift or meandering, transmural bending, twisting, and break-up. If the scroll-wave filament exhibits weak meandering, then there is a fine balance between the anchoring of this wave at the inho-mogeneity and a disruption of wave-pinning by fiber rotation. If this filament displays strong meandering, then again the anchoring is suppressed by fiber rotation; also, the scroll wave can be eliminated from most of the layers only to be regenerated by a seed wave. Ionic inhomogeneities can also lead to an anchoring of the scroll wave; scroll waves can now enter the region inside an ionic inhomogeneity and can display a coexistence of spatiotemporal chaos and quasi-periodic behavior in different parts of the simulation domain. We discuss the experimental implications of our study. In Chapter 3 we present a comprehensive numerical study of plane and scroll waves of electrical activation in two state-of-the-art ionic models for rabbit and pig cardiac tissue. We use anatomically realistic, 3D simulation domains, account for muscle-fiber rotation, and show how to include conduction and ionic inhomogeneities in these models; we consider both localized and randomly distributed inhomogeneities. Our study allows us to compare scroll-wave dynamics, with and without inhomogeneities, in these rabbit-and pig-heart models at a level that has not been attempted hitherto. We begin with a comparison of single-cell action potentials (APs) and ionic currents in the Bers-Puglisi (BP) and modified-Luo-Rudy I (mLRI) models for rabbit- and pig-myocytes, respec-tively. We then show how, for plane-wave propagation in rabbit- and pig-heart models, the conduction velocity CV and wavelength λ depend on the distance of the plane of measurement from the plane containing the heart apex. Without inhomogeneities, and in the parameter r´egime in which these models display scroll waves, the rabbit-heart model supports a single scroll wave, which rotates periodically, whereas the pig-heart model supports two scroll waves, which rotate periodically, but with a slight difference in phase; this is partly because the rabbit-heart model is smaller in size, than the pig-heart one. With randomly-distributed inhomogeneities, we find that the rabbit-heart model loses its ability to support electrical activity, even at inhomogeneity concentra-tions as low as 5%. In the pig-heart model, we obtain rich, scroll-wave dynamics in the presence of localized or distributed inhomogeneities, both of conduction and ionic types; often, but not always, scroll waves get anchored to localized inhomogeneities; and distributed inhomogeneities can lead to scroll-wave break up. In Chapter 4, we present a comprehensive numerical study of spiral-and scroll-wave dynamics in a state-of-the-art mathematical model for human ventricular tissue with fiber rotation, transmural heterogeneity, myocytes, and fibroblasts. Our mathematical model introduces fibroblasts randomly, to mimic diffuse fibrosis, in the ten Tusscher-Noble-Noble-Panfilov (TNNP) model for human ventricular tissue; the passive fibrob-lasts in our model do not exhibit an action potential in the absence of coupling with myocytes; and we allow for a coupling between nearby myocytes and fibroblasts. Our study of a single myocyte-fibroblast (MF) composite, with a single myocyte coupled to Nf fibroblasts via a gap-junctional conductance Ggap, reveals five qualitatively different responses for this composite. Our investigations of two-dimensional domains with a ran-dom distribution of fibroblasts in a myocyte background reveal that, as the percentage Pf of fibroblasts increases, the conduction velocity of a plane wave decreases until there is conduction failure. If we consider spiral-wave dynamics in such a medium we find, in two dimensions, a variety of nonequilibrium states, temporally periodic, quasiperi-odic, chaotic, and quiescent, and an intricate sequence of transitions between them; we also study the analogous sequence of transitions for three-dimensional scroll waves in a three-dimensional version of our mathematical model that includes both fiber rotation and transmural heterogeneity. We thus elucidate random-fibrosis-induced nonequilib-rium transitions, which lead to conduction block for spiral waves in two dimensions and scroll waves in three dimensions. We explore possible experimental implications of our mathematical and numerical studies for plane-, spiral-, and scroll-wave dynamics in cardiac tissue with fibrosis. In Chapter 5 we present a detailed numerical study of the electrophysiological in-teractions between a random Purkinje network and simulated human endocardial tissue, (a) in the presence of, and (b) in the absence of existing electrical excitation in the system. We study the dependence of the activation-onset-time (ta) on the strength of coupling (Dmp) between the myocyte layer and the Purkinje network, in the absence of any external stimulus. Since the connection between the endocardial layer and the Purkinje network occurs only at discrete points, we also study the dependence of ta on the number of Purkinje-myocyte junctions (PMJs) at fixed values of Dmp, in the ab-sence of any applied excitation. We study signal propagation in the system; our results demonstrate the situations of (a) conduction block from the Purkinje layer to the endo-cardial layer, (b) anterograde propagation of the excitation from the Purkinje layer to the endocardium, (c) retrograde propagation of the excitation from the endocardium to the Purkinje layer and (d) development of reentrant circuits in the Purkinje layer that lead to formation of ectopic foci at select PMJs. We extend our study to explore the effects of Purkinje-myocyte coupling on spiral wave dynamics, whereby, we find that such coupling can lead to the distortion and breakage of the parent rotor into multiple rotors within the system; with or without internal coherence. We note that retrograde propa-gation leads to the development of reentrant circuits in the Purkinje network that help to initiate and stabilize ectopic foci. However, in some cases, Purkinje-myocyte coupling can also lead to the suppression of spiral waves. Finally we conduct four representative simulations to study the effects of transmural heterogeneity, fiber rotation and coupling with a non-penetrating Purkinje network on a three dimensional slab of cardiac tissue. Lastly, In Chapter 6, we study reentry associated with inexcitable obstacles in the ionically-realistic TNNP model for human ventricular tissue, under the influence of high-frequency stimulation. When a train of plane waves successively impinge upon an obstacle, the obstacle splits these waves as they tend to propagate past it; the emergent broken waves can either travel towards each other, bridging the gap introduced by the obstacle at the time of splitting, or, they can travel away from each other, resulting in the growth of the gap. The second possibility eventually results in the formation of spiral waves. This phenomenon depends on frequency of the waves. At high frequency, the excitability of the tissue decreases and the broken waves have a tendency to move apart. Hence high-frequency stimulation increases the chances of reentry in cardiac tissue. We correlate the critical period of pacing that leads to reentry in the presence of an inexcitable obstacle, with the period of spiral waves, formed in the homogeneous domain, and study how the critical period of pacing depends on the parameters of the model.

Improving imaging hardware, computational power, and algorithmic design are driving advances in interventional medical imaging. We lay the groundwork here for more effective use of machine learning and image registration in clinical electrophysiology. To achieve identification of atrial fibrosis using image data, we registered the electroanatomic map (EAM) data of atrial fibrillation (AF) patients undergoing pulmonary vein isolation (PVI) with MR (n = 16) or CT (n = 18) images. The relationship between image features and bipolar voltage was evaluated using single-parameter regression and random forest models. Random forest performed significantly better than regression, identifying fibrosis with area under the receiver operating characteristic curve (AUC) 0.746 (MR) and 0.977 (CT). This is the first evaluation of voltage prediction using image data. Next, we compared the character of native atrial fibrosis with ablation scar in MR images. Fourteen AF patients undergoing repeat PVI were recruited. EAM data from their first PVI was registered to the MR images acquired before the first PVI (‘pre-operative’) and before the second PVI ('post-operative' with respect to the first PVI). Non-ablation map points had similar characteristics in the two images, while ablation points exhibited higher intensity and more heterogeneity in post-operative images. Ablation scar is more strongly enhancing and more heterogeneous than native fibrosis. Finally, we addressed myocardial measurement in 3-D echocardiograms. The circular Hough transform was modified with a feature asymmetry filter, epicardial edges, and a search constraint. Manual and Hough measurements were compared in 5641 slices from 3-D images. The enhanced Hough algorithm was more accurate than the unmodified version (Dice coefficient 0.77 vs. 0.58). This method promises utility in segmentation-assisted cross-modality registration. By improving the information that can be extracted from medical images and the ease with which that information can be accessed, this progress will contribute to the advancing integration of imaging in electrophysiology.

Le travail de thèse porte sur l'analyse de la fonction électrique et mécanique du cœur afin d'étudier les effets de l'insuffisance cardiaque. Il débouche sur un ensemble d'outils qui peuvent aider le clinicien à mieux comprendre et traiter l'asynchronisme cardiaque, un des aspects de l'insuffisance cardiaque. Il a pour principal objectif de résoudre le problème inverse du couplage électro-cinématique : estimer l'électrophysiologie cardiaque sans avoir à effectuer des procédures invasives de cartographie cardiaque. Les séquences cardiaques acquises de manière non-invasive sont déjà largement utilisées dans les centres cliniques et pourraient permettre de caractériser l'électrophysiologie cardiaque sans procédure invasive. La première contribution de ce travail est l'évaluation d'une méthode de recalage non-linéaire appliquée sur des séquences cardiaques pour l'estimation du mouvement. La deuxième est une nouvelle approche de simulation de séquences synthétiques d'images cardiaque. Nous utilisons des séquences réelles et un modèle électromécanique du cœur pour créer des séquences synthétiques contrôlées. Le réalisme des séquences générées repose sur l'utilisation conjointe d'un modèle biophysique et d'images réelles lors de la simulation. Enfin, la troisième contribution concerne une méthode d'estimation de la carte d'activation électrique du cœur à partir d'images médicales. Pour ce faire, nous utilisons une base de données d'images synthétiques cardiaques personnalisée à chaque patient. Ces images et les cartes d'activation électrique utilisées lors de la simulation fournissent une base d'entrainement pour apprendre la relation électro-cinématique du cœur. / This thesis focuses on the analysis of the cardiac electrical and kinematic function for heart failure patients. An expected outcome is a set of computational tools that may help a clinician in understanding, diagnosing and treating patients suffering from cardiac motion asynchrony, a specific aspect of heart failure. Understanding the inverse electro-kinematic coupling relationship is the main task of this study. With this knowledge, the widely available cardiac image sequences acquired non-invasively at clinics could be used to estimate the cardiac electrophysiology (EP) without having to perform the invasive cardiac EP mapping procedures. To this end, we use real clinical cardiac sequence and a cardiac electromechanical model to create controlled synthetic sequence so as to produce a training set in an attempt to learn the cardiac electro-kinematic relationship. Creating patient-specific database of synthetic sequences allows us to study this relationship using a machine learning approach. A first contribution of this work is a non-linear registration method applied and evaluated on cardiac sequences to estimate the cardiac motion. Second, a new approach in the generation of the synthetic but virtually realistic cardiac sequence which combines a biophysical model and clinical images is developed. Finally, we present the cardiac electrophysiological activation time estimation from medical images using a patient-specific database of synthetic image sequences.

Evidence that radiation-related cardiovascular disease and second primary cancers can occur in cancer survivors following radiation therapy (RT) has emerged from several independent sources. Cardiotoxicity and second cancers are of particular concern for patients with good prognosis, such as those with Hodgkin lymphoma (HL). HL patients are among the youngest to receive RT, which means that those who are cured of their cancer have decades-long natural life-expectancies during which treatment-related long-term toxicities may cause years of excess morbidity or premature mortality. A considerable amount of research has been conducted to investigate the risk of radiation-related cardiotoxicity and second cancers. However, there are still substantial gaps in knowledge. It is therefore important to improve our understanding regarding these risks and develop treatment approaches and survivorship care to minimise their impact on patients' quality of life. In this thesis, I have investigated the risk of congestive heart failure (CHF) in a cohort of 2619 HL survivors and presented, for the first time, dose-response relationships for risk of CHF versus cardiac radiation doses. I also validated the radiation dosimetry method used to estimate the cardiac doses in this study as well as for other reconstruction methods, versus a gold standard based on the patients' own computed tomography scans. Additionally, I investigated what effect the dose reconstruction errors had on the dose-response relationships. I then focused on modern RT methods and specifically on proton RT. Based on published dose-response relationships (including that developed in this thesis) I predicted cardiovascular and second cancer risks for patients treated with advanced RT. This thesis has provided new knowledge in the study of late effects in HL patients who were treated decades ago as well as for patients treated more recently with advanced RT methods. The results here can be used to facilitate progress towards personalised RT in terms of choosing the appropriate RT method by integrating individualised risk prediction in advanced RT treatment planning. The research here provides the basis for further work towards evidence-based case selection for HL patients for the first NHS proton therapy centres in the UK, opening in 2018-2021.

Made available in DSpace on 2014-12-17T14:14:01Z (GMT). No. of bitstreams: 1 RobsonMF_DISSERT.pdf: 1631191 bytes, checksum: 260bb5fe4f1e2f487d506e21842e62a3 (MD5) Previous issue date: 2013-05-06 / Funda??o de Amparo a Pesquisa do Estado de S?o Paulo / There is no data about cardiac measurements em Brazilians obtained by CMR. This a muldisciplinary study with the objective of obtaining measurements of the left ventricle (LV) and right ventricle (RV) diastolic diameter (Dd), systolic diameter (Ds), diastolic volume (Dv), systolic volume (Sv), ejection fraction (EF) and myocardial mass in Brazilians. One hundred and seven (54 men and 53 women, mean age of 43.4 ? 13.1 years) asymptomatic individuals without heart disease were submitted to cardiac magnetic resonance (cMR) studies using steady state free precession technique. The means and standard deviations of the parameters of the LV and RV were respectively: LVDD = 4,8 ? 0,5 cm; LVSD = 3,0?0,6 cm; LVDV = 128,4?29,6 ml; LVSV = 45,2?16,6 ml; LVEF = 65,5?6,3%; LV mass = 95,2?30,8.1 g; RVDD = 3,9?1,3 cm; RVSD = 2,5?0,5 cm; RVDV = 126,5?30,7 ml; RVSV = 53.6?18,4 ml; RVEF = 58.3?8,0.0% and RV mass = 26,1?6,1 g. The masses and volumes were significantly higher in men, except for the LVSV. The RV EF was significantly higher in women. There was inverse correlation between RV systolic volume and with age, being more significant in men. This study describes for the first time benchmarks for cardiac measurements obtained by CMR among asymptomatic Brazilians individuals without heart disease and demonstrated differences according to sex and age / N?o h? dados nacionais sobre medidas card?acas obtidas por Resson?ncia Magn?tica Card?aca (RMc). Esse trabalho multidisciplinar teve como objetivo obter medidas do di?metro diast?lico (Dd), di?metro sist?lico (Ds), volume diast?lico final (VdF), volume sist?lico final (VsF), fra??o de eje??o (FE) e da massa mioc?rdica dos ventr?culos esquerdo (VE) e direito (VD) em brasileiros. Cento e sete (107) indiv?duos, 54 homens e 53 mulheres, com idade m?dia de 43,4 ? 13,1 anos, assintom?ticos e sem cardiopatias, foram submetidos ? RMc, utilizando t?cnica de precess?o livre em estado de equil?brio. As m?dias e os desvios padr?es dos par?metros do VE e VD foram respectivamente: Dd VE = 4,8 ? 0,5 cm; Ds VE = 3,0 ? 0,6 cm; VdF VE = 128,4 ? 29,6 ml; VsF VE = 45,2 ? 16,6 ml; FEVE = 65,5 ? 6,3%; massa do VE = 95,2 ? 30,8 g; Dd VD = 3,9 ? 1,3 cm; Ds VD = 2,5 ? 0,5cm; VdF VD = 126,5 ? 30,7 ml; VsF VD = 53,6 ? 18,4 ml; FEVD = 58,3 ? 8,0% e massa do VD = 26,1 ? 6,1 g. As massas e volumes foram significativamente maiores nos homens, exceto para o VsF do VE. A fra??o de eje??o do VD foi significativamente maior nas mulheres. Houve correla??o significativa e inversa do Vs do VD com o aumento da idade, sendo mais significativo nos homens. Esse estudo descreve, pela primeira vez, medidas card?acas obtidas pela RMc em brasileiros, as quais revelam diferen?as de acordo com o sexo e a idade

L'objectif de ce travail était de mieux appréhender les mécanismes impliqués dans la réponse à la resynchronisation biventriculaire (BIV) en insistant sur la caractérisation du substrat électrique éligible à la thérapie et l'intérêt de la resynchronisation électrique. Nous avons démontré qu'il existe une relation forte entre l'asynchronisme électrique de base défini tant par l'ECG de surface que par cartographie détaillée de l'activation ventriculaire (ECM) et la réponse hémodynamique à la stimulation BIV. Par rapport à l'ECG de surface, l'ECM permet une caractérisation plus fine de l'asynchronisme électrique ventriculaire avec une meilleure prédiction de la réponse clinique à la stimulation BIV. La présence d'un asynchronisme de base minimum, en particulier d'un retard d'activation ventriculaire gauche (VG) par rapport au ventricule droit (typiquement >SOms), est un prérequis à l'efficacité de la thérapie. Les patients avec bloc de branche gauche présentent un haut degré d'asynchronisme et la stimulation BIV agit sur ce substrat par resynchronisation de l'activation électrique. A contrario, la stimulation BIV dégrade la séquence d'activation ainsi que l'hémodynamique des patients à QRS fins (dyssynchronie iatrogène). Les patients présentant un trouble de conduction aspécifique présentent des degrés variables d'asynchronie électrique et en conséquence des réponses contrastées à la stimulation BIV. De même, l'analyse ECM de l'asynchronisme des patients chroniquement stimulés sur le ventricule droit a permis de mettre en évidence des degrés variables de retard d'activation du VG. Si la resynchronisation électrique est garante d'une amélioration de la fonction cardiaque, d'autres mécanismes sont impliqués telle la redistribution du travail segmentaire au sein du myocarde ventriculaire. L'efficacité de la stimulation mono-VG implique une participation accrue du ventricule droit au travail global (interaction ventriculaire). / We aimed to characterize the electrical substrate amenable to biventricular pacing (BVP) and to assess the actual value of electrical resynchronization. We showed, both with respect to surface ECG and detailed ventricular electrocardiographic mapping (ECM), a strong relationship between the baseline electrical dyssnchrony and the hemodynamic response to BIV pacing. Compared with standard ECG, ECM allows a more detailed analysis of the ventricular dyssynchrony and better predicts clinical outcomes after BVP. A minimal amount of electrical dyssynchrony, in particular a sufficient LV activation delay relative to right ventricular activation, is a prerequisite to the hemodynamic response to BVP. Due to their advanced electrical dyssynchrony, patients with left bundle branch block present potential for BVP positive response which acts by electrical resynchronization. Conversely, BVP worsens the electrical activation (iatrogenic dyssynchrony) and hemodynamics in patients with narrow QRS suffering from insufficient electrical dyssynchrony at baseline. Patients with unspecified conduction disorders show variable levels of electrical dyssynchrony and as a consequence mixed results to BVP. Similarly, ECM reveals a variable degree of left ventricular activation delay in patients chronically paced in the right ventricle. Beside the electrical resynchronization, other mechanisms are involved in the cardiac pump function improvement such as the redistribution of the mechanical work over the right and left ventricles. Through ventricular interaction, the RV myocardium importantly contributes to the improvement in LV pump function induced by single site LV pacing.