Chronic myocardial infarction promotes atrial action potential alternans, afterdepolarisations and fibrillation

Aims: Atrial fibrillation (AF) is increased in patients with heart failure resulting from myocardial infarction (MI). We aimed to determine the effects of chronic ventricular MI in rabbits on the susceptibility to AF, and underlying atrial electrophysiological and Ca2+-handling mechanisms. Methods and results: In Langendorff-perfused rabbit hearts, under beta-adrenergic-stimulation with isoproterenol (1 µM; ISO), 8 weeks MI decreased AF threshold, indicating increased AF-susceptibility. This was associated with increased atrial action potential duration-alternans at 90% repolarisation, by 147%, and no significant change in mean APD or atrial global conduction velocity (n=6-13 non-MI hearts, 5-12 MI). In atrial isolated myocytes, also under beta-stimulation, L-type Ca2+ current (ICaL) density and intracellular Ca2+-transient amplitude were decreased by MI, by 35% and 41%, respectively, and the frequency of spontaneous depolarisations (SDs) was substantially increased. MI increased atrial myocyte size and capacity, and markedly decreased transverse-tubule density. In non-MI hearts perfused with ISO, the ICaL-blocker nifedipine, at a concentration (0.02 µM) causing an equivalent ICaL-reduction (35%) to that from the MI, did not affect AF-susceptibility, and decreased APD. Conclusion: chronic MI in rabbits remodels atrial structure, electrophysiology and intracellular Ca2+-handling. Increased susceptibility to AF by MI, under beta-adrenergic-stimulation, may result from associated production of atrial APD-alternans and SDs, since steady-state APD and global conduction velocity were unchanged under these conditions, and may be unrelated to the associated reduction in whole-cell ICaL. Future studies may clarify potential contributions of local conduction changes, and cellular and sub-cellular mechanisms of alternans, to the increased AF-susceptibility

Doctor of Philosophy

dissertationFibrillation is defined as turbulent cardiac electrical activity and results in the inability of the myocardium to contract. When fibrillation occurs in the ventricles, it is known as ventricular fibrillation (VF). The consequence of VF is sudden death unless treated immediately. Fibrillation can also occur in the atria and is known as atrial fibrillation (AF). The consequences of atrial fibrillation (AF) are less immediate; however, it leads to increased risk of stroke. Despite the impact of fibrillatory arrhythmias, there are many gaps in our mechanistic knowledge of these arrhythmias. The purpose of this dissertation is to study through several projects how different cardiac substrates help initiate and/or sustain fibrillation. The first project examined several properties of the ventricular conduction system during VF. The conduction system coordinates excitation and consequently coordinates the contraction of the ventricles. Despite the conduction system's unique structure, its role in VF remains unclear. We examined the proximal conduction system and found that it develops a more rapid activation rate than the ventricular myocardium during prolonged VF, and may be driving the arrhythmia. The second and third projects examined the effects of fibrosis on electrical conduction to initiate and/or sustain AF. Despite fibrosis being associated with AF, it is still unknown whether it is a byproduct of an underlying heart disease and does not in itself promote AF, or if it affects the organization of conduction during fibrillation to promote AF. In the second project we studied the effect of fibrosis on conduction following different types of triggers. We found that fibrosis causes transverse conduction slowing following premature stimulation, which makes AF more likely to initiate. As AF persists, single episodes of AF last longer before the patient transitions into normal sinus rhythm, and in some cases AF can become permanent. The third project examined why some patients may never transition from AF to normal sinus rhythm. Specifically, this project found that regions of dense fibrosis anchor high-frequency activation that may be driving the arrhythmia. These studies showed that fibrosis causes conduction changes that make AF more likely to initiate and to be sustained

A Multiscale in Silico Study to Characterize the Atrial Electrical Activity of Patients With Atrial Fibrillation. A Translational Study to Guide Ablation Therapy

[ES] La fibrilación auricular es la arritmia cardíaca más común. Durante la fibrilación auricular, el sustrato auricular sufre una serie de cambios o remodelados a nivel eléctrico y estructural. La remodelación eléctrica se caracteriza por la alteración de una serie de canales iónicos, lo que cambia la morfología del potential de transmembrana conocido como potencial de acción. La remodelación estructural es un proceso complejo que involucra la interacción de varios procesos de señalización, interacción celular y cambios en la matriz extracelular. Durante la remodelación estructural, los fibroblastos que abundan en el tejido cardíaco, comienzan a diferenciarse en miofibroblastos que son los encargados de mantener la estructura de la matriz extracelular depositando colágeno. Además, la señalización paracrina de los miofibroblastos afecta a los canales iónicos de los miocitos circundantes. Se utilizaron modelos computacionales muy detallados a diferentes escalas para estudiar la remodelación estructural inducida a nivel celular y tisular. Se realizó una adaptación de un modelo de fibroblastos humanos a nivel celular para reproducir la electrofisiología de los miofibroblastos durante la fibrilación auricular. Además, se evaluó la exploración de la interacción del calcio en la electrofisiología de los miofibroblastos ajustando el canal de calcio a los datos experimentales. A nivel tisular, se estudió la infiltración de miofibroblastos para cuantificar el aumento de vulnerabilidad a una arritmia cardíaca. Los miofibroblastos cambian la dinámica de la reentrada. Una baja densidad de miofibroblastos permite la propagación a través del área fibrótica y crea puntos de salida de actividad focal y roturas de ondas dentro de esta área. Además, las composiciones de fibrosis juegan un papel clave en la alteración del patrón de propagación. La alteración del patrón de propagación afecta a los electrogramas recogidos en la superficie del tejido. La morfología del electrograma se alteró dependiendo de la disposición y composición del tejido fibrótico. Se combinaron modelos detallados de tejido cardíaco con modelos realistas de los catéteres de mapeo disponibles comercialmente para comprender las señales registradas clínicamente. Se generó un modelo de ruido a partir de señales clínicas para reproducir los artefactos de señal en el modelo. Se utilizaron electrogramas de modelos de dos dominios altamente detallados para entrenar un algoritmo de aprendizaje automático para caracterizar el sustrato fibrótico auricular. Las características que cuantifican la complejidad de las señales fueron extraídas para identificar la densidad fibrótica y la transmuralidad fibrótica. Posteriormente, se generaron mapas de fibrosis utilizando el registro del paciente como prueba de concepto. El mapa de fibrosis proporciona información sobre el sustrato fibrótico sin utilizar un valor único de corte de 0,5 milivoltios. Además, utilizando la medición del flujo de información como la entropía de transferencia combinada con gráficos dirigidos, en este estudio, se siguió la dirección de propagación del frente de onda. La transferencia de entropía con gráficos dirigidos proporciona información crucial durante la electrofisiología para comprender la dinámica de propagación de ondas durante la fibrilación auricular. En conclusión, esta tesis presenta un estudio in silico multiescala que proporciona información sobre los mediadores celulares responsables de la remodelación de la matriz extracelular y su electrofisiología. Además, proporciona una configuración realista para crear datos in silico que pueden ser usados para aplicaciones clínicas y servir de soporte al tratamiento de ablación.[CA] La fibril·lació auricular és l'arrítmia cardíaca més freqüent, en la qual el substrat auricular patix una sèrie de remodelacions elèctriques i estructurals. La remodelació de tipus elèctric es caracteritza per l'alteració d'un conjunt de canals iònics que modifica la morfologia del voltatge transmembrana, conegut com a potencial d'acció. La remodelació estructural és un fenomen complex que implica la relació entre diversos processos de senyalització, interaccions cel·lulars i canvis en la matriu extracel·lular. Durant la remodelació estructural, els abundants fibroblasts presents en el teixit cardíac comencen a diferenciar-se en miofibroblasts, els quals s'encarreguen de mantenir l'estructura de la matriu extracel·lular dipositant-hi col·lagen. A més, la senyalització paracrina dels miofibroblasts amb els miòcits circumdants també afectarà els canals iònics. Es van utilitzar models computacionals molt detallats a diferents escales per estudiar la remodelació estructural induïda a nivell tissular i cel·lular. Es va fer una adaptació a nivell cel·lular d'un model de fibroblasts humans per reproduir-hi l'electrofisiologia dels miofibroblasts durant la fibril·lació auricular. A més, l'exploració de la interacció del calci amb l'electrofisiologia dels miofibroblasts va ser avaluada mitjançant l'adequació del canal de calci a les dades experimentals. A nivell tissular es va estudiar la infiltració de miofibroblasts per tal de quantificar l'augment de vulnerabilitat que això conferia per patir una arrítmia cardíaca. Els miofibroblasts canvien la dinàmica de la reentrada, i presentar-ne una baixa densitat permet la propagació a través de la zona fibròtica, tot creant punts de sortida d'activitat focal i trencaments d'ones dins d'aquesta àrea. A més, les composicions de fibrosi tenen un paper clau en l'alteració del patró de propagació, afectant els electrogrames recollits en la superfície del teixit. La morfologia dels electrogrames es va veure alterada en funció de la disposició i la composició del teixit fibròtic. Per comprendre els senyals clínicament registrats es van combinar models detallats de teixits cardíacs amb models realistes dels catèters de cartografia disponibles comercialment. Es va generar un model de soroll a partir de senyals clínics per reproduir-hi els artefactes de senyal. Es van utilitzar electrogrames de models de bidominis molt detallats per entrenar un algoritme d'aprenentatge automàtic destinat a caracteritzar el substrat fibròtic auricular. Les característiques que quantifiquen la complexitat dels senyals van ser extretes per identificar la densitat i transmuralitat fibròtica. Posteriorment, es van generar mapes de fibrosi mitjançant la gravació del pacient com a prova de concepte. El mapa de fibrosi proporciona informació sobre el substrat fibròtic sense utilitzar un sol valor de tensió de tall de 0,5 mV. A més, utilitzant la mesura del flux d'informació com l'entropia de transferència combinada amb gràfics dirigits, en aquest estudi es va fer un seguiment de la direcció de propagació de l'ona. L'entropia de transferència amb gràfics dirigits proporciona informació crucial durant l'electrofisiologia per entendre la dinàmica de propagació d'ones durant la fibril·lació auricular. En conclusió, aquesta tesi presenta un estudi multi-escala in silico que proporciona informació sobre els mediadors cel·lulars responsables de la remodelació de la matriu extracel·lular i la seva electrofisiologia. A més, proporciona una configuració realista per crear dades in silico que es poden traduir a aplicacions clíniques que puguen donar suport al tractament de l'ablació.[EN] Atrial fibrillation is the most common cardiac arrhythmia. During atrial fibrillation, the atrial substrate undergoes a series of electrical and structural remodeling. The electrical remodeling is characterized by the alteration of specific ionic channels, which changes the morphology of the transmembrane voltage known as action potential. Structural remodeling is a complex process involving the interaction of several signalling pathways, cellular interaction, and changes in the extracellular matrix. During structural remodeling, fibroblasts, abundant in the cardiac tissue, start to differentiate into myofibroblasts, which are responsible for maintaining the extracellular matrix structure by depositing collagen. Additionally, myofibroblasts paracrine signalling with surrounding myocytes will also affect ionic channels. Highly detailed computational models at different scales were used to study the effect of structural remodeling induced at the cellular and tissue levels.At the cellular level, a human fibroblast model was adapted to reproduce the myofibroblast electrophsyiology during atrial fibrillation. Additionally, the calcium handling in myofibroblast electrophysiology was assessed by fitting calcium ion channel to experimental data. At the tissue level, myofibroblasts infiltration was studied to quantify the increase of vulnerability to cardiac arrhythmia. Myofibroblasts alter the dynamics of reentry. A low density of myofibroblasts allows the propagation through the fibrotic area and creates focal activity exit points and wave breaks inside this area. Moreover, fibrosis composition plays a key role in the alteration of the propagation pattern. The alteration of the propagation pattern affects the electrograms computed at the surface of the tissue. Electrogram morphology was altered depending on the arrangement and composition of the fibrotic tissue. Detailed cardiac tissue models were combined with realistic models of the commercially available mapping catheters to understand the clinically recorded signals. A noise model from clinical signals was generated to reproduce the signal artifacts in the model. Electrograms from highly detailed bidomain models were used to train a machine learning algorithm to characterize the atrial fibrotic substrate. Features that quantify the complexity of the signals were extracted to identify fibrotic density and fibrotic transmurality. Subsequently, fibrosis maps were generated using patient recordings as a proof of concept. Fibrosis map provides information about the fibrotic substrate without using a single cut-off voltage value of 0.5 mV. Furthermore, in this study, using information theory measurements such as transfer entropy combined with directed graphs, the wave propagation direction was tracked. Transfer entropy with directed graphs provides crucial information during electrophysiology to understand wave propagation dynamics during atrial fibrillation. In conclusion, this thesis presents a multiscale in silico study atrial fibrillation mechanisms providing insight into the cellular mediators responsible for the extracellular matrix remodeling and its electrophysiology. Additionally, it provides a realistic setup to create in silico data that can be translated to clinical applications that could support ablation treatment.Sánchez Arciniegas, JP. (2021). A Multiscale in Silico Study to Characterize the Atrial Electrical Activity of Patients With Atrial Fibrillation. A Translational Study to Guide Ablation Therapy [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/171456TESI

Gap junction remodelling and conduction abnormalities in the heart

Electrical coupling between mammalian cardiac myocytes allows orderly spread of excitation and is mediated by gap junction (GJ) channels composed of connexin (Cx) proteins. In normal myocardium, gap junctions within the intercalated disc allow intercellular transfer of ions and represent low resistance pathways for electrical propagation. GJ remodelling describes either a change in connexin expression and/or redistribution toward the lateral cell borders. This remodelling is thought to play a crucial role in arrhythmogenesis. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. AF becomes more persistent over time (“AF begets AF”). This self perpetuating nature of AF is poorly understood and may be associated with GJ remodelling. The aim of this thesis was to characterise the GJ structural remodelling that occurs alongside electrical changes in AF and to investigate the role of gap junction modulation on changes in electrical propagation, using animal and cell models. The findings of the in vivo goat burst-pacing model suggest that late AF-induced electrical remodelling occurs with a similar time course to connexin remodelling. These consistencies in the timescale of remodelling suggest that structural GJ remodelling is a likely determinant of the development of persistent AF. Although electrical remodelling is unaffected by the angiotensin receptor blocker, candesartan, its administration does attenuate GJ remodelling. HL-1 is a cardiac muscle cell line with a phenotype that is similar to atrial myocytes, particularly in connexin expression. Rapid pacing did not induce a change in the pattern of activation. GJ uncoupling with carbenoxolone resulted in reversible slowing of conduction and could be used as a method of modifying conduction. This thesis provides an insight into the role of gap junctions in conduction propagation both in the intact myocardium in an animal model of AF and in an in vitro cell model

A Multiscale In Silico Study to Characterize the Atrial Electrical Activity of Patients With Atrial Fibrillation : A Translational Study to Guide Ablation Therapy

The atrial substrate undergoes electrical and structural remodeling during atrial fibrillation. Detailed multiscale models were used to study the effect of structural remodeling induced at the cellular and tissue levels. Simulated electrograms were used to train a machine-learning algorithm to characterize the substrate. Also, wave propagation direction was tracked from unannotated electrograms. In conclusion, in silico experiments provide insight into electrograms\u27 information of the substrate

Mechanisms of Atrial Flutter in Man and a New Technique for Electrical Conversion of Atrial Flutter

Abstract Not Provided

A Review of Healthy and Fibrotic Myocardium Microstructure Modeling and Corresponding Intracardiac Electrograms

Computational simulations of cardiac electrophysiology provide detailed information on the depolarization phenomena at different spatial and temporal scales. With the development of new hardware and software, in silico experiments have gained more importance in cardiac electrophysiology research. For plane waves in healthy tissue, in vivo and in silico electrograms at the surface of the tissue demonstrate symmetric morphology and high peak-to-peak amplitude. Simulations provided insight into the factors that alter the morphology and amplitude of the electrograms. The situation is more complex in remodeled tissue with fibrotic infiltrations. Clinically, different changes including fractionation of the signal, extended duration and reduced amplitude have been described. In silico, numerous approaches have been proposed to represent the pathological changes on different spatial and functional scales. Different modeling approaches can reproduce distinct subsets of the clinically observed electrogram phenomena. This review provides an overview of how different modeling approaches to incorporate fibrotic and structural remodeling affect the electrogram and highlights open challenges to be addressed in future research

The contact electrogram and its architectural determinants in atrial fibrillation

The electrogram is the sine qua non of excitable tissues, yet classification in atrial fibrillation (AF) remains poorly related to substrate factors. The objective of this thesis was to establish the relationship between electrograms and two commonly implicated substrate factors, connexin 43 and fibrosis in AF. The substrates and methods chosen to achieve this ranged from human acutely induced AF using open chest surgical mapping (Chapter 6), ex vivo whole heart Langendorff (Chapter 7) with in vivo telemetry confirming spontaneous AF in a new species of rat, the Brown Norway and finally isolated atrial preparations from an older cohort of rats using orthogonal pacing and novel co-localisation methods at sub-millimetre resolution and in some atria, optical mapping (Chapter 8). In rodents, electrode size and spacing was varied (Chapters 5, 10) to study its effects on structure function correlations (Chapter 9). Novel indices of AF organisation and automated electrogram morphology were used to quantify function (Chapter 4). Key results include the discoveries that humans without any history of prior AF have sinus rhythm electrograms with high spectral frequency content, that wavefront propagation velocities correlated with fibrosis and connexin phosphorylation ratios, that AF heterogeneity of conduction correlates to fibrosis and that orthogonal pacing in heavily fibrosed atria causes anisotropy in electrogram-fibrosis correlations. Furthermore, fibrosis and connexin 43 have differing and distinct spatial resolutions in their relationship with AF organisational indices. In conclusion a new model of AF has been found, and structure function correlations shown on an unprecedented scale, but with caveats of electrode size and direction dependence. These findings impact structure function methods and prove the effect of substrate on AF organisation.Open Acces

Doctor of Philosophy

dissertationAtrial fibrillation (AF) is the leading cause of ischemic stroke and is the most commonly observed arrhythmia in clinical cardiology. Catheter ablation of AF, in which specific regions of cardiac anatomy associated with AF are intenionally injured to create scar tissue, has been honed over the last 15 years to become a relatively common and safe treatment option. However, the success of these anatomically driven ablation strategies, particularly in hearts that have been exposed to AF for extended periods, remains poor. AF induces changes in the electrical and structural properties of the cardiac tissue that further promotes the permanence of AF. In a process known as electroanatomical (EAM) mapping, clinicians record time signals known as electrograms (EGMs) from the heart and the locations of the recording sites to create geometric representations, or maps, of the electrophysiological properties of the heart. Analysis of the maps and the individual EGM morphologies can indicate regions of abnormal tissue, or substrates that facilitate arrhythmogenesis and AF perpetuation. Despite this progress, limitations in the control of devices currently used for EAM acquisition and reliance on suboptimal metrics of tissue viability appear to be hindering the potential of treatment guided by substrate mapping. In this research, we used computational models of cardiac excitation to evaluate param- eters of EAM that affect the performance of substrate mapping. These models, which have been validated with experimental and clinical studies, have yielded new insights into the limitations of current mapping systems, but more importantly, they guided us to develop new systems and metrics for robust substrate mapping. We report here on the progress in these simulation studies and on novel measurement approaches that have the potential to improve the robustness and precision of EAM in patients with arrhythmias. Appropriate detection of proarrhythmic substrates promises to improve ablation of AF beyond rudimentary destruction of anatomical targets to directed targeting of complicit tissues. Targeted treatment of AF sustaining tissues, based on the substrate mapping approaches described in this dissertation, has the potential to improve upon the efficacy of current AF treatment options