Slow Conduction through an Arc of Block: A Basis for Arrhythmia Formation Post-Myocardial Infarction

Introduction The electrophysiologic basis for characteristic rate-dependent, constant-late-coupled (390 + 54 milliseconds) premature ventricular beats (PVBs) present 4–5 days following coronary artery occlusion were examined in 108 anesthetized dogs. Methods and results Fractionated/double potentials were observed in injured zone bipolar and composite electrograms at prolonged sinus cycle lengths (1,296 ± 396 milliseconds). At shorter cycle lengths, conduction of the delayed potential decremented, separating from the initial electrogram by a progressively prolonged isoelectric interval. With sufficient delay of the second potential following an isoelectric interval, a PVB was initiated. Both metastable and stable constant-coupled PVBs were associated with Wenckebach-like patterns of delayed activation following an isoelectric interval. Signal-averaging from the infarct border confirmed the presence of an isoelectric interval preceding the PVBs (N = 15). Pacing from the site of double potential formation accurately reproduced the surface ECG morphology (N = 15) of spontaneous PVBs. Closely-spaced epicardial mapping demonstrated delayed activation across an isoelectric interval representing “an arc of conduction block.” Rate-dependent very slow antegrade conduction through a zone of apparent conduction block (N = 8) produced decremental activation delays until the delay was sufficient to excite epicardium distal to the original “arc of conduction block,” resulting in PVB formation. Conclusion The present experiments demonstrate double potential formation and rate-dependent constant-coupled late PVB formation in infarcted dog hearts. Electrode recordings demonstrate a prolonged isoelectric period preceding PVB formation consistent with very slow conduction (<70 mm/s) across a line of apparent conduction block and may represent a new mechanism of PVB formation following myocardial infarction

New Paradigm of Defibrillation: Towards Painless Therapy

Sudden cardiac death: SCD) causes approximately 300,000 - 400,000 deaths a year in the United States. It usually starts as ventricular tachycardia: VT) and then degenerates into ventricular fibrillation: VF). Implantable cardioverter defibrillator: ICD) therapy is the only reliable treatment of VT/VF and has been shown to effectively reduce mortality by many clinical trials. However, high-voltage ICD shocks could result in myocardial dysfunction and damage. The majority of patients receiving ICD therapy have a history of coronary disease; their hearts develop myocardium infarction, which could provide a substrate for reentrant tachy-arrhythmias. Other than lethal ventricular tachycardia, atrial fibrillation: AF) became the most common arrhythmia by affecting 2.2 to 5.6 millions of Americans. The complications of AF include an increased rate of mortality, heart failure, stroke, etc. In this dissertation, we explore mechanisms of sustained ventricular and atrial tachyarrhythmias and the mechanisms of defibrillation using the conventional high-voltage single shock. Through the use of novel fluorescent optical mapping techniques and several animal models of ventricular and atrial arrhythmias, we develop and validate several novel low-voltage defibrillation therapies for atrial and ventricular arrhythmias. Several important previous studies on mechanisms of arrhythmia maintenance and termination using mathematical and experimental models are overviewed in Chapter 2. A study on multiple monophasic shocks improving electrotherapy of ventricular tachycardia in rabbit model of chronic infarction is presented in Chapter 3. Ventricular arrhythmias and low-voltage defibrillation therapy are studied in a more clinically-relevent in vivo canine model of healing myocardial infarction in Chapter 4. Finally, Chapter 5 presents a novel multi-stage low-energy defibrillation therapy for atrial fibrillation in in vivo canine hearts

Assessing the ability of substrate mapping techniques to guide ventricular tachycardia ablation using computational modelling

BACKGROUND: Identification of targets for ablation of post-infarction ventricular tachycardias (VTs) remains challenging, often requiring arrhythmia induction to delineate the reentrant circuit. This carries a risk for the patient and may not be feasible. Substrate mapping has emerged as a safer strategy to uncover arrhythmogenic regions. However, VT recurrence remains common. GOAL: To use computer simulations to assess the ability of different substrate mapping approaches to identify VT exit sites. METHODS: A 3D computational model of the porcine post-infarction heart was constructed to simulate VT and paced rhythm. Electroanatomical maps were constructed based on endocardial electrogram features and the reentry vulnerability index (RVI - a metric combining activation (AT) and repolarization timings to identify tissue susceptibility to reentry). Since scar transmurality in our model was not homogeneous, parameters derived from all signals (including dense scar regions) were used in the analysis. Potential ablation targets obtained from each electroanatomical map during pacing were compared to the exit site detected during VT mapping. RESULTS: Simulation data showed that voltage cut-offs applied to bipolar electrograms could delineate the scar, but not the VT circuit. Electrogram fractionation had the highest correlation with scar transmurality. The RVI identified regions closest to VT exit site but was outperformed by AT gradients combined with voltage cut-offs. The performance of all metrics was affected by pacing location. CONCLUSIONS: Substrate mapping could provide information about the infarct, but the directional dependency on activation should be considered. Activation-repolarization metrics have utility in safely identifying VT targets, even with non-transmural scars

Computational modelling of the human heart and multiscale simulation of its electrophysiological activity aimed at the treatment of cardiac arrhythmias related to ischaemia and Infarction

[ES] Las enfermedades cardiovasculares constituyen la principal causa de morbilidad y mortalidad a nivel mundial, causando en torno a 18 millones de muertes cada año. De entre ellas, la más común es la enfermedad isquémica cardíaca, habitualmente denominada como infarto de miocardio (IM). Tras superar un IM, un considerable número de pacientes desarrollan taquicardias ventriculares (TV) potencialmente mortales durante la fase crónica del IM, es decir, semanas, meses o incluso años después la fase aguda inicial. Este tipo concreto de TV normalmente se origina por una reentrada a través de canales de conducción (CC), filamentos de miocardio superviviente que atraviesan la cicatriz del infarto fibrosa y no conductora. Cuando los fármacos anti-arrítmicos resultan incapaces de evitar episodios recurrentes de TV, la ablación por radiofrecuencia (ARF), un procedimiento mínimamente invasivo realizado mediante cateterismo en el laboratorio de electrofisiología (EF), se usa habitualmente para interrumpir de manera permanente la propagación eléctrica a través de los CCs responsables de la TV. Sin embargo, además de ser invasivo, arriesgado y requerir mucho tiempo, en casos de TVs relacionadas con IM crónico, hasta un 50% de los pacientes continúa padeciendo episodios recurrentes de TV tras el procedimiento de ARF. Por tanto, existe la necesidad de desarrollar nuevas estrategias pre-procedimiento para mejorar la planificación de la ARF y, de ese modo, aumentar esta tasa de éxito relativamente baja. En primer lugar, realizamos una revisión exhaustiva de la literatura referente a los modelos cardiacos 3D existentes, con el fin de obtener un profundo conocimiento de sus principales características y los métodos usados en su construcción, con especial atención sobre los modelos orientados a simulación de EF cardíaca. Luego, usando datos clínicos de un paciente con historial de TV relacionada con infarto, diseñamos e implementamos una serie de estrategias y metodologías para (1) generar modelos computacionales 3D específicos de paciente de ventrículos infartados que puedan usarse para realizar simulaciones de EF cardíaca a nivel de órgano, incluyendo la cicatriz del infarto y la región circundante conocida como zona de borde (ZB); (2) construir modelos 3D de torso que permitan la obtención del ECG simulado; y (3) llevar a cabo estudios in-silico de EF personalizados y pre-procedimiento, tratando de replicar los verdaderos estudios de EF realizados en el laboratorio de EF antes de la ablación. La finalidad de estas metodologías es la de localizar los CCs en el modelo ventricular 3D para ayudar a definir los objetivos de ablación óptimos para el procedimiento de ARF. Por último, realizamos el estudio retrospectivo por simulación de un caso, en el que logramos inducir la TV reentrante relacionada con el infarto usando diferentes configuraciones de modelado para la ZB. Validamos nuestros resultados mediante la reproducción, con una precisión razonable, del ECG del paciente en TV, así como en ritmo sinusal a partir de los mapas de activación endocárdica obtenidos invasivamente mediante sistemas de mapeado electroanatómico en este último caso. Esto permitió encontrar la ubicación y analizar las características del CC responsable de la TV clínica. Cabe destacar que dicho estudio in-silico de EF podría haberse efectuado antes del procedimiento de ARF, puesto que nuestro planteamiento está completamente basado en datos clínicos no invasivos adquiridos antes de la intervención real. Estos resultados confirman la viabilidad de la realización de estudios in-silico de EF personalizados y pre-procedimiento de utilidad, así como el potencial del abordaje propuesto para llegar a ser en un futuro una herramienta de apoyo para la planificación de la ARF en casos de TVs reentrantes relacionadas con infarto. No obstante, la metodología propuesta requiere de notables mejoras y validación por medio de es[CA] Les malalties cardiovasculars constitueixen la principal causa de morbiditat i mortalitat a nivell mundial, causant entorn a 18 milions de morts cada any. De elles, la més comuna és la malaltia isquèmica cardíaca, habitualment denominada infart de miocardi (IM). Després de superar un IM, un considerable nombre de pacients desenvolupen taquicàrdies ventriculars (TV) potencialment mortals durant la fase crònica de l'IM, és a dir, setmanes, mesos i fins i tot anys després de la fase aguda inicial. Aquest tipus concret de TV normalment s'origina per una reentrada a través dels canals de conducció (CC), filaments de miocardi supervivent que travessen la cicatriu de l'infart fibrosa i no conductora. Quan els fàrmacs anti-arítmics resulten incapaços d'evitar episodis recurrents de TV, l'ablació per radiofreqüència (ARF), un procediment mínimament invasiu realitzat mitjançant cateterisme en el laboratori de electrofisiologia (EF), s'usa habitualment per a interrompre de manera permanent la propagació elèctrica a través dels CCs responsables de la TV. No obstant això, a més de ser invasiu, arriscat i requerir molt de temps, en casos de TVs relacionades amb IM crònic fins a un 50% dels pacients continua patint episodis recurrents de TV després del procediment d'ARF. Per tant, existeix la necessitat de desenvolupar noves estratègies pre-procediment per a millorar la planificació de l'ARF i, d'aquesta manera, augmentar la taxa d'èxit, que es relativament baixa. En primer lloc, realitzem una revisió exhaustiva de la literatura referent als models cardíacs 3D existents, amb la finalitat d'obtindre un profund coneixement de les seues principals característiques i els mètodes usats en la seua construcció, amb especial atenció sobre els models orientats a simulació de EF cardíaca. Posteriorment, usant dades clíniques d'un pacient amb historial de TV relacionada amb infart, dissenyem i implementem una sèrie d'estratègies i metodologies per a (1) generar models computacionals 3D específics de pacient de ventricles infartats capaços de realitzar simulacions de EF cardíaca a nivell d'òrgan, incloent la cicatriu de l'infart i la regió circumdant coneguda com a zona de vora (ZV); (2) construir models 3D de tors que permeten l'obtenció del ECG simulat; i (3) dur a terme estudis in-silico de EF personalitzats i pre-procediment, tractant de replicar els vertaders estudis de EF realitzats en el laboratori de EF abans de l'ablació. La finalitat d'aquestes metodologies és la de localitzar els CCs en el model ventricular 3D per a ajudar a definir els objectius d'ablació òptims per al procediment d'ARF. Finalment, a manera de prova de concepte, realitzem l'estudi retrospectiu per simulació d'un cas, en el qual aconseguim induir la TV reentrant relacionada amb l'infart usant diferents configuracions de modelatge per a la ZV. Validem els nostres resultats mitjançant la reproducció, amb una precisió raonable, del ECG del pacient en TV, així com en ritme sinusal a partir dels mapes d'activació endocardíac obtinguts invasivament mitjançant sistemes de mapatge electro-anatòmic en aquest últim cas. Això va permetre trobar la ubicació i analitzar les característiques del CC responsable de la TV clínica. Cal destacar que aquest estudi in-silico de EF podria haver-se efectuat abans del procediment d'ARF, ja que el nostre plantejament està completament basat en dades clíniques no invasius adquirits abans de la intervenció real. Aquests resultats confirmen la viabilitat de la realització d'estudis in-silico de EF personalitzats i pre-procediment d'utilitat, així com el potencial de l'abordatge proposat per a arribar a ser en un futur una eina de suport per a la planificació de l'ARF en casos de TVs reentrants relacionades amb infart. No obstant això, la metodologia proposada requereix de notables millores i validació per mitjà d'estudis de simulació amb grans cohorts de pacients.[EN] Cardiovascular diseases represent the main cause of morbidity and mortality worldwide, causing around 18 million deaths every year. Among these diseases, the most common one is the ischaemic heart disease, usually referred to as myocardial infarction (MI). After surviving to a MI, a considerable number of patients develop life-threatening ventricular tachycardias (VT) during the chronic stage of the MI, that is, weeks, months or even years after the initial acute phase. This particular type of VT is typically sustained by reentry through slow conducting channels (CC), which are filaments of surviving myocardium that cross the non-conducting fibrotic infarct scar. When anti-arrhythmic drugs are unable to prevent recurrent VT episodes, radiofrequency ablation (RFA), a minimally invasive procedure performed by catheterization in the electrophysiology (EP) laboratory, is commonly used to interrupt the electrical conduction through the CCs responsible for the VT permanently. However, besides being invasive, risky and time-consuming, in the cases of VTs related to chronic MI, up to 50% of patients continue suffering from recurrent VT episodes after the RFA procedure. Therefore, there exists a need to develop novel pre-procedural strategies to improve RFA planning and, thereby, increase this relatively low success rate. First, we conducted an exhaustive review of the literature associated with the existing 3D cardiac models in order to gain a deep knowledge about their main features and the methods used for their construction, with special focus on those models oriented to simulation of cardiac EP. Later, using a clinical dataset of a chronically infarcted patient with a history of infarct-related VT, we designed and implemented a number of strategies and methodologies to (1) build patient-specific 3D computational models of infarcted ventricles that can be used to perform simulations of cardiac EP at the organ level, including the infarct scar and the surrounding region known as border zone (BZ); (2) construct 3D torso models that enable to compute the simulated ECG; and (3) carry out pre-procedural personalized in-silico EP studies, trying to replicate the actual EP studies conducted in the EP laboratory prior to the ablation. The goal of these methodologies is to allow locating the CCs into the 3D ventricular model in order to help in defining the optimal ablation targets for the RFA procedure. Lastly, as a proof-of-concept, we performed a retrospective simulation case study, in which we were able to induce an infarct-related reentrant VT using different modelling configurations for the BZ. We validated our results by reproducing with a reasonable accuracy the patient's ECG during VT, as well as in sinus rhythm from the endocardial activation maps invasively recorded via electroanatomical mapping systems in this latter case. This allowed us to find the location and analyse the features of the CC responsible for the clinical VT. Importantly, such in-silico EP study might have been conducted prior to the RFA procedure, since our approach is completely based on non-invasive clinical data acquired before the real intervention. These results confirm the feasibility of performing useful pre-procedural personalized in-silico EP studies, as well as the potential of the proposed approach to become a helpful tool for RFA planning in cases of infarct-related reentrant VTs in the future. Nevertheless, the developed methodology requires further improvements and validation by means of simulation studies including large cohorts of patients.During the carrying out of this doctoral thesis, the author Alejandro Daniel López Pérez was financially supported by the Ministerio de Economía, Industria y Competitividad of Spain through the program Ayudas para contratos predoctorales para la formación de doctores, with the grant number BES-2013-064089.López Pérez, AD. (2019). Computational modelling of the human heart and multiscale simulation of its electrophysiological activity aimed at the treatment of cardiac arrhythmias related to ischaemia and Infarction [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/124973TESI

Electrophysiologic Characterization of the Arrhythmogenic Substrate in Reentrant Atrial and Ventricular Arrhythmias Insights from the Clinical and Experimental Electrophysiology Laboratories

This thesis encompasses an overview and critical analysis of 11 publications of clinical and translational cardiac electrophysiology research that has been executed over the last seven years. The focus of this dissertation and the selected papers is on the use of electroanatomic mapping technology to define the arrhythmogenic substrate in patients with structural heart disease and ventricular arrhythmias. Such advancements in elucidating the mechanisms and pathophysiology underlying scar-related ventricular tachycardia have yielded improved clinical outcomes for patients with drug-refractory ventricular arrhythmias. Chapter 1 describes the epidemiologic background and introduces the concept of intracardiac mapping and the technological evolution that has provided the basis for this current body of work. Chapter 2 and Chapter 3 provide a detailed description of how electroanatomic mapping studies have provided critical insight into disease pathogenesis in patients with dilated nonischemic cardiomyopathy arrhythmogenic right ventricular cardiomyopathy (ARVC). The clinical impact and relevance of these studies are discussed based on conventional electroanatomic mapping technologies to define abnormal physiological substrates. Chapter 3 also addresses important considerations regarding percutaneous epicardial mapping and ablation that have been derived from extensive clinical experience. Chapter 4 and Chapter 5 describe the evolution of mapping technologies and the use of high-resolution mapping system technologies. These chapters discuss the potential clinical advantages of these technologies during substrate and activation mapping, particularly in post-infarct ventricular scar and VT. Finally, Chapter 6 concludes this thesis with final thoughts on the broader context of the lessons that have been learned from the studies that are presented in this thesis and implications for future work

G-CSF/SCF reduces inducible arrhythmias in the infarcted heart potentially via increased connexin43 expression and arteriogenesis

Granulocyte colony-stimulating factor (G-CSF), alone or in combination with stem cell factor (SCF), can improve hemodynamic cardiac function after myocardial infarction. Apart from impairing the pump function, myocardial infarction causes an enhanced vulnerability to ventricular arrhythmias. Therefore, we investigated the electrophysiological effects of G-CSF/SCF and the underlying cellular events in a murine infarction model

Noninvasive Electrocardiographic Imaging (ECGi) to Guide Catheter Ablation of Scar-related Ventricular Tachycardia

Scar-related VT is caused by local \textit{short circuits} of electrical propagation formed by slow-conducting channels of surviving tissue within a scar. Catheter ablation treats scar-related VT by destroying the critical channel of surviving tissues. Its efficacy heavily relies on how well the channels critical to the formation of VT circuits can be localized. Unfortunately, in current practice, this relies on invasive catheter mapping that falls short in several critical aspects: up to 90$\%$ of the VT circuits are too short-lived to be mapped, the mapping cannot be done non-invasively prior to the ablation procedure, and the mapping is restricted to one heart surface at a time. Electrocardiographic imaging (ECGi) is a noninvasive approach that reconstructs cardiac electrical signals from a very dense body surface electrocardiogram (ECG) in combination with patient-specific geometries of the heart and torso. In this dissertation, we investigate the clinical utility of ECGi in guiding catheter ablation of scar-related VT. Specifically, we investigate two open questions that are not well-understood in the potential of ECGi for mapping VT circuits. First, instead of commonly-used epicardial ECGi, we investigate the validity of simultaneous epicardial and endocardial ECGi mapping of VT circuits, and the possibility of using information from these two surfaces to infer the morphology of 3D circuits. Second, we investigate the integration of ECGi electrical information of VT circuits with magnetic resonance imaging (MRI) of scar analysis for joint electrical and structural delineation of the substrates for VT circuits. These studies were performed on a combination of computer simulation, animal model, and human subject data. Experimental results showed that epi-endo ECGi mapping could reconstruct VT circuits, differentiate 2D versus 3D circuits, and provide information about the location of the VT circuit beneath the surface. They also showed that integrated MRI-ECGi analysis offered a quantitative characterization of the scar substrate that forms a VT circuit. These outcomes showed that simultaneous epi-endo ECGi in the combination of MRI structural scar imaging may provide a viable augmentation to the current practice of invasive catheter mapping. It may help clinicians plan for the ablation prior to the procedure by equipping them with knowledge about a VT circuit\u27s critical components, the surfaces that are involved, and the 3D morphology of the VT circuit

Ursodeoxycholic acid: a potential anti-arrhythmic and anti-fibrotic agent in adult hearts

Acute myocardial ischaemia and reperfusion (I-R) are major causes of ventricular arrhythmias. In the chronic post-ischaemic heart, the presence of a healed fibrotic scar contributes to the occurrence of malignant arrhythmias, and development of post-myocardial infarction (MI) left ventricular (LV) remodelling and heart failure (HF). The aim of the work in this thesis was to investigate if ursodeoxycholic acid (UDCA) protects against acute I-R-induced arrhythmias, and if it plays cardioprotective and anti-arrhythmic roles in the chronic post-MI adult myocardium. An ex vivo rat model of acute I-R was used to study the effect of UDCA on arrhythmia incidence. UDCA administration reduced acute ischaemia-induced arrhythmias, with no effect on reperfusion arrhythmias. The antiarrhythmic effect of UDCA is partially mediated by an increase in cardiac wavelength, due to the attenuation of conduction velocity (CV) slowing, and the preservation of Connexin43 phosphorylation during acute ischaemia. Multiple in vitro models of cardiac fibrosis were used to study the potential of UDCA as treatment of cardiac fibrosis. UDCA was proven to reduce cardiac fibrosis and preserve the associated changes in contractile functions and electrophysiology. The antifibrotic mechanism of action of UDCA is partially mediated by TGR5 modulation via dephosphorylation of ERK protein. A sixteen-week post-MI model was generated to explore the effects of UDCA on late post-MI arrhythmias and LV remodeling. UDCA prevented the adverse LV remodeling associated with the progression of MI and reduced fibrosis and the healed ischaemic border zone (IBZ) sizes. This resulted in reduced late susceptibility to ventricular arrhythmias and improved CV across the IBZ in UDCA-treated hearts at 16 weeks post MI. We generated robust novel data highlighting the potential application of UDCA in the prevention of ventricular arrhythmias during acute MI in the adult myocardium as well as against cardiac arrhythmias that are associated with cardiac fibrosis, due to its cardioprotective effect in the post-MI heart.Open Acces

High-Resolution Whole-Heart Imaging and Modeling for Studying Cardiac Arrhythmia

Cardiac arrhythmia is a life-threatening heart rhythm disorder affecting millions of people worldwide. The underlying structure of the heart plays an important role in cardiac activity and could promote rhythm disorders. Accurate knowledge of whole-heart cardiac geometry and microstructure in normal and disease hearts is essential for a complete understanding of the mechanisms of arrhythmias. This dissertation presents novel structural data at the whole-heart level aimed at advancing knowledge of cardiac structure in normal and infarcted hearts, and at constructing whole-heart computational models. A 3D diffusion tensor MRI (DTMRI) technique was implemented on a clinical scanner to image intact large animal and human hearts with high image quality and spatial resolution ex vivo. This method was first applied to reconstruct the 3D myofiber organization in 8 human atria nondestructively and at submillimeter resolution. The findings showed that the main features of atrial anatomy are mostly preserved across subjects despite variability in the exact location and orientation of the bundles. Further, we were able to cluster, visualize, and characterize the distinct major bundles in the human atria. Quantitative analysis of the fiber angles across the atrial wall revealed that the transmural fiber angle distribution is heterogeneous throughout the atria. We next studied microstructural remodeling in infarcted porcine and human hearts by combining DTMRI with high-resolution Late Gadolinium Enhancement imaging. This enabled us to provide reconstructions of both fiber architecture and scar distribution in infarcted hearts with an unprecedented level of detail, and to systematically quantify the transmural pattern of diffusion eigenvector orientation. Our results demonstrated that the fiber orientation is generally preserved inside the scar but at a higher transmural gradient of inclination angle. Lastly, we employed the obtained data to generate whole-heart computational models of infarcted hearts with detailed scar geometry and subject-specific fiber orientation. We used these models in simulations to investigate the contribution of the infarct microarchitecture to ventricular tachycardia. The simulation results showed that the reentry circuits traverse thin viable tissues with complex geometries located inside of the infarct. The high resolution of the images enabled 3D reconstruction and characterization of such structures