The European Network for Translational Research in Atrial Fibrillation (EUTRAF): objectives and initial results.

Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population. As an age-related arrhythmia AF is becoming a huge socio-economic burden for European healthcare systems. Despite significant progress in our understanding of the pathophysiology of AF, therapeutic strategies for AF have not changed substantially and the major challenges in the management of AF are still unmet. This lack of progress may be related to the multifactorial pathogenesis of atrial remodelling and AF that hampers the identification of causative pathophysiological alterations in individual patients. Also, again new mechanisms have been identified and the relative contribution of these mechanisms still has to be established. In November 2010, the European Union launched the large collaborative project EUTRAF (European Network of Translational Research in Atrial Fibrillation) to address these challenges. The main aims of EUTRAF are to study the main mechanisms of initiation and perpetuation of AF, to identify the molecular alterations underlying atrial remodelling, to develop markers allowing to monitor this processes, and suggest strategies to treat AF based on insights in newly defined disease mechanisms. This article reports on the objectives, the structure, and initial results of this network

A study on stability analysis of atrial repolarization variability using ARX model in sinus rhythm and atrial tachycardia ECGs

© 2016 Elsevier Ireland Ltd Background The interaction between the PTa and PP interval dynamics from the surface ECG is seldom explained. Mathematical modeling of these intervals is of interest in finding the relationship between the heart rate and repolarization variability. Objective The goal of this paper is to assess the bounded input bounded output (BIBO) stability in PTa interval (PTaI) dynamics using autoregressive exogenous (ARX) model and to investigate the reason for causing instability in the atrial repolarization process. Methods Twenty-five male subjects in normal sinus rhythm (NSR) and ten male subjects experiencing atrial tachycardia (AT) were included in this study. Five minute long, modified limb lead (MLL) ECGs were recorded with an EDAN SE-1010 PC ECG system. The number of minute ECGs with unstable segments (N us ) and the frequency of premature activation (PA) (i.e. atrial activation) were counted for each ECG recording and compared between AT and NSR subjects. Results The instability in PTaI dynamics was quantified by measuring the numbers of unstable segments in ECG data for each subject. The unstable segments in the PTaI dynamics were associated with the frequency of PA. The presence of PA is not the only factor causing the instability in PTaI dynamics in NSR subjects, and it is found that the cause of instability is mainly due to the heart rate variability (HRV). C onclusion The ARX model showed better prediction of PTa interval dynamics in both groups. The frequency of PA is significantly higher in AT patients than NSR subjects. A more complex model is needed to better identify and characterize healthy heart dynamics

Nonlinear physics of electrical wave propagation in the heart: a review

The beating of the heart is a synchronized contraction of muscle cells (myocytes) that are triggered by a periodic sequence of electrical waves (action potentials) originating in the sino-atrial node and propagating over the atria and the ventricles. Cardiac arrhythmias like atrial and ventricular fibrillation (AF,VF) or ventricular tachycardia (VT) are caused by disruptions and instabilities of these electrical excitations, that lead to the emergence of rotating waves (VT) and turbulent wave patterns (AF,VF). Numerous simulation and experimental studies during the last 20 years have addressed these topics. In this review we focus on the nonlinear dynamics of wave propagation in the heart with an emphasis on the theory of pulses, spirals and scroll waves and their instabilities in excitable media and their application to cardiac modeling. After an introduction into electrophysiological models for action potential propagation, the modeling and analysis of spatiotemporal alternans, spiral and scroll meandering, spiral breakup and scroll wave instabilities like negative line tension and sproing are reviewed in depth and discussed with emphasis on their impact in cardiac arrhythmias.Peer ReviewedPreprin

Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies

[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI

Inducibility of atrial fibrillation after catheter ablation predicts recurrences of atrial fibrillation: a meta-analysis

Background Pulmonary vein isolation (PVI) is a component of standard care for patients with symptomatic atrial fibrillation (AF). Procedural inducibility of AF following PVI has been suggested as predictor of AF recurrence but is discussed controversially. This meta-analysis aimed at evaluating the relevance of electrophysiological inducibility of AF following PVI for future AF recurrences. Methods A literature search of MEDLINE and Web of Science was performed until April 2020. Prospective trials of PVI in patients with AF and post-procedural atrial stimulation to test for inducibility of AF as well as adequate follow-up for AF recurrence (defined as AF >10 s to >10 min at follow-up) were included. Odds ratios (ORs) were analyzed using random-effects models. Results A total of 11 trials with 1544 patients (follow-up 7–39 months, age 56 ± 6 years, predominantly male 74 ± 6%) were included. Inducibility of AF post-PVI was predictive for AF recurrence during follow-up (OR 2.08; 95% CI 1.25 to 3.46). Prediction for AF recurrence at follow-up was better for patients with paroxysmal AF (OR 4.06; 95% CI 1.39 to 11.91), stimulation in the CS (OR 2.82, 95% CI 1.17 to 6.79). A trend towards higher ORs was seen without the use of isoproterenol (OR 2.43; 95% CI 1.17 to 5.07), as well as few stimulations during induction and a short definition of AF in meta-regression analyses. Conclusions Electrophysiological inducibility of AF following PVI was predictive for future recurrence of AF, in particular in patients with paroxysmal AF, stimulation in only CS and no use of isoproterenol

The burden of proof: the current state of atrial fibrillation prevention and treatment trials

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3–5, 2015

A note on stress-driven anisotropic diffusion and its role in active deformable media

We propose a new model to describe diffusion processes within active deformable media. Our general theoretical framework is based on physical and mathematical considerations, and it suggests to use diffusion tensors directly coupled to mechanical stress. A proof-of-concept experiment and the proposed generalised reaction-diffusion-mechanics model reveal that initially isotropic and homogeneous diffusion tensors turn into inhomogeneous and anisotropic quantities due to the intrinsic structure of the nonlinear coupling. We study the physical properties leading to these effects, and investigate mathematical conditions for its occurrence. Together, the experiment, the model, and the numerical results obtained using a mixed-primal finite element method, clearly support relevant consequences of stress-assisted diffusion into anisotropy patterns, drifting, and conduction velocity of the resulting excitation waves. Our findings also indicate the applicability of this novel approach in the description of mechano-electrical feedback in actively deforming bio-materials such as the heart

HD Physiology Project-Japanese efforts to promote multilevel integrative systems biology and physiome research.

The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research