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

From 12 to 1 ECG lead: multiple cardiac condition detection mixing a hybrid machine learning approach with a one-versus-rest classification strategy

Objective. Detecting different cardiac diseases using a single or reduced number of leads is still challenging. This work aims to provide and validate an automated method able to classify ECG recordings. Performance using complete 12-lead systems, reduced lead sets, and single-lead ECGs is evaluated and compared.Approach. Seven different databases with 12-lead ECGs were provided during thePhysioNet/Computing in Cardiology Challenge2021, where 88 253 annotated samples associated with none, one, or several cardiac conditions among 26 different classes were released for training, whereas 42 896 hidden samples were used for testing. After signal preprocessing, 81 features per ECG-lead were extracted, mainly based on heart rate variability, QRST patterns and spectral domain. Next, a One-versus-Rest classification approach made of independent binary classifiers for each cardiac condition was trained. This strategy allowed each ECG to be classified as belonging to none, one or several classes. For each class, a classification model among two binary supervised classifiers and one hybrid unsupervised-supervised classification system was selected. Finally, we performed a 3-fold cross-validation to assess the system's performance.Main results. Our classifiers received scores of 0.39, 0.38, 0.39, 0.38, and 0.37 for the 12, 6, 4, 3 and 2-lead versions of the hidden test set with the Challenge evaluation metric (CM). Also, we obtained a meanG-score of 0.80, 0.78, 0.79, 0.79, 0.77 and 0.74 for the 12, 6, 4, 3, 2 and 1-lead subsets with the public training set during our 3-fold cross-validation.Significance. We proposed and tested a machine learning approach focused on flexibility for identifying multiple cardiac conditions using one or more ECG leads. Our minimal-lead approach may be beneficial for novel portable or wearable ECG devices used as screening tools, as it can also detect multiple and concurrent cardiac conditions

From 12 to 1 ECG lead: multiple cardiac condition detection mixing a hybrid machine learning approach with a one-vs-rest classification strategy

[EN] Objective: Detecting different cardiac diseases using a single or reduced number of leads is still challenging. This work aims to provide and validate an automated method able to classify ECG recordings. Performance using complete 12-lead systems, reduced lead sets, and single-lead ECGs is evaluated and compared. Approach: Seven different databases with 12-lead ECGs were provided during the PhysioNet/Computing in Cardiology Challenge 2021, where 88,253 annotated samples associated with none, one, or several cardiac conditions among 26 different classes were released for training, whereas 42,896 hidden samples were used for testing. After signal preprocessing, 81 features per ECG-lead were extracted, mainly based on heart rate variability, QRST patterns and spectral domain. Next, a One-vs-Rest classification approach made of independent binary classifiers for each cardiac condition was trained. This strategy allowed each ECG to be classified as belonging to none, one or several classes. For each class, a classification model among two binary Supervised Classifiers and one Hybrid Unsupervised-Supervised classification system was selected. Finally, we performed a 3-fold cross-validation to assess the system's performance. Main results: Our classifiers received scores of 0.39, 0.38, 0.39, 0.38, and 0.37 for the 12, 6, 4, 3 and 2-lead versions of the hidden test set with the Challenge evaluation metric (CM). Also, we obtained a mean G-score of 0.80, 0.78, 0.79, 0.79, 0.77 and 0.74 for the 12, 6, 4, 3, 2 and 1-lead subsets with the public training set during our 3-fold cross-validation. Significance: We proposed and tested a machine learning approach focused on flexibility for identifying multiple cardiac conditions using one or more ECG leads. Our minimal-lead approach may be beneficial for novel portable or wearable ECG devices used as screening tools, as it can also detect multiple and concurrent cardiac conditions.This work was supported by PID2019-109547RB-I00 (National Research Program, Ministerio de Ciencia e Innovación, Spanish Government) and CIBERCV CB16/11/00486 (Instituto de Salud Carlos III).Jiménez-Serrano, S.; Rodrigo, M.; Calvo Saiz, CJ.; Millet Roig, J.; Castells, F. (2022). From 12 to 1 ECG lead: multiple cardiac condition detection mixing a hybrid machine learning approach with a one-vs-rest classification strategy. Physiological Measurement. 43(6):1-17. https://doi.org/10.1088/1361-6579/ac72f511743

Multiple Cardiac Disease Detection from Minimal-Lead ECG Combining Feedforward Neural Networks with a One-vs-Rest Approach

[EN] Although standard 12-lead ECG is the primary technique in cardiac diagnostic, detecting different cardiac diseases using single or reduced number of leads is still challenging. The purpose of our team, itaca-UPV, is to provide a method able to classify ECG records using minimal lead information in the context of the 2021 PhysioNet/Computing in Cardiology Challenge, also using only a single-lead. We resampled and filtered the ECG signals, and extracted 109 features mostly based on Hearth Rhythm Variability (HRV). Then, we used selected features to train one feed-forward neural network (FFNN) with one hidden layer for each class using a One-vs-Rest approach, thus allowing each ECG to be classified as belonging to none or more than one class. Finally, we performed a 3-fold cross validation to assess the model performance. Our classifiers received scores of 0.34, 0.34, 0.27, 0.30, and 0.34 (ranked 26th, 21th, 29th, 25th, and 22th out of 39 teams) for the 12, 6, 4, 3 and 2-lead versions of the hidden test set with the Challenge evaluation metric. Our minimal-lead approach may be beneficial for novel portable or wearable ECG devices used as screening tools, as it can also detect multiple and concurrent cardiac conditions. Accuracy in detection can be improved adding more disease-specific features.Jiménez-Serrano, S.; Rodrigo Bort, M.; Calvo Saiz, CJ.; Castells, F.; Millet Roig, J. (2021). Multiple Cardiac Disease Detection from Minimal-Lead ECG Combining Feedforward Neural Networks with a One-vs-Rest Approach. 1-4. https://doi.org/10.22489/CinC.2021.1091

Hydrogen Sulfide Improves Cardiomyocyte Function in a Cardiac Arrest Model

[EN] Background: Cardioplegic arrest is a common procedure for many types of cardiac surgery, and different formulations have been proposed to enhance its cardio-protective effect. Hydrogen sulfide is an important signaling molecule that has cardio-protective properties. We therefore studied the cardio-protective effect of hydrogen sulfide in cardiac cell culture and its potential therapeutic use in combination with cardioplegia formulations. Materials/Methods: We added hydrogen sulfide donor GYY4137 to HL-1 cells to study its protective effect in nutrient starved conditions. In addition, we tested the potential use of GYY4137 when it is added into two different cardioplegia formulations: Cardi-Braun (R) solution and del Nido solution in an ex vivo Langendorff perfused rat hearts model. Results: We observed that eight-hour pre-treatment with GYY4137 significantly suppressed apoptosis in nutrient-starved HL-1 cells (28% less compared to untreated cells; p<0.05), maintained ATP content, and reduced protein synthesis. In ex vivo experiments, Cardi-Braun (R) and del Nido cardioplegia solutions supplemented with GYY4137 significantly reduced the pro-apoptotic protein caspase-3 content and preserved ATP content. Furthermore, GYY4137 supplemented cardioplegia solutions decreased the S-(5-adenosyl)-L-methionine/S-(adenosyl)-L-homocysteine ratio, reducing the oxidative stress in cardiac tissue. Finally, heart beating analysis revealed the preservation of the inter-beat interval and the heart rate in del Nido cardioplegia solution supplemented with GYY4137. Conclusions: GYY4137 preconditioning preserved energetic state during starved conditions, attenuating the cardiomyocytes apoptosis in vitro. The addition of GYY4137 to cardioplegia solutions prevented apoptosis, ATP consumption, and oxidative stress in perfused rat hearts, restoring its electrophysiological status after cardiac arrest. These findings suggested that GYY4137 sulfide donor may improve the cardioplegia solution performance during cardiac surgery.Instituto de Salud Carlos III grants (PI10/743, PI13/0414) and RETICS RD12/0019/0025 co-funded by FEDER "Una Manera de Hacer Europa". AG. acknowledges a fellowship from Erasmus Mundus Eurotango Program. ADJ acknowledges support from the Ramon y Cajal program (RYC-2008-02378). P.S. acknowledges support from PI10/743, PI13/414 grants and the Miguel Servet I3SNS and RETICS Program (RD12/0025). We thank Dr Kenneth McCreath for helpful comments on the manuscript.Garcia, NA.; Moncayo-Arlandi, J.; Vázquez Sánchez, A.; Genoves, P.; Calvo Saiz, CJ.; Millet Roig, J.; Martí, N.... (2017). Hydrogen Sulfide Improves Cardiomyocyte Function in a Cardiac Arrest Model. Annals of Transplantation. 22:285-295. https://doi.org/10.12659/AOT.901410S2852952

Estudio de la dispersión regional de corrientes iónicas en la localización preferencial de fuentes durante fibrilación auricular paroxística

[ES] La Fibrilación Auricular (FA) es una de las patologías cardíacas sostenidas más comúnmente encontradas en la práctica clínica afectando a la población general. A pesar de los últimos avances tecnológicos, es necesaria una comprensión detallada de los mecanismos subyacentes para el desarrollo de estrategias de control de ritmo y procedimientos de ablación más eficaces. Evidencias experimentales y clínicas han hecho recientemente que la comunidad científica acepte ampliamente la hipótesis de que la FA está, en muchos casos, mantenida por fuentes de reentrada continuas y muy rápidas (rotores), activaciones de alta frecuencia preferencialmente localizadas en la pared posterior de la aurícula izquierda (PPAI) alrededor de las venas pulmonares (VP). Sin embargo, no se ha establecido un enlace mecanístico detallado entre las propiedades heterogéneas del sustrato activo auricular, el control de la dinámica de reentrada y la localización espacio-temporal de estas fuentes. En base a evidencia científica en la literatura y a resultados experimentales previos sobre cómo la dispersión de las corrientes iónicas afectan el control y la dinámica de estas fuentes, el presente Trabajo Final de Master presenta un estudio de modelado y simulación junto con un análisis numérico justificado y detallado de cómo la distribución heterogénea de estas corrientes no solo genera dispersión y un sustrato para la aparición de actividad fibrilatoria sino directamente a la estabilidad de estas fuentes reentrantes candidatas directoras de la FA, y así, por tanto, al mantenimiento de la misma. A continuación se introduce un nuevo concepto por el que estas fuentes son atraídas hacia sumideros de excitabilidad mediados de manera dominante por la corriente IK1. Se demuestra que estos sumideros de excitabilidad son parcialmente responsables de la actividad fibrilatoria en la unión entre PPAI y VP, unión PVLAJ. Se discuten y destacan las condiciones que desvían esta propuesta de la proposición existente en la bibliografía sobre IK1 y los rotores madre. Dado que una verificación experimental/clínica de las propiedades ionicas relevantes a esta nueva hipótesis de trabajo es limitada, se plantean medidas alternativas a partir de estudios de electrofisiología convencionales y sus limitaciones.[EN] Atrial Fibrillation ( AF) is one of the most common sustained cardiac arrhytmias encountered in clinical practice affecting the general population. Despite recent technological advances , we need a detailed understanding of the underlying mechanisms for the development of rhythm control strategies and more effective ablation procedures . Experimental and clinical evidences widely accepted scientific community hypothesized that the FA is , in many cases , maintained by continuous reentrant sources, very fast ( rotors), high-frequency activation preferentially located at de left atrial posterior wall ( LAPW ) around the pulmonary veins (PV). However, it hasn't been established a detailed mechanistic link between the heterogeneous properties of active atrial substrate , controlling reentry dynamics and spatiotemporal localization of these sources. Based on scientific evidence in the literature and previous experimental results about how dispersion on ionic currents affect the dynamics and control of these sources , the present Master Final Project presents a modeling and simulation study along with a justification and detailed numerical analysis of how the heterogeneous distribution of these currents, not only generates a substrate for the appearance of fibrillatory conduction but affects directly to the stability of these reentrant sources driving AF, thus, contributing to its maintenance. Here we introduce a novel concept by which these sources are attracted to IK1-mediated excitability sinks. We show that these excitability sinks are partially responsible for the espatiotemporal dynamics of fibrillatory activity at the junction between PLAW and PVs (PV-LA Junction). We discuss and highlight the conditions that divert from the existing proposition in the literature on IK1 and mother rotors. As an experimental or clinical verification of the importance of ionic properties is limited, we suggest new measurements, alternative measures, that can be used in conventional electrophysiology studies and discuss their limitations.Calvo Saiz, CJ. (2013). Estudio de la dispersión regional de corrientes iónicas en la localización preferencial de fuentes durante fibrilación auricular paroxística. http://hdl.handle.net/10251/37145Archivo delegad

Estudio experimental de los efectos de EIPA, losartán y BQ-123 sobre las modificaciones electrofisiológicas inducidas por el estiramiento miocárdico

[ES] Introducción y objetivos Se han implicado diversos mecanismos en la respuesta mecánica al estiramiento miocárdico, que incluyen la activación del intercambiador Na+/H+ por acciones autocrinas y paracrinas. Se estudia la participación de estos mecanismos en las respuestas electrofisiológicas al estiramiento agudo miocárdico mediante el análisis de los cambios inducidos con fármacos. Métodos Se analizan las modificaciones de la fibrilación ventricular inducidas por el estiramiento agudo miocárdico en corazones de conejo aislados y perfundidos utilizando electrodos múltiples epicárdicos y técnicas cartográficas. Se estudian 4 series: control (n = 9); durante la perfusión del antagonista de los receptores de la angiotensina II, losartán (1 ¿M, n = 8); durante la perfusión del bloqueador del receptor de la endotelina A, BQ-123 (0,1 ¿M, n = 9), y durante la perfusión del inhibidor del intercambiador Na+/H+, EIPA (5-[N-ethyl-N-isopropyl]-amiloride) (1 ¿M, n = 9). Resultados EIPA atenuó el aumento de la frecuencia dominante de la fibrilación producido por el estiramiento (control = 40,4%; losartán = 36% [no significativo]; BQ-123 = 46% [no significativo], y EIPA = 22% [p < 0,001]). Durante el estiramiento, la complejidad de los mapas de activación fue menor en la serie con EIPA (p < 0,0001) y también en esta serie fue mayor la concentración espectral de la arritmia (mayor regularidad): control = 18 ± 3%; EIPA = 26 ± 9% (p < 0,02); losartán = 18 ± 5% (no significativo), y BQ-123 = 18 ± 4% (no significativo). Conclusiones El inhibidor del intercambiador Na+/H+ EIPA atenúa los efectos electrofisiológicos responsables de la aceleración y del aumento de la complejidad de la fibrilación ventricular producidos por el estiramiento agudo miocárdico. Por el contrario, el antagonista de los receptores de la angiotensina II, losartán, y el del receptor A de la endotelina, BQ-123, no modifican estos efectos.[EN] Introduction and objectives Mechanical response to myocardial stretch has been explained by various mechanisms, which include Na+/H+ exchanger activation by autocrine-paracrine system activity. Drug-induced changes were analyzed to investigate the role of these mechanisms in the electrophysiological responses to acute myocardial stretch. Methods Multiple epicardial electrodes and mapping techniques were used to analyze changes in ventricular fibrillation induced by acute myocardial stretch in isolated perfused rabbit hearts. Four series were studied: control (n = 9); during perfusion with the angiotensin receptor blocker losartan (1 ¿M, n = 8); during perfusion with the endothelin A receptor blocker BQ-123 (0.1 ¿M, n = 9), and during perfusion with the Na+/H+ exchanger inhibitor EIPA (5-[N-ethyl-N-isopropyl]-amiloride) (1 ¿M, n = 9). Results EIPA attenuated the increase in the dominant frequency of stretch-induced fibrillation (control = 40.4%; losartan = 36% [not significant]; BQ-123 = 46% [not significant]; and EIPA = 22% [P < .001]). During stretch, the activation maps were less complex (P < .0001) and the spectral concentration of the arrhythmia was greater (greater regularity) in the EIPA series: control = 18 (3%); EIPA = 26 (9%) (P < .02); losartan = 18 (5%) (not significant); and BQ-123 = 18 (4%) (not significant). Conclusions The Na+/H+ exchanger inhibitor EIPA attenuated the electrophysiological effects responsible for the acceleration and increased complexity of ventricular fibrillation induced by acute myocardial stretch. The angiotensin II receptor antagonist losartan and the endothelin A receptor blocker BQ-123 did not modify these effects.This study was funded by the Spanish Department of Science (Instituto de Salud Carlos III): projects FIS PS09/02417, FIS PI12/00407, and RETIC "RIC" RD12/0042/0048, and Generalitat Valenciana: project PROMETEO 2010/093Chorro, FJ.; Canto Serrano, ID.; Brines, L.; Such-Miquel, L.; Calvo Saiz, CJ.; Soler, C.; Zarzoso, M.... (2015). Experimental Study of the Effects of EIPA, Losartan, and BQ-123 on Electrophysiological Changes Induced by Myocardial Stretch. Revista Española de Cardiología. 68(12):1101-1110. https://doi.org/10.1016/j.rec.2014.12.023S11011110681