Estudio experimental de los efectos de la hipotermia y la hipertermia locales sobre los parámetros electrofisiológicos del miocardio y la frecuencia de activación de la fibrilación ventricular

La influencia de la temperatura sobre la electrofisiología cardíaca es un hecho conocido, aunque los efectos de sus variaciones regionales sobre los parámetros electrofisiológicos del miocardio y sobre las características de la activación durante la fibrilación ventricular (FV) no han sido suficientemente investigados. En modelos experimentales, el análisis del efecto modulador ejercido por los cambios locales de temperatura puede aportar información sobre los mecanismos que sustentan la FV o los procedimientos encaminados a su control efectivo. En esta Tesis Doctoral se ha desarrollado un sistema de modificación de la temperatura miocárdica, en modelos de corazón aislado, capaz de crear condiciones de hipotermia e hipertermia controladas circunscritas a una región limitada del tejido. En su implementación se ha empleado un electrodo extraplano fabricado en tecnología thick-film que permite la aplicación de estímulos y el registro simultáneo de los electrogramas ventriculares a distintas temperaturas. Este sistema ha sido utilizado, en corazones aislados y perfundidos de conejo, para cuantificar los efectos de la hipotermia y la hipertermia locales sobre los parámetros característicos de la frecuencia de activación de la FV y sobre los parámetros electrofisiológicos obtenidos durante estimulación basal. Para ello, se ha modificado la temperatura epicárdica de la pared libre del ventrículo izquierdo entre 17 ºC y 42 ºC. Los resultados obtenidos muestran que la hipotermia local prolonga los períodos refractarios ventriculares y reduce la velocidad de conducción durante la estimulación basal, teniendo la hipertermia el efecto contrario. A pesar de estas variaciones, la longitud de onda del proceso de activación no sufre cambios significativos. Por otra parte, durante la FV la hipertermia local acelera de manera reversible la activación en la zona en la que es aplicada, mientras que la hipotermia la enlentece. En el margen de temperaturas estudiado, existe una relaciónTormos Ferrando, Á. (2005). Estudio experimental de los efectos de la hipotermia y la hipertermia locales sobre los parámetros electrofisiológicos del miocardio y la frecuencia de activación de la fibrilación ventricular [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/1824Palanci

Flexible Hybrid Electrodes for Continuous Measurement of the Local Temperature in Long-Term Wounds

[EN] Long-term wounds need a continuous assessment of different biophysical parameters for their treatment, and there is a lack of affordable biocompatible devices capable of obtaining that uninterrupted flow of data. A portable prototype that allows caregivers to know the local temperature behavior of a long-term wound over time and compare it with different reference zones has been developed. Alternative flexible substrates, screen-printing techniques, polymeric inks, and an embedded system have been tested to achieve potential indicators of the status and evolution of chronic wounds. The final system is formed by temperature sensors attached to a flexible and stretchable medical-grade substrate, where silver conductive tracks have been printed as interconnections with the data-acquisition unit. In addition, a specific datalogger has been developed for this system. The whole set will enable health personnel to acquire the temperature of the wound and its surroundings in order to make decisions regarding the state and evolution of the wound.This research was supported by the Spanish Government/FEDER funds (RTI2018-100910B-C43) (MINECO/FEDER). The work presented also was funded by the Conselleria d'Economia Sostenible, Sectors Productius i Treball, through IVACE (Instituto Valenciano de Competitividad Empresarial). HYBRID II Project-Application No.: IMAMCI/2021/1.Rodes-Carbonell, AM.; Torregrosa-Valls, J.; Guill Ibáñez, A.; Tormos Ferrando, Á.; Juan Blanco, MA.; Cebrián Ferriols, AJ. (2021). Flexible Hybrid Electrodes for Continuous Measurement of the Local Temperature in Long-Term Wounds. Sensors. 21(8):1-24. https://doi.org/10.3390/s21082741S12421

Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic : a matched analysis

The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with COVID-19-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior non-invasive respiratory support on outcomes. This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICU) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of intensive care unit (ICU) admission. Propensity score (PS) matching was used to achieve balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different timepoint (48 h from ICU admission) for early and delayed intubation. Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After PS matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%, p =0.01), ICU mortality (25.7% versus 36.1%, p=0.007) and 90-day mortality (30.9% versus 40.2%, p=0.02) when compared to the early intubation group. Very similar findings were observed when we used a 48-hour timepoint for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth wave, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (n=294) who were intubated earlier. The subgroup of patients undergoing NIV (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received high-flow nasal cannul

Mini Peltier Cell Array System for the Generation of Controlled Local Epicardial Heterogeneities

[EN] The present study aims to design and fabricate a system capable of generating heterogeneities on the epicardial surface of an isolated rabbit heart perfused in a Langendorff system. The system consists of thermoelectric modules that can be independently controlled by the developed hardware, thereby allowing for the generation of temperature gradients on the epicardial surface, resulting in conduction slowing akin to heterogeneities of pathological origin. A comprehensive analysis of the system's viability was performed through modeling and thermal simulation, and its practicality was validated through preliminary tests conducted at the experimental cardiac electrophysiology laboratory of the University of Valencia. The design process involved the use of Fusion 360 for 3D designs, MATLAB/Simulink for algorithms and block diagrams, LTSpice and Altium Designer for schematic captures and PCB design, and the integration of specialized equipment for animal experimentation. The objective of the study was to efficiently capture epicardial recordings under varying conditions.Clinical relevance- The proposed system aims to induce local epicardial heterogeneities to generate labeled correct signals that can serve as a golden standard for improving algorithms that identify and characterize fibrotic substrates. This improvement will enhance the efficacy of ablation processes and potentially reduce the ablated surface area.This work was supported by PID2019-109547RB-I00 (National Research Program, Ministerio de Ciencia e Innovacion, Spanish Government) and CIBERCV CB16/11/00486 (Instituto de Salud Carlos III).Segarra, I.; Cebrián Ferriols, AJ.; Ruiperez-Campillo, S.; Tormos Ferrando, Á.; Chorro, FJ.; Castells, F.; Alberola, A.... (2023). Mini Peltier Cell Array System for the Generation of Controlled Local Epicardial Heterogeneities. IEEE. 1-4. https://doi.org/10.1109/EMBC40787.2023.103403691

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

Modificaciones de la fibrilación ventricular y de la capacidad de captura inducidas por una lesión lineal con radiofrecuencia

[EN] Introduction and objectives: An analysis was made of the effects of a radiofrequency-induced linear lesion during ventricular fibrillation and the capacity to capture myocardium through high-frequency pacing. Methods: Using multiple epicardial electrodes, ventricular fibrillation was recorded in 22 isolated perfused rabbit hearts, analyzing the activation maps upon applying trains of stimuli at 3 different frequencies close to that of the arrhythmia: a) at baseline; b) after radio-frequency ablation to induce a lesion of the left ventricular free wall (length=10 [1] mm), and c) after lengthening the lesion (length=23 [2] mm). Results: Following lesion induction, the regularity of the recorded signals decreased and significant variations in the direction of the activation fronts were observed. On lengthening the lesion, there was a slight increase in the episodes with at least 3 consecutive captures when pacing at cycles 10% longer than the arrhythmia (baseline: 0.6 [0.7]; initial lesion: 1 [1] no significant differences; lengthened lesion: 3 [2.8]; P<.001), while a decrease was observed in those obtained upon pacing at cycles 10% shorter than the arrhythmia. Conclusions: The radio-frequency -induced lesion increases the heterogeneity of myocardial activation during ventricular fibrillation and modifies arrival of the activation fronts in the adjacent zones. High-frequency pacing during ventricular fibrillation produces occasional captures during at least 3 consecutive stimuli. The lengthened lesion in turn slightly increases capture capacity when using cycles slightly longer than the arrhythmia. (C) 2011 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L. All rights reserved.[ES] Introducción y objetivos Analizar los efectos, en la fibrilación ventricular y en la capacidad de capturar al miocardio mediante estimulación a frecuencias rápidas, de una lesión lineal producida con radiofrecuencia. Métodos En 22 corazones de conejo aislados y perfundidos, se utilizaron electrodos múltiples epicárdicos para registrar la fibrilación ventricular. Se analizaron los mapas de activación al aplicar trenes de estímulos a tres frecuencias distintas, cercanas a las de la arritmia, en tres situaciones: a) basalmente, b) tras producir con radiofrecuencia una lesión en la pared libre del ventrículo izquierdo (longitud, 10 ± 1 mm), y c) tras ampliar su extensión (longitud, 23 ± 2 mm). Resultados Tras la lesión, se observó una disminución de la regularidad de las señales registradas y variaciones significativas en la dirección de los frentes de activación. Con la lesión ampliada, se incrementaron ligeramente los episodios con al menos tres capturas consecutivas al estimular con ciclos un 10% más largos que los de la arritmia (basal, 0,6 ± 0,7; lesión inicial, 1 ± 1, diferencias no significativas; lesión ampliada, 3 ± 2,8; p < 0,001), mientras que se redujeron los obtenidos al estimular con ciclos un 10% más cortos que los de la arritmia. Conclusiones La lesión efectuada con radiofrecuencia aumenta la heterogeneidad de la activación miocárdica durante la fibrilación ventricular y modifica la llegada de los frentes de activación a las zonas adyacentes. La estimulación durante la fibrilación ventricular a frecuencias rápidas provoca capturas ocasionales durante al menos tres estímulos consecutivos. La lesión ampliada incrementa ligeramente la capacidad de captura al utilizar ciclos ligeramente más largos que los de la fibrilación ventricular.This study was funded by research grants from the Instituto de Salud Carlos III FIS PI06/0758-PS09/02417 and RETIC REDINSCOR RD06/0003/0010, from the Generalitat Valenciana PROMETEO 2010/093, and from the Sociedad Espanola de Cardiologia.Chorro, FJ.; Pelechano Ribes, F.; Trapero, I.; Ibañez Catala, X.; Such-Miquel, L.; Tormos Ferrando, Á.; Guerrero, J.... (2012). Modifications in Ventricular Fibrillation and Capture Capacity Induced by a Linear Radiofrequency Lesion. Revista Española de Cardiología. 65(2):143-151. https://doi.org/10.1016/j.rec.2011.09.016S14315165

Effects of the inhibition of late sodium current by GS967 on stretch-induced changes in cardiac electrophysiology

[EN] PurposeMechanical stretch increases sodium and calcium entry into myocytes and activates the late sodium current. GS967, a triazolopyridine derivative, is a sodium channel blocker with preferential effects on the late sodium current. The present study evaluates whether GS967 inhibits or modulates the arrhythmogenic electrophysiological effects of myocardial stretch.MethodsAtrial and ventricular refractoriness and ventricular fibrillation modifications induced by acute stretch were studied in Langendorff-perfused rabbit hearts (n=28) using epicardial multiple electrodes and high-resolution mapping techniques under control conditions and during the perfusion of GS967 at different concentrations (0.03, 0.1, and 0.3M).ResultsOn comparing ventricular refractoriness, conduction velocity and wavelength obtained before stretch had no significant changes under each GS967 concentration while atrial refractoriness increased under GS967 0.3M. Under GS967, the stretch-induced changes were attenuated, and no significant differences were observed between before and during stretch. GS967 0.3M diminished the normal stretch-induced changes resulting in longer (less shortened) atrial refractoriness (13826ms vs 95 +/- 9ms; p<0.01), ventricular refractoriness (155 +/- 18ms vs 124 +/- 16 ms; p<0.01) and increments in spectral concentration (23 +/- 5% vs 17 +/- 2%; p<0.01), the fifth percentile of ventricular activation intervals (46 +/- 8ms vs 31 +/- 3ms; p<0.05), and wavelength of ventricular fibrillation (2.5 +/- 0.5cm vs 1.7 +/- 0.3cm; p<0.05) during stretch. The stretch-induced increments in dominant frequency during ventricular fibrillation (control=38%, 0.03M=33%, 0.1M=33%, 0.3M=14%; p<0.01) and the stretch-induced increments in arrhythmia complexity index (control=62%, 0.03M=41%, 0.1M=32%, 0.3M=16%; p<0.05) progressively decreased on increasing the GS967 concentration.Conclusions GS967 attenuates stretch-induced changes in cardiac electrophysiology.This work was supported by the Spanish Ministry of Economy and Competiveness (Carlos III Health Institute)/European Regional Development Fund (FEDER) (Grants FIS PI12/00407, PI15/01408, PIE15/00013, CB16/11/00486) and by the Generalitat Valenciana (Grant PROMETEO FASE II 2014/037).Canto Serrano, ID.; Santamaría, L.; Genovés, P.; Such-Miquel, L.; Arias-Mutis, ÓJ.; Zarzoso Muñoz, M.; Soler, C.... (2018). Effects of the inhibition of late sodium current by GS967 on stretch-induced changes in cardiac electrophysiology. 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