Alteration of Ventricular Fibrillation by Flecainide, Verapamil, and Sotalol

Background—The purpose of this study was to determine whether the myocardial electrophysiological properties are useful for predicting changes in the ventricular fibrillatory pattern. Methods and Results—Thirty-two Langendorff-perfused rabbit hearts were used to record ventricular fibrillatory activity with an epicardial multiple electrode. Under control conditions and after flecainide, verapamil, or d,l-sotalol, the dominant frequency (FrD), type of activation maps, conduction velocity, functional refractory period, and wavelength (WL) of excitation were determined during ventricular fibrillation (VF). Flecainide (1.9±0.3 versus 2.4±0.6 cm, P<0.05) and sotalol (2.1±0.3 versus 2.5±0.5 cm, P<0.05) prolonged WL and diminished FrD during VF, whereas verapamil (2.0±0.2 versus 1.7±0.2 cm, P<0.001) shortened WL and increased FrD. Simple linear regression revealed an inverse relation between FrD and the functional refractory period (r=0.66, P<0.0001), a direct relation with respect to conduction velocity (r=0.33, P<0.01), and an inverse relation with respect to WL estimated during VF (r=0.49, P<0.0001). By stepwise multiple regression, the functional refractory periods were the only predictors of FrD. Flecainide and sotalol increased the circuit size of the reentrant activations, whereas verapamil decreased it. The 3 drugs significantly reduced the percentages of more complex activation maps during VF. Conclusions—The activation frequency is inversely related to WL during VF, although a closer relation is observed with the functional refractory period. Despite the diverging effects of verapamil versus flecainide and sotalol on the activation frequency, WL, and size of the reentrant circuits, all 3 drugs reduce activation pattern complexity during VF.Chorro Gasco, Francisco Javier, [email protected] ; Guerrero Martinez, Juan Francisco, [email protected] ; Sanchis Fores, Juan, [email protected] ; Such Belenguer, Luis, [email protected]

Análisis del efecto del ejercicio físico en la homogeneidad espacial del espectro de la señal de fibrilación ventricular

El presente trabajo estudia las modificaciones intrínsecas que el ejercicio físico produce en la respuesta cardíaca durante fibrilación ventricular (FV), tanto en condiciones de perfusión estable como cuando se produce isquemia en una zona del miocardio. Se estudiarán dichas modificaciones comparándolas con las producidas por el efecto de un fármaco (Glibenclamida) y con un grupo control. El análisis se realizará desde el punto de vista del dominio frecuencial, estudiando la homogeneidad espacial de la frecuencia dominante (ROIsaFD) y de la energía normalizada (ROIsaEN), en registros de cartografía cardíaca unipolar de corazón aislado de conejo. Se utilizarán tres grupos de conejos: control (GC: sin entrenamiento, N=18), entrenados (GE: N=9) y fármaco (GF: sin entrenamiento, con tratamiento, N=15). Se realizarán comparaciones intergrupos, teniendo en cuenta el hecho de que se realizan medidas repetidas en el tiempo, y se harán comparaciones intragrupos para estudiar el efecto del tiempo. Los resultados obtenidos sugieren que los efectos intrínsecos producidos por ejercicio físico sobre la homogeneidad espacial de la respuesta espectral de la FV son similares a los producidos por el tratamiento con Glibenclamida, especialmente cuando se tienen zonas isquémicas

Análisis de regularidad en fibrilación ventricular: aplicación a registros de mapeado cardíaco

Las técnicas utilizadas en el análisis de la señal de fibrilación ventricular (FV), obtenida mediante sistemas de mapeado utilizando matrices de electrodos, extraen información del proceso a partir de parámetros calculados principalmente en el dominio del tiempo o de la frecuencia. El presente trabajo plantea la aplicación del índice de regularidad (IR), propuesto inicialmente para caracterizar la fibrilación auricular humana, a la señal de FV en un modelo experimental de corazón animal. Los resultados obtenidos muestran que el IR permite extraer información de los mapas de FV no disponible de forma directa cuando se estudian mediante los métodos clásicos en el tiempo o la frecuencia, cuantificando el grado de modificación en la morfología de las ondas de activación durante la FV

Modifications on regularity and spectrum of ventricular fibrillation signal induced by physical training

The objective of this work is to study the modifications on cardiac response during ventricular fibrillation (VF) induced by physical training. The analysis was performed in the frequency domain of VF, and the regularity of the signal was also considered. Two sets of records were acquired: control (G1: without physical training, N=10), and trained (G2, N=9). Cardiac registers were obtained using a 240-electrodes matrix located on left ventricle of isolated rabbit heart. A Langendorff system was used to maintain the heart perfusion. VF was induced by increased frequencies. To analyze the time course of VF, records were processed in 4-second segments. For every segment and channel, Welch periodogram with Hanning window, two non-overlapped sections and zero padding, was computed. Parameters considered in frequency domain are: dominant frequency (DF) and normalized energy (NE: spectral energy in the window DF±1Hz, normalized by spectral energy in 5-35Hz band). For every segment and channel, a regularity analysis of VF was performed, obtaining the regularity index (RI), which is a measure of similarity among local activation waves present in every channel. Mean values for the parameters (DF, NE and RI) of the whole set of electrodes were computed for every segment. Obtained results show that DF is lower for trained rabbits (G1: 18.234±1, 241Hz; G2: 14.370±0, 866Hz; p<0.001). NE is greater for this group (G1: 0.140±0.006; G2: 0.263±0.017; p<0.001), suggesting a greater spectral concentration around DF. Finally, a greater regularity has been observed in the fibrillation signal for trained group (IR, G1: 0.756±0.026; G2: 0.834±0.014; p<0.001). As a summary, the results suggest that both spectral characteristics and regularity of VF signal are clearly different for G1 and G2 groups. The trained group (G2) shows greater regularity, lower DF and spectral dispersion. These factors should be interpreted as a more stable cardiac response to V

Analysis of spatial and temporal evolution of regularity maps during ventricular fibrillation

The analysis of cardiac mapping allows investigating the structure of ventricular fibrillation (VF). This work analyzes regions of interest (ROI) on cardiac maps obtained from the regularity analysis of VF records, providing information about signal regularity at each time instant and its spatial distribution. Cardiac registers were obtained using a 240- electrodes matrix located on left ventricle of isolated rabbit heart. A Langendorff system was used to maintain the heart perfusion. VF was induced by increased frequencies. Two groups of records were considered: control (G1: without physical training, N=10), and trained (G2, N=9). Records were processed in consecutive 4-second segments. Regularity index (RI) was obtained for every segment and channel. RI is a measure of similarity degree among local activation waves for every channel. A map with the RI value of each channel was computed for the 82 register segments. To analyze the spatial distribution of RI, a threshold value was determined experimentally and applied to the map in order to obtain the ROI. Two parameters were calculated: ROI spatial number (ROIsn, a measure of spatial fragmentation), and ROI spatial area (ROIsa, the percentage of area map occupied by ROI). In case of the time course of ROI, two additional parameters were computed: the number of electrodes which value had changed respect to the threshold in two consecutive maps (ROIen, which is related with the change size), and the cumulative absolute differences of RI values for the electrodes which are changed (ROIed). Obtained results for spatial analysis show that the number of ROI is lower for trained rabbits (ROIsn; G1: 4.465±1.120; G2: 2.,227±0.623; p<0.001), but ROI spatial area is greater than the control group (ROIsa; G1: 76.235±5.355%; G2: 88.163±2.885%; p<0.001). Time-course analysis shows that more electrodes change between consecutive maps in the control group (ROIen, G1: 22.455±6.702; G2: 13.877±2.485; p<0.001). No significant differences were found for ROIed (G1: 18.509±6.932; G2: 18.619±4.196; n.s.). To conclude, ROI analysis on RI maps applied to trained and no trained rabbits groups shows that VF cardiac response is more irregular and spatially fragmented in no trained group. In addition, regularity maps are more stable with time in trained group

Relación entre el espectro y la regularidad en la señal de fibrilación ventricular modificada por el ejercicio físico

El presente trabajo estudia las modificaciones intrínsecas que el ejercicio físico produce en la respuesta cardíaca durante la FV. Se han calculado dos parámetros relacionados con el espectro de la señal (FD: frecuencia dominante, y EN: energía normalizada), y otro relacionado con la regularidad de las OAL (IR: índice de regularidad), Se ha realizado un análisis de correlación entre los tres parámetros para valorar su grado de complementariedad. Se consideraron dos grupos de conejos: control (G1: sin entrenamiento, N=10) y entrenados (G2, N=9). Se utilizó un electrodo matricial de 240 canales localizado en ventrículo izquierdo de corazón aislado de conejo perfundido mediante un sistema de Langendorff. La FV se indujo por estimulación a frecuencias crecientes. Los resultados muestran que el grupo entrenado presenta una mayor regularidad de la señal (IR: G1: 0,757+-0,091; G2: 0,845+-0,084; p<0.001), así como menor FD (G1: 18.23±2.96Hz; G2: 14.13+-1.73Hz; p<0.001) y dispersión espectral (EN: G1: 0,138+-0.105; G2: 0,293+-0,176; p<0.001). El análisis de las relaciones entre parámetros muestra correlaciones significativas entre los parámetros para todos los casos excepto para IR y FD en G2, por lo que estos parámetros proporcionan información complementaria, ya que analizan aspectos diferentes de la señal como la morfología de las ondas de activación y su frecuencia. La existencia de correlación entre ambas para G1 puede ser debida a otras causas, tales como las modificaciones en ambos factores inducidas por la presencia de reentradas o colisiones entre frentes de activación.. Como conclusión, los resultados obtenidos sugieren que el entrenamiento físico produce una respuesta cardíaca más estable ante FV, debida a modificaciones intrínsecas en las características electrofisiológicas cardíacas

Application of machine learning techniques to analyse the effects of physical exercise in ventricular fibrillation

This work presents the application of machine learning techniques to analyze the influence of physical exercise in the heart's physiological properties, during ventricular fibrillation. With that purpose, different kinds of classifiers (linear and neural models) were used to classify between trained and sedentary rabbit hearts. These classifiers were used to perform knowledge extraction through a wrapper feature selection algorithm. The obtained results showed the higher performance of the neural models compared to the linear classifier (higher performance measures and higher dimensionality reduction). The most relevant features to describe the benefits of physical exercise are those related to myocardial heterogeneity, mean activation rate and activation complexity

Analysis of the influence of parasympathetic postganglionic neurons on cardiac response in ventricular fibrillation

Physical training modifies the sympathetic-vagal balance of autonomic nervous system. Previous studies have shown that such training also produces intrinsic modifications of cardiac electrophysiological properties in isolated heart during Ventricular Fibrillation (VF). Ten NZW trained rabbits were studied to test if the modifications are related to the activity of postganglionic parasympathetic neurons. Two records per subject were acquired during VF: before (G1) and after (G2) the infusion of atropine to inhibit the activity of neurons. Mapping records were obtained using a 240-channel electrode array located in the left ventricle of isolated heart (perfused by Langendorff system). VF was induced by stimulation at increasing frequencies. To analyze the time course of fibrillation, the records were processed in 4-second consecutive segments. For each channel and segment, the following parameters were computed: 1) Dominant Frequency (DF), obtained by the Welch periodogram b) Normalized Energy (NE) in a frequency band centered at the DF; c) Regularity Index (RI), which analyzes the similarity of local activation waves in every segment and channel; d) Coefficients of Variance of DF (CVDF), NE (CVNE) and RI (CVRI). For each segment, we obtained the average value of each of the parameters analyzed for all electrodes. The results are: a) DF (G1: 13.671 ± 0.509 Hz, G2: 14.783 ± 0.455 Hz), b) NE (G1: 0.398 ± 0.014; G2: 0.380 ± 0.013); c) RI (G1: 0.855 ± 0.017; G2: 0.865 ± 0.015), d) CVDF (G1: 0.109 ± 0.009; G2: 0.098 ± 0.008), e) CVNE (G1: 0.398 ± 0.014; G2: 0.380 ± 0.013 ) f) CVRI (G1: 0.084 ± 0.009; G2: 0.078 ± 0.008). None of these parameters showed significant differences between groups. Thus, the parasympathetic postganglionic neurons seem to have no effect on the cardiac response in VF due to physical training

Efectos electrofisiológicos miocárdicos intrínsecos producidos por la inhibición del sistema de intercambio sodio-protón, en condiciones de normoxia, y tras la isquemia miocárdica regional. Estudio experimental.

RESUMEN Hemos investigado: 1) los efectos protectores del intercambiador sodio-protón (NHE), con el 5-(N-etil-N-isopropil) amiloride (EIPA), a concentración 0.4 M, sobre la inducibilidad de la fibrilación ventricular (FV), y sobre la refractariedad miocárdica ventricular, tras la oclusión arterial coronaria; 2) los efectos electrofisiológicos intrínsecos producidos por la inhibición del NHE, administrando EIPA 0.4 y 1 M, en condiciones de normal oxigenación, sobre el automatismo sinusal, la conducción sinoauricular y auriculoventricular (AV), y sobre la refractariedad auricular, ventricular, y del sistema de conducción AV; y 3) los efectos electrofisiológicos miocárdicos intrínsecos producidos por la inhibición del NHE, con EIPA 0.4 y 1 M, sobre la frecuencia dominante (FD) de la FV inducida, en condiciones de normoxia, como característica electrofisiológica estrechamente relacionada con la refractariedad ventricular. Todos los experimentos se realizaron en corazón aislado y perfundido de conejo (preparación tipo Langendorff). Para conseguir el primer objetivo aplicamos el test del extraestímulo (TEE) ventricular con uno, dos, y tres extraestímulos, para tratar de inducir la FV. La aplicación del primer extraestímulo sirvió además para establecer el periodo refractario objeto de investigación. Las determinaciones se realizaron previamente y tras la oclusión arterial coronaria circunfleja, en dos grupos de experimentos: control y tratados con EIPA 0.4 M. Para cumplimentar el segundo objetivo analizamos: a) periodos refractarios efectivo y funcional auricular y del sistema de conducción AV mediante el TEE auricular, periodos refractarios efectivo y funcional ventricular mediante el TEE ventricular; b) automatismo sinusal mediante la determinación de la longitud del ciclo sinusal y del tiempo de recuperación del nodo sinusal; y c) tiempo de conducción sinoauricular con el test de Narula, conducción AV y conducción ventriculoauricular retrógrada, mediante la medición de la longitud del ciclo de Wenckebach y la longitud del ciclo de Wenckebach retrógrado respectivamente. Finalmente, para acometer el tercer objetivo analizamos, por el método de Welch, la FD media, máxima y mínima de la FV inducida por estimulación a frecuencias crecientes. Los parámetros citados se estudiaron en situación control e inhibiendo el NHE, con EIPA. Utilizamos dos concentraciones de dicho inhibidor: 0.4 y 1 M; la primera se halla en el rango de la IC50 para el NHE y la segunda es la concentración más comúnmente usada en los estudios de protección miocárdica. La inhibición del NHE con EIPA 0.4 M protegió al miocardio isquémico, al dificultar la inducibilidad de la FV. Este efecto protector, probablemente está relacionado, al menos en parte, con el mantenimiento de la refractariedad ventricular en el miocardio isquémico, lo cual ha sido también observado en el presente trabajo. Excepto para el caso del periodo refractario efectivo del sistema de conducción AV, que aumentó ligeramente con EIPA 1 M, la inhibición del NHE con EIPA 0.4 y 1 M en condiciones de normal oxigenación, no modificó la refractariedad intrínseca ventricular, auricular, ni del sistema de conducción AV, así como tampoco la FD de la FV inducida, mientras que deprimió ligeramente el cronotropismo sinusal y la conducción AV, si bien estos últimos podrían ser efectos secundarios, relacionados con la capacidad depresora del automatismo sinusal y la conducción AV que ejerce el amiloride, precursor del EIPA. El hecho de que la inhibición del NHE, manifestara efectos electrofisiológicos antiarrítmicos intrínsecos sobre el miocardio isquémico, impidiendo la caída de la refractariedad, y no ejerciera ninguna modificación electrofisiológica, en condiciones de normal oxigenación, sobre la refractariedad y la FD de la FV, propiedades ligadas a la aparición de arritmias por reentrada, coincide con lo relatado por diversos investigadores acerca del escaso, sino nulo, papel del NHE en situación fisiológica y su importancia en circunstancias fisiopatológicas como la isquemia. __________________________________________________________________________________________________We have investigated the protective effects of the sodium-proton exchanger (NHE) inhibition using 5-(N-ethyl-N-isopropyl) amiloride (EIPA) 0.4 M, on the incidence of induced ventricular fibrillation (VF), and on intrinsic ventricular refractoriness, after circumflex coronary artery occlusion. Experiments were performed on isolated rabbit heart. To induce VF extrastimulus test with one, two and three extrastimuli, was used; the first extrastimulus application also served to determine refractory periods. Parameters were determined previously and after coronary occlusion, in both control and EIPA 0.4 M treated groups. In order to investigate whether the NHE inhibition produces some myocardial intrinsic electrophysiological effect, we have also investigated using EIPA, 0.4 and 1 M, in normoxic condition: a) the sinus cycle length and sinus node recovery time, as an automatism index; b) the sinoatrial conduction (Narulas test), and atrioventricular (AV) and ventricleatrial conduction, by anterograde and retrograde Wenckebach cycle length determination respectively; c) atrial, ventricular, and AV conduction system, effective and functional refractory periods using the extrastimulus test; and d) mean, minimum and maximum dominant frequency (DF) of VF by the Welchs method, which are properties closely related with ventricular refractoriness. NHE inhibition with 0.4 M protected the ischemic myocardium, decreasing VF inducibility, at least in part, by the maintenance of ischemic myocardium refractoriness, observed in this study. No modification on refractoriness was observed, in normoxic conditions, except an AV conduction system effective refractory period increase, with EIPA 1 M. The DF of VF was either not modified. EIPA 0.4 and 1 M also slightly depressed sinus chronotropism and AV conduction

Expression of sterol regulatory element-binding proteins in epicardial adipose tissue in patients with coronary artery disease and diabetes mellitus: preliminary study

[Abstract] Objectives: Sterol regulatory element-binding proteins (SREBP) genes are crucial in lipid biosynthesis and cardiovascular homeostasis. Their expression in epicardial adipose tissue (EAT) and their influence in the development of coronary artery disease (CAD) and type-2 diabetes mellitus remain to be determined. The aim of our study was to evaluate the expression of SREBP genes in EAT in patients with CAD according to diabetes status and its association with clinical and biochemical data. Methods: SREBP-1 and SREBP-2 mRNA expression levels were measured in EAT from 49 patients with CAD (26 with diabetes) and 23 controls without CAD or diabetes. Results: Both SREBPs mRNA expression were significantly higher in patients with CAD and diabetes (p<0.001) and were identified as independent cardiovascular risk factor for coronary artery disease in patients with type-2 diabetes (SREBP-1: OR 1.7, 95%CI 1.1-2.5, p=0.02; SREBP-2: OR 1.6, 95%CI 1.2-3, p=0.02) and were independently associated with the presence of multivessel CAD, left main and anterior descending artery stenosis, and higher total and LDL cholesterol levels, and lower HDL cholesterol levels, in patients with CAD and diabetes. Conclusions: SREBP genes are expressed in EAT and were higher in CAD patients with diabetes than those patients without CAD or diabetes. SREBP expression was associated as cardiovascular risk factor for the severity of CAD and the poor lipid control. In this preliminary study we suggest the importance of EAT in the lipid metabolism and cardiovascular homeostasis for coronary atherosclerosis of patients with diabetes and highlight a future novel therapeutic target.Instituto de Salud Carlos III; PI13/02542Instituto de Salud Carlos III; PI11/01661Red de Investigación Cardiovascular; RD12/0042/003