Luis Such

Alteration of Ventricular Fibrillation by Flecainide, Verapamil, and Sotalol An Experimental Study

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.

Modificaciones agudas de la longitud de onda del proceso de activación auricular inducidas por la dilatación. Estudio experimental

Objetivos Estudiar en un modelo experimental las modificaciones agudas de la longitud de onda del proceso de activacion auricular inducidas por la dilatacion auricular. Material y metodos En 10 preparaciones de corazon aislado y perfundido de conejo segun la tecnica de Langendorff, mediante mapeo epicardico con un electrodo multiple se determina en la auricula derecha la longitud de onda del proceso de activacion auricular (periodo refractario funcional × velocidad de conduccion) y se analiza la inducibilidad de respuestas repetitivas auriculares rapidas, cuantificando su numero tras 20 episodios de sobreestimulacion auricular rapida. Las determinaciones se efectuan en situacion basal, tras provocar dos grados de estiramiento de la pared auricular con un balon intraauricular derecho (D1 y D2), y tras suprimir la dilatacion auricular. Resultados En el estudio basal la longitud de onda es 72,6 ± 7,7 mm (ciclos de 250 ms) y 54,0 ± 5,1 mm (ciclos de 100 ms). En el estadio D1 (incremento longitudinal de la pared auricular = 24 ± 3%) la longitud de onda disminuye a 59,8 ± 6,6 mm (ciclos de 250 ms; p Conclusiones En el modelo experimental utilizado la dilatacion auricular aguda provoca un acortamiento de la refractariedad y una disminucion de la velocidad de conduccion. Ambos efectos dan lugar a una disminucion de la longitud de onda del proceso de activacion auricular que facilita la induccion de arritmias auriculares. Los efectos observados revierten tras suprimir la dilatacion auricular.

Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit hearts

Stretch induces modifications in myocardial electrical and mechanical activity. Besides the effects of substances that block the stretch-activated channels, other substances could modulate the effects of stretch through different mechanisms that affect Ca(2+) handling by myocytes. Thirty-six Langendorff-perfused rabbit hearts were used to analyze the effects of the Na(+)/Ca(2+) exchanger blocker KB-R7943, propranolol, and the adenosine A(2) receptor antagonist SCH-58261 on the acceleration of ventricular fibrillation (VF) produced by acute myocardial stretching. VF recordings were obtained with two epicardial multiple electrodes before, during, and after local stretching in four experimental series: control (n = 9), KB-R7943 (1 microM, n = 9), propranolol (1 microM, n = 9), and SCH-58261 (1 microM, n = 9). Both the Na(+)/Ca(2+) exchanger blocker KB-R7943 and propranolol induced a significant reduction (P < 0.001 and P < 0.05, respectively) in the dominant frequency increments produced by stretching with respect to the control and SCH-58261 series (control = 49.9%, SCH-58261 = 52.1%, KB-R7943 = 9.5%, and propranolol = 12.5%). The median of the activation intervals, the functional refractory period, and the wavelength of the activation process during VF decreased significantly under stretch in the control and SCH-58261 series, whereas no significant variations were observed in the propranolol and KB-R7943 series, with the exception of a slight but significant decrease in the median of the fibrillation intervals in the KB-R7943 series. KB-R7943 and propranolol induced a significant reduction in the activation maps complexity increment produced by stretch with respect to the control and SCH-58261 series. In conclusion, the electrophysiological effects responsible for stretch-induced VF acceleration in the rabbit heart are reduced by the Na(+)/Ca(2+) exchanger blocker KB-R7943 and by propranolol but not by the adenosine A(2) receptor antagonist SCH-58261.

Protective effect of N-acetylcysteine on ischaemia-induced myocardial damage in canine heart

SummaryThe glutathione redox pathway is an important antioxidant system in the myocardium. N-Acetylcysteine is a low molecular weight glutathione precursor that has been used clinically to replenish glutathione stores. The present study was aimed at evaluating the protective effect of N-acetylcysteine on myocardial damage resulting from permanent coronary occlusion (without reperfusion) in anaesthetized dogs. N-Acetylcysteine (150 mg kg−1 i.v.) administered 2 min before occlusion rerduced infarct size in dogs subjected to 24 h ischemia. The infarct size as a percentage of the area at risk was 86.8 ± 3.6% (n = 11) in control (salinetreated) dogs and 68.2 ± 2.4% (n = 7; P < 0.05 vs control) in N-acetylcysteine-treated animals. Haemodynamic variables (heart rate, mean arterial pressure and ratepressure product) were similar in the control and the treated group. Regional myocardial blood flow was determined with radioactive microspheres in ischaemic and non-ischaemic zones before occlusion and 3 h post-ocelusion. N-Acetylcysteine did not influence the regional distribution of myocardial blood flow. The myocardial content of reduced glutathione was significantly (P < 0.05) decreased 3 h post-occlusion (0.53 ± 0.19 μmol/ g−1 ; n = 5) compared to either pre-occlusion values (0.94 ± 0.03 μmol/g−1; n = 8) or values 3 h post-ocelusion in sham-operated animals (0.93 ± 0.15 μmo1/g−1 ; n = 5). Depletion of myocardial glutathione 3 h post-ocelusion was not observed in dogs treated with N-acetylcysteine (0.87 ± 0.11 μmol/g−1; n = 5). Superoxide dismutase activity and malondialdehyde levels were determined in blood samples obtained from the coronary vein draining the ischaemic zone. Superoxide dismutase activity increased 10 min post-occlusion in control but not in N-acetylcysteine-treated dogs. Malondialdehyde levels were elevated in both groups after occlusion but this increase failed to reach statistical significance in the animals treated with N-acetylcysteine. This study demon strates that N-acetylcysteine treatment reduces myocardial damage after permanent coronary occlusion. The beneficial effect may be due to maintenance of myocardial glutathione and to protection against free-radicalmediated damage during the early phase of ischaemia.

Opposite effects of myocardial stretch and verapamil on the complexity of the ventricular fibrillatory pattern: an experimental study.

CHORRO, F.J., et al.: Opposite Effects of Myocardial Stretch And Verapamil on The Complexity of The Ventricular Fibrillatory Pattern: An Experimental Study. An experimental model is used to analyze the effects of ventricular stretching and verapamil on the activation patterns during VF. Ten Langendorff‐perfused rabbit hearts were used to record VF activity with an epicardial multiple electrode before, during, and after stretching with an intraventricular balloon, under both control conditions and during verapamil (Vp) infusion (0.4–0.8 μmol). The analyzed parameters were dominant frequency (FrD) spectral analysis, the median (MN) of the VF intervals, and the type of activation maps during VF (I = one wavelet without block lines, II = two simultaneous wavelets with block lines, III = three or more wavelets with block lines). Stretch accelerates VF (FrD: 22.8 ± 6.4 vs 15.2 ± 1.0 Hz, P < 0.01; MN: 48 ± 13 vs 68 ± 6 ms, P < 0.01). On fitting the FrD time changes to an exponential model after applying and suppressing stretch, the time constants (stretch: 101.2 ± 19.6 s; stretch suppression: 97.8 ± 33.2 s) do not differ significantly. Stretching induces a significant variation in the complexity of the VF activation maps with type III increments and type I and II decrements (control: I = 17.5%, II = 50.5%, III = 32%; stretch: I = 7%, II = 36.5%, III = 56.5%, P < 0.001). Vp accelerates VF (FrD: 20.9 ± 1.9 Hz, P < 0.001 vs control; MN: 50 ± 5 ms, P < 0.001 vs control) and diminishes activation maps complexity (I = 25.5%, II = 60.5%, III = 14%, P < 0.001 vs control). On applying stretch during Vp perfusion, the fibrillatory process is not accelerated to any greater degree. However, type I and II map decrements and type III increments are recorded, though reaching percentages similar to control (I = 16.5%, II = 53%, III = 30.5%, NS vs control). The following conclusions were found: (1) myocardial stretching accelerates VF and increases the complexity of the VF activation pattern; (2) time changes in the FrD of VF during and upon suppressing stretch fit an exponential model with similar time constants; and (3) although stretching and verapamil accelerate the VF process, they exert opposite effects upon the complexity of the fibrillatory pattern.

The Effects of Selective Stellate Ganglion Manipulation on Ventricular Refractoriness and Excitability

The effects of selective stellate ganglion stimulation or stellectomy on ventricular excitability were studied in 30 open chest mongrel dogs anesthetized with alpha‐chloralose. The elective refractory period (ERP) and strength interval curves (stimulus intensity (S2) = twice the diastolic threshold (ERP), and 2, 3, 5, 7, and 14 mA) were determined using bipolar epicardial electrodes placed in the mid‐anterior wall of the right ventricle (RV) and the mid‐posterolateral wall of the left ventricle (LV) during left stellate ganglion stimulation (LSGSt, n = 8) or right stellate ganglion stimulation (RSGSt, n = 8), or after left stellectomy (LSGEx, n = 7) or right stellectomy (RSGEx, n = 7). LSGEx prolonged ERP‐LV (172 ± 9 vs 167 ± 8 msec, P < 0.05) and ERP‐RV (163 ± 10 vs 158 ± 14 msec, P < 0.05). RSGEx prolonged ERP‐LV (168 ± 17 vs 162 ± 15 msec, P < 0.01) and ERP‐RV (166 ± 14 vs 160 ± 13 msec, P < 0.01), and the times of the strength interval curves obtained for each S2 intensity in both ventricles. LSGSt decreased ERP‐LV (157 ± 11 vs 163 ± 12 msec, P < 0.01) and ERP‐RV (147 ± 18 vs 157 ± 17 msec, P < 0.05), and the times of the strength interval curves obtained for each S2 intensity in both ventricles. RSGSt did not significantly decreased ERP‐LV (152 ± 11 vs 156 ± 9 msec); however, it significantly shortened the times of the strength interval curves obtained for S2 intensities of 2 and 7 mA in the LV, and shortened ERP‐RV (139 ± 10 vs 145 ± 7 msec, P < 0.01) and the times of the strength interval curve for S2 intensities of 2, 3, and 5 mA in the RV. A significant interaction (MANOVA test) was observed between the ventricle studied and the ganglion stimulated for S2 intensities of 2 and 3 mA, and between the effect of stimulation and the ganglion stimulated for S2 intensities of 3 and 14 mA. To conclude, selective stellectomy prolonged epicardial ventricular refractoriness in both the mid‐anterior wall of the RV and the mid‐posterolateral wall of the LV; the magnitude of the epicardial excitability variations in both areas was different during selective stellate ganglion stimulation,

A halocin acting on Na+/H+ exchanger of Haloarchaea as a new type of inhibitor in NHE of mammals

The capability of halocin H6 (a bacteriocin-like protein produced by haloarchaeaHaloferax gibbonsii) to inhibit Na+/H+ exchange (NHE) in mammalian cells and its cardio-protective efficacy on the ischemic and reperfused myocardium were evaluated in the present study. H6 inhibits NHE activity (measured by a flow cytometry method) in a dose-dependent form of cell lines of mammalian origin (HEK293, NIH3T3, Jurkat and HL-1) as well as in primary cell culture from human skeletal muscle (myocytes and fibroblasts).In vivo, an ischemia-reperfusion model in dogs by coronary arterial occlusion was used (two hours of regional ischemia and three hours of reperfusion). In animals treated with halocin H6 there was a significant reduction of premature ventricular ectopic beats and infarct size, whereas blood pressure and heart rate remained unchanged. Up to date, halocin H6 is the only described biological molecule that exerts a, specific inhibitory activity in NHE of eukaryotic cells.ResumenEn el presente trabajo se evalúa la capacidad de la halocina H6 (una proteína tipo bacteriocina producida por la haloarchaeaHaloferax gibbonsii) para inhibir el intercambiador Na+/H+ (NHE) de céludas de mamífero y su posible eficacia cardioprotectora frente a los daños causados por isquemia-reperfusión del miocardio. En experimentosin vitro H6 inhibe la actividad de NHE (determinada por citometría de flujo) de forma dosis-dependiente tanto en líneas celulares de mamíferos (HEK293, NIH3T3, Jurkat y HL-1) como en cultivos primarios de miocitos y fibroblastos aislados de músculo esquelético humano. En experimentosin vivo se utilizó un modelo de isquemia-reperfusión en perros por oclusión de la arteria coronaria (dos horas de isquemia y tres de reperfusión). En animales tratados con halocina H6 se produjo una disminución significativa a nivel estadístico, tanto del número de latidos ectópicos ventriculares como del tamaño del infarto, mientras que no se produjeron cambios tanto en la presión sanguínea como en el ritmo cardíaco. Hasta la fecha la halocina H6 es la única molécula biológica descrita que ejerce una actividad inhibidora específica sobre el NHE de células eucariotas.

Análisis tiempo-frecuencia de la fibrilación ventricular. Estudio experimental

INTRODUCTION AND OBJECTIVES The analysis of frequency variability during ventricular fibrillation has yielded inconsistent results. We used an experimental model of ventricular fibrillation, with a short timescale, to analyze variations in frequency and their associated spatial distribution. METHODS Epicardial recordings of ventricular fibrillation were made in 10 perfused isolated rabbit heart preparations using a multiple electrode system (i.e., 240 unipolar electrodes). Both spectral and time-frequency analysis were used to derive the dominant frequency in the anterolateral wall of the left ventricle. RESULTS Linear regression analysis showed that there was a good correlation between the dominant frequency obtained using the two signal analysis methods: frequency (spectral analysis) = 1.01 x frequency (time-frequency analysis) -- 0.4 (r=0.9; P< .0001; standard error of the estimate, 2.2 Hz). In all cases except one, the dominant frequency exhibited a significant temporal variation on a short timescale (time-frequency analysis); the coefficient of variation was between 0.19 (0.06) and 0.24 (0.07) (NS). In all cases, there were significant differences between regions. The location at which the frequency was highest varied according to the timepoint considered, though it was predominantly in the apical or anterior zone. CONCLUSIONS In the absence of external modulating factors, the frequency of ventricular fibrillation exhibits temporal and spatial variations which can be observed at short timescales. In the free wall of the left ventricle, the dominant frequency is highest in the apical and anterior zones, and the maximum frequencies are most often found in these zones.Introduccion y objetivos El analisis de la variabilidad de la frecuencia durante la fibrilacion ventricular ha aportado resultados no uniformes. En un modelo experimental de fibrilacion ventricular se analiza, en una escala temporal reducida, las variaciones de la frecuencia y su distribucion espacial. Metodos En 10 preparaciones de corazon aislado y perfundido de conejo, se efectuan registros epicardicos de la fibrilacion ventricular con un electrodo multiple (240 electrodos unipolares) y se aplican metodos de analisis espectrales y de tiempo-frecuencia para obtener la frecuencia dominante en la pared anterolateral del ventriculo izquierdo. Resultados La recta de regresion obtenida al relacionar los valores de la frecuencia dominante obtenidos con los 2 metodos de analisis muestra una buena correlacion entre ambos: frecuencia (metodo espectral) = 1,01 × frecuencia (metodo tiempo-frecuencia) – 0,4 (r = 0,9; p Conclusiones En ausencia de factores moduladores externos, la fibrilacion ventricular presenta variaciones temporales y espaciales de la frecuencia que se objetivan en escalas de tiempo reducidas. En la pared libre del ventriculo izquierdo, la frecuencia dominante es mayor en las zonas apicales y anteriores, zonas en las que se ubican con mayor frecuencia los valores maximos.

Intravenous BQ-123 and phosphoramidon reduce ventricular ectopic beats and myocardial infarct size in dogs submitted to coronary occlusion and reperfusion.

The aim of this work was to investigate the influence of endothelin on myocardial ischemia and reperfusion in anaesthetized dogs. Animals were submitted to left thoracotomy and 120 min of left anterior descending coronary occlusion, followed by 180 min of reperfusion. Arterial blood pressure and electrocardiogram (ECG) were recorded in order to analyze heart rate (HR)-pressure product and production of ectopic beats. Infarcted areas were identified by a macroscopic staining method and infarct size was expressed as percentage of risk zone. To inhibit the effects of endothelin in a group of animals, we administered intravenously an endothelin synthesis inhibitor (phosphoramidon) and in another group, an endothelin-1 A receptor blocker (BQ-123). Phosphoramidon decreased the HR-pressure product during reperfusion period, and both, phosphoramidon and BQ-123 decreased infarct size by 40% and the number of ventricular ectopic beats by 88% and 68%, respectively, as compared to the saline treated dogs. In conclusion, endothelin seems to play a deleterious role on the myocardium submitted to ischemia and reperfusion.

Closed Chest Radiofrequency Ablation of the Sinoatrial Node in Dogs

Transcatheter ablation of the sinoatrial node with radiofrequency energy (0.6 MHZ, 2.5–5 watts) was performed in 10 dogs under fluoroscopic monitoring and autonomic blockade. Sinus function was previously studied in terms of cycle length, recovery time and atrial activation pattern by catheter mapping. Several discharges (8–22) were applied for variable periods of time (maximum 1 minute). Sinus tachycardia and/or sinus arrest during ablation confirmed correct catheter position. Sinus rhythm was abolished in eight dogs. The ectopic rhythm was atrial in six and AV nodal in two dogs. Ectopic atrial cycle length and recovery time were longer than the baseline sinus values: 724 ± 321 versus 509 ± 147, P < 0.05; 1103 ± 775 versus 638 ± 151, P < 0.05 (values in msec). The study was repeated 10–14 days later in six dogs; three maintained the same atrial rhythm, one persisted in sinus rhythm, and one dog changed from atrial to sinus rhythm, whereas another changed from sinus to atrial rhythm. Gross findings revealed transmural lesions in all dogs, without perforation. Histology in chronic dogs showed sinus cell necrosis and its replacement by granulation tissue. In conclusion: sinus function may be abolished by closed chest radiofrequency ablation.