Joaquín Cánoves

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.

Quantification of the Modifications in the Dominant Frequency of Ventricular Fibrillation under Conditions of Ischemia and Reperfusion: An Experimental Study

The characteristics of ventricular fibrillatory signals vary as a function of the time elapsed from the onset of arrhythmia and the maneuvers used to maintain coronary perfusion. The dominant frequency (FrD) of the power spectrum of ventricular fibrillation (VF) is known to decrease after interrupting coronary perfusion, though the corresponding recovery process upon reestablishing coronary flow has not been quantified to date. With the aim of investigating the recovery of the FrD during reperfusion after a brief ischemic, period, 11 isolated and perfused rabbit heart preparations were used to analyze the signals obtained with three unipolar epicardial electrodes (E1‐E3) and a bipolar electrode immersed in the thermostatizfid organ bath (E4), following the electrical induction of VF. Recordings were made under conditions of maintained coronary perfusion (5 min), upon interrupting perfusion (15 mini, and after reperfusion (5 min), FrD was determined using Welchs method. The variations in FrD were quantified during both ischemia and reperfusion, based on an exponential model AFrD = A exp (‐t/C). During ischemia ΔFrD is the difference between FrD and the minimum value, while t is the time elapsed from the interruption of coronary perfusion. During reperfusion ΔFrD is the difference between the maximum value and FrD, while t is the time elapsed from the restoration of perfusion, A is one of the constants of the model, and C is the time constant. FrD exhibited respective initial values of 16.20 ± 1.67, 16.03 ± 1.38, and 16.03 ± 1.80 Hz in the epicardial leads, and 15.09 ±1.07 Hz in the bipolar lead within the bath. No significant variations were observed during maintained coronary perfusion. The fit of the FrD variations to the model during ischemia and reperfusion proved significant in nine experiments. The mean time constants C obtained on fitting to the model during ischemia were as follows: El =294.4 ± 75.6, E2 = 225.7 ± 48.5, E3 = 327.4 ± 79.7, and E4 = 298.7 ± 43.9 seconds. The mean values of C obtained during reperfusion, and the significance of the differences with respect to the ischemic period were: El = 57.5 ± 8.4 (P ± 0.01), E2 = 64.5 ± 11.2 (P0.01), E3 = 80.7 ± 13.3 (P < 0.01), and E4 = 74.9 ± 13.6 (P < 0.0001). The time course variations of the FrD of the VF power spectrum fit an exponential model during ischemia and reperfusion. The time constants of the model during reperfusion after a brief ischemic period are significantly shorter than those obtained during ischemia.

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.

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.

Mapping of atrial activation patterns after inducing contiguous radiofrequency lesions: an experimental study.

CHORRO, F.J., et al.: Mapping of Atrial Activation Patterns After Inducing Contiguous Radiofrequency Lesions: An Experimental Study. High resolution mapping techniques are used to analyze the changes in atrial activation patterns produced by contiguous RF induced lesions. In 12 Langendorff‐perfused rabbit hearts, left atrial activation maps were obtained before and after RF induction of epicardial lesions following a triple‐phase sequential protocol: (phase 1) three separate lesions positioned vertically in the central zone of the left atrial wall; (phase 2) the addition of two lesions located between the central lesion and the upper and lower lesions; and (phase 3) the placement of four additional lesions between those induced in the previous phases. In six additional experiments a pathological analysis of the individual RF lesions was performed. In phase 1 (lesion diameter = 2.8 ± 0.2 mm, gap between lesions = 3 ± 0.8 mm), the activation process bordered the lesions line in two (2.0‐ms cycles) and four experiments (1.0‐ms cycles). In phase 2, activation bordered the lesions line in eight (2.0‐ms cycles, P < 0.01 vs control) and nine experiments (1.0‐ms cycles, P < 0.001), and in phase 3 this occurred in all experiments except one (both cycles, P < 0.001 vs control). In the experiments with conduction block, the increment of the interval between activation times proximal and distal to the lesions showed a significant correlation to the length of the lesions (r = 0.68, P < 0.05, 100‐ms cycle). In two (17%) experiments, sustained regular tachycardias were induced with reentrant activation patterns around the lesions line. In conclusion, in this acute model, atrial RF lesions with intact tissue gaps of 3 mm between them interrupt conduction occasionally, and conduction block may be frequency dependent. Lesion overlap is required to achieve complete conduction block lines. Tachycardias with reentrant activation patterns around a lesions line may be induced.

Efecto del estiramiento miocárdico sobre las frecuencias de activación determinadas mediante análisis espectral durante la fibrilación ventricular

Introduction and objectives. The aim of this study was to analyze the effects of myocardial stretching on excitation frequencies, as determined by spectral analysis, during ventricular fibrillation. Methods. In 12 isolated rabbit heart preparations, ventricular activation during ventricular fibrillation was recorded with multiple electrodes. Recordings were obtained before, during and after ventricular dilatation produced with an intraventricular balloon. The dominant frequency of the signals obtained with each of the electrodes was determined by spectral analysis. Results. During the control phase, the mean, minimum and maximum dominant frequencies were, respectively, 14.3 ± 1.7, 12.5 ± 1.7, and 16.2 ± 1.4 Hz, and the average difference between the maximum and minimum frequencies was 3.6 ± 2.1 Hz. This difference was over 4 Hz in four cases, and in no case did it exceed 8 Hz. During ventricular stretching, the mean dominant frequency increased significantly (21.1 ± 6.1 Hz; p < 0.0001), as did the minimum values (14 ± 2.6 Hz; p < 0.05) and especially the maximum values (26.6 ± 7.7 Hz; p < 0.0001). The difference between the maximum and minimum frequencies (12.6 ± 6.4 Hz; p < 0.001) was over 4 Hz in all cases except one, and over 8 Hz in 9 cases. The maximum values were distributed heterogeneously during ventricular stretching. Upon suppressing ventricular stretching, the dominant frequency did not differ from controls. Conclusions. Myocardial frequency maps during ventricular fibrillation show limited variations in the dominant frequency of the signals recorded in the lateral wall of the left ventricle. During stretching, the patterns were heterogeneous, due mainly to the marked increase in the maximum dominant frequency. In the experimental model used, the effects of stretching remitted after suppressing ventricular dilatation.

Reduction of Atrial Fibrillation Inducibility by Radiofrequency Ablation: An Experimental Study

A study is made of the antifibrillatory effects of radiofrequency (RF)‐induced atrial lesions using nine Langendorff‐perfused rabbit hearts in which the atrial electrophysiological properties and atrial fibrillation (AF) inducibility were modified by atrial stretching. Using a multiple electrode consisting of 121 unipolar electrodes, determinations were made of the atrial refractory periods, conduction velocity, wavelength of the atrial activation process, and the inducibility of sustained AF episodes (duration over 30 s) by atrial burst pacing in four situations: (a) control; (b) following dilatation of the right atrium; (c) after adding an RF linear lesion at the cava‐tricuspid annulus isthmus; and (d) after adding two RF linear lesions rounding the base of the right atrial appendage and extending from the inferior zone of the sulcus terminalis to the anterior wall of the appendage. Under control conditions, AF was not induced in any of the experiments. The wavelengths were 10.5 ± 1.2 cm for basic cycles of 250 ms and 6.6 ± 0.5 cm for cycles of 100 ms. Following dilatation, a significant decrease was recorded in the atrial refractory periods, conduction velocity, and wavelength, which reached values of 6.1 ± 0.7 cm (250‐ms cycle, P < 0.01), and 3.9 ± 0.3 cm (100‐ms cycle, P < 0.01); AF was induced in five cases (P < 0.05). After producing the lesion at the cava‐tricuspid isthmus, the electrophysiological modifications induced by atrial dilatation persisted (wavelength = 6.2 ± 0.6 cm (250‐ms cycle) and 4.3 ± 0.3 cm (100‐ms cycle); P < 0.01 vs the control) and AF was triggered in eight cases (P < 0.0001). In turn, on adding the two lesions at the right atrial free wall and appendage, AF was induced only in one experiment (P = NS vs control), and the dilatation‐induced decrease in refractoriness and wavelength was attenuated. Nevertheless, differences remained significant with respect to the controls, with the exception of the functional refractory periods determined at cycles of 100 ms. In this phase, the wavelength was 6.6 ± 0.7 cm (250‐ms cycle, P < 0.01 vs control) and 4.9 ± 0.5 cm (100‐ms cycle; P < 0.05). Atrial conduction between the zones separated by the lesions was blocked at any frequency, or selectively at rapid atrial activation frequencies. In conclusion: (a) the production of three linear lesions in the right atrium (cava‐tricuspid isthmus, atrial appendage, and inferior free wall) reduces AF inducibility in the experimental model used; (b) conduction block (either absolute or frequency dependent) through the lesions, reduction in tissue mass caused by lesion creation, and possibly the attenuation of the shortening of atrial refractoriness and wavelength in the zones not separated by the lesions are implicated in the reduction of AF inducibility; and (c) the single lesion in the cava‐tricuspid isthmus does not impede AF inducibility.

Analyzing the electrophysiological effects of local epicardial temperature in experimental studies with isolated hearts.

As a result of their modulating effects upon myocardial electrophysiology, both hypo- and hyperthermia can be used to study the mechanisms that generate or sustain cardiac arrhythmias. The present study describes an original electrode developed with thick-film technology and capable of controlling regional temperature variations in the epicardium while simultaneously registering its electrical activity. In this way, it is possible to measure electrophysiological parameters of the heart at different temperatures. The results obtained with this device in a study with isolated and perfused rabbit hearts are reported. An exploration has been made of the effects of local temperature changes upon the electrophysiological parameters implicated in myocardial conduction. Likewise, an analysis has been made of the influence of local temperature upon ventricular fibrillation activation frequency. It is concluded that both regional hypo- and hyperthermia exert reversible and opposite effects upon myocardial refractoriness and conduction velocity in the altered zone. The ventricular activation wavelength determined during constant pacing at 250 ms cycles is not significantly modified, however. During ventricular fibrillation, the changes in the fibrillatory frequency do not seem to be transmitted to normal temperature zones.

Acute Effects of Radiofrequency Ablation upon Atrial Conduction in Proximity to the Lesion Site

The electrophysiological effects of RF ablation upon the areas in proximity to the lesioned zones have not yet been well characterized. An experimental model is used to investigate atrial conduction in the boundaries of RF damaged zones. In 11 isolated and perfused rabbit hearts, endocardial atrial electrograms were recorded using an 80‐Iead multiple electrode positioned in the left atrium. Both before and after the RF application (5 W, 8 s, 1‐mm diameter unipolar epicardial electrode) in the mid‐portion of the free left atrial wall, measurements were made of conduction time from the pacing zone (posterior wall of the left atrium) to three points between 7.5 and 7.9 mm distal to the damaged zone. Conduction velocity and the direction of the activation propagation vector were determined in ten groups of four electrodes positioned around the damaged zone, and at the left atrial appendage. The mean diameter (± SEM) of the transmural lesions produced by RF ablation and defined by macroscopic examination was 4.2 ± 0.2 mm. The conduction times to the three points distal to the lesion site were significantly prolonged as a result of RF ablation: 7.6 ± 0.4, 7.4 ± 0.5, and 6.9 ± 1.0 ms (control); and 11.3 ± 1.0 (P ≤ 0.01), 11.1 ± 1.3 (P < 0.01), 10.6 ± 1.4 ms (P < 0.05) (post‐RF). The differences between the conduction velocities determined in the areas surrounding the lesion, before and after RF application, failed to reach statistical significance: 86.2 ± 6.5 cm/s (control) versus 75.5 ± 5.7 cm/s (post‐RF) (NS). After RF, significant variations were only observed in the direction of impulse propagation in the proximal‐inferior quadrant adjacent to the lesion site, the difference being ‐61°± 18° (P < 0.02). In 2 of 4 experiments in which the lesion size was increased by a second RF application (5 W, 16 s), tachycardias with activation sequence around the lesion could be induced, with cycle lengths of 56 and 50 ms, respectively. In the atrial wall, the conduction times to the regions distal to the RF lesion are significantly prolonged. No significant changes are observed in conduction velocity in the areas in proximity to the lesion. Prolonged conduction to the areas distal to the ablation site is due to the lengthened pathway traveled by the impulses in reaching these areas. Tachycardias with activation patterns that suggest reentry around the RF damaged zone may be induced.