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Vol. 57. Issue 1.
Pages 69-79 (January 2004)
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Vol. 57. Issue 1.
Pages 69-79 (January 2004)
DOI: 10.1016/S1885-5857(06)60089-3
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Ionic Currents and Ventricular Fibrillation Dynamics
Corrientes iónicas y dinámica de la fibrilación ventricular
Javier Morenoa, Mark Warrenb, José Jalifeb
a Unidad de Arritmias. Instituto Cardiovascular. Hospital Clínico San Carlos. Madrid. España. Institute for Cardiovascular Research. SUNY Upstate Medical University. Syracuse. New York. Estados Unidos.
b Institute for Cardiovascular Research. SUNY Upstate Medical University. Syracuse. New York. Estados Unidos.
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Figure 1. A: wavefront (red) and tail (green) in the vicinity of the rotor core (black dash circle). The wavefront propagation velocity (black arrows) becomes reduced towards the tip. At the tip, or phase singularity (yellow circle), conduction is blocked because the great curvature causes an excessive imbalance between the depolarization charge of the wavefront and the surrounding non-excited tissue. The phase singularity pivots around the core which is maintained in an excitable but unexcited state. The numbers 1 and 2 correspond to points on the wavefront and tail respectively that are close to the core. B: reentrant excitation wave obtained by numerical simulation (Luo-Rudy cellular ionic model). The wavefront is shown in red, the tail in green, and the resting tissue in blue. The wavefront follows a spiral trajectory whose curvature increases towards the center. The dotted circle indicates the limit of the core (N). AP1 represents a very short-lasting action potential close to the core. The duration increases progressively as the distance from the core increases, as shown by AP2 and AP3. C: plate showing a localized rotor in the left ventricle of an isolated guinea pig heart (from Samie et al61). D: action potential (solid line) in the immediate vicinity of the core. Its premature repolarization is due the strong electrotonic effect of the non-depolarized core (inclined arrow). After reaching the threshold voltage for IK1 activation, this current repolarizes the membrane to resting potential. In this diagram, the wavefront and the tail are propagated towards the left under the influence of independent ionic mechanisms (black arrow, gray arrow). The action potential represented by the dotted line corresponds to conditions of propagation, which do not lead to reentry. The color scale represents the same sequence of action potential phases as in panels B and C.
Figure 2. Effect of blocking sodium current (with tetrodotoxin) and calcium current (with verapamil) on the dynamics of ventricular fibrillation. A: changes in the maximum dominant frequency. B: increase in core area.*Significant change (P < .05) with respect to baseline values.
Figure 3. Luo-Rudy anisotropic model simulating sustained reentrant activity. The figure shows the effect of reducing the slow inward calcium current (Isi) on the size of the core and the rotation period. A: three dimensional representation of a reentrant wave under control conditions (Isi=100%). The rotation period is 133 ms; the size of the core, for an isopotential of ­30 mV, is 17.5 mm2. B: after reducing Isi by 75% compared to the control situation, the core increases to 23.5 mm2 (isopotential=­30 mV) and the period of rotation becomes 148 ms. C: comparison of core size at Isi=100% and at Isi=25% (from Samie et al)44.
Figure 4. Computer simulations of reentry propagation: (A) longer wavelength, (B) shorter wavelength. The perimeter of the core is marked by the white circle.
Figure 5. Correlation between dominant frequencies during ventricular fibrillation and the ventricular distribution of IK1 in guinea pig hearts. A: map of dominant frequencies, anterior face of the heart. The numbers indicate the local dominant frequency (see color scale). Two fluorescent signals are also shown which were obtained from a single camera pixel recording from the left ventricle and another one from the right ventricle, with their respective Fourier transformations and dominant frequencies. B: mean rectification profiles for IK1 for the left and right ventricles; the right ventricle clearly shows greater rectification. C: bands showing mRNA values for the proteins Kir2.1 and Kir2.3 in the left and right ventricles of a single heart obtained with the RNAse protection assay. The message of both proteins is stronger in the left ventricle (from Samie et al61 and Warren et al).62
Figure 6. Blockade of IK1 and ventricular fibrillation. A: rectification of IK1 in left ventricular myocytes from a guinea pig heart under baseline conditions and during perfusion with barium chloride at 2 different concentrations. B: mean maps for the dominant frequencies (DFs); barium administration reduces DF in both ventricles. However, the effect is much stronger in the left ventricle. C: electrocardiogram and Fourier transformations during VF (upper panels) and after barium administration. Note conversion to sinus rhythm with polymorphic ventricular complexes of focal origin (from Warren et al62).
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Ventricular fibrillation is the principal immediate cause of sudden cardiac death. Yet, in contrast to other arrhythmias, ventricular fibrillation is considered to be inaccessible to pharmacologic therapy because of its characteristic and apparently never-ending disarray of electrical waves that seem to propagate chaotically throughout the ventricles. Its prevention has historically been focused on the suppression of ventricular ectopy, with the idea of eliminating potential triggers of fibrillation, which from a clinical standpoint has proven to be detrimental. During the last decade, the application of the theory of wave propagation in non-linear excitable media to the study of cardiac fibrillation has led to a dramatic increase in our understanding of its mechanisms. It is now clear that fibrillation is generated and maintained by rotors that gyrate at exceedingly high frequencies. From such rotors emanate spiral waves of excitation that propagate throughout the myocardium in very complex ways. Among the most important factors that determine rotor dynamics are the electrophysiological properties of the ventricular cells, established by their underlying transmembrane ionic currents. Thus, in recent years, studies have focused on the roles played by specific ionic mechanisms and their modulation by antiarrhythmic drugs in ventricular fibrillation dynamics. This review article summarizes the main findings of such studies, which pave the way for a better understanding of fibrillation, and for the development of new pharmacological approaches that aim to prevent rotor formation and maintenance rather than to suppress the triggering ectopic event.
Antiarrhythmics agents
La fibrilación ventricular es la causa principal de muerte súbita cardíaca. A diferencia de otras arritmias, en general se ha considerado farmacológicamente inabordable, dado que parece una sucesión de innumerables frentes eléctricos descoordinados que circulan de manera caótica desde su inicio. Durante varias décadas, su prevención se centró básicamente en la supresión de las extrasístoles ventriculares que pudieran precipitarla. Este enfoque terapéutico se tradujo en pésimos resultados clínicos. En la última década, gracias a los conceptos de la teoría de propagación de ondas en medios no lineales, la visión global de la fibrilación ventricular ha cambiado de manera radical. Se ha demostrado que la fibrilación está mediada por reentradas funcionales con forma helicoidal que rotan siguiendo una dinámica determinada por su pivote organizativo o rotor. Estos rotores se comportarían como el centro que genera los múltiples frentes de activación eléctricos. Los rotores, a su vez, están condicionados por las propiedades electrofisiológicas del miocardio, determinadas por la dinámica de las diferentes corrientes iónicas. Así, recientemente se han publicado numerosos trabajos experimentales y de simulación sobre el papel que desempeña cada corriente en la dinámica de los rotores y se han analizado los efectos de su bloqueo mediante antiarrítmicos. Esta revisión detalla los hallazgos de los principales trabajos publicados, así como los análisis teóricos que describen sus autores. De estos trabajos se desprenden nuevos enfoques terapéuticos farmacológicos que buscarían evitar no ya el latido desencadenante, sino el propio mantenimiento de la fibrilación.
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