Publish in this journal
Journal Information
Vol. 57. Issue 1.
Pages 69-79 (January 2004)
Share
Share
Download PDF
More article options
Vol. 57. Issue 1.
Pages 69-79 (January 2004)
DOI: 10.1016/S1885-5857(06)60089-3
Full text access
Ionic Currents and Ventricular Fibrillation Dynamics
Corrientes iónicas y dinámica de la fibrilación ventricular
Visits
6432
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.
This item has received
6432
Visits
Article information
Abstract
Bibliography
Download PDF
Statistics
Tables (6)
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).
Show moreShow less
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.
Keywords:
Fibrillation
Ions
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.
Palabras clave:
Fibrilación
Iones
Antiarrítmicos
Full text is only aviable in PDF
Bibliography
[1]
Lal R, Chapman PD, Naccarelli GV, Schechtman KB, Rinkenberger RL, Troup PJ, et al..
Flecainide in the treatment of nonsustained ventricular tachycardia..
Ann Intern Med, 105 (1986), pp. 493-8
[2]
Salerno DM, Gillingham KJ, Berry DA, Hodges M..
A comparison of antiarrhythmic drugs for the suppression of ventricular ectopic depolarizations: a meta-analysis..
Am Heart J, 120 (1990), pp. 340-53
[3]
Cairns JA, Connolly SJ, Roberts R, Gent M..
Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators..
Lancet, 349 (1997), pp. 675-82
[4]
Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, et al..
Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators..
Lancet, 349 (1997), pp. 667-74
[5]
Kober L, Bloch Thomsen PE, Moller M, Torp-Pedersen C, Carlsen J, Sandoe E, et al..
Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial..
Lancet, 356 (2000), pp. 2052-8
[6]
Ruskin JN..
The cardiac arrhythmia suppression trial (CAST)..
N Engl J Med, 321 (1989), pp. 386-8
[7]
Morganroth J, Goin JE..
Quinidine-related mortality in the short-to-medium-term treatment of ventricular arrhythmias. A meta-analysis..
Circulation, 84 (1991), pp. 1977-83
[8]
Berntsen RF, Rasmussen K..
Lidocaine to prevent ventricular fibrillation in the prehospital phase of suspected acute myocardial infarction: the North-Norwegian Lidocaine Intervention Trial..
Am Heart J, 124 (1992), pp. 1478-83
[9]
Waldo AL, Camm AJ, DeRuyter H, Friedman PL, MacNeil DJ, Pauls JF, et al..
Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol..
Lancet, 348 (1996), pp. 7-12
[10]
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial..
Lancet, 353 (1999), pp. 9-13
[11]
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF)..
Lancet, 353 (1999), pp. 2001-7
[12]
Pachón IM, Jalife J..
Nuevos conceptos sobre los mecanismos de la fibrilación ventricular..
Rev Esp Cardiol, 54 (2001), pp. 373-82
[13]
Davidenko JM, Pertsov AV, Salomonsz R, Baxter W, Jalife J..
Stationary and drifting spiral waves of excitation in isolated cardiac muscle..
Nature, 355 (1992), pp. 349-51
[14]
Pertsov AM, Davidenko JM, Salomonsz R, Baxter WT, Jalife J..
Spiral waves of excitation underlie reentrant activity in isolated cardiac muscle..
Circ Res, 72 (1993), pp. 631-50
[15]
Gray RA, Jalife J, Panfilov AV, Baxter WT, Cabo C, Davidenko JM, et al..
Mechanisms of cardiac fibrillation..
Science, 270 (1995), pp. 1222-3
[16]
Winfree AT..
Stably rotating patterns of reaction and diffusion..
Prog Theor Chem, 4 (1978), pp. 1-51
[17]
Winfree AT..
When time breaks down. New Jersey: Princeton Univ Press.
When time breaks down. New Jersey: Princeton Univ Press, (1987), pp. 108-10
[18]
Zykov VS..
Analytic evaluation of the relationship between the speed of a wave of excitation in a two-dimensional excitable medium and the curvature of its front..
Biofizika, 25 (1980), pp. 888-92
[19]
Pertsov AM, Khramov RN, Panfilov AV..
Sharp increase in refractory period induced by oxidation suppression in Fitz Hugh-Nagumo model. New mechanism of antiarrhythmic drug action..
Biofizika, 26 (1981), pp. 1077-81
[20]
Chorro FJ, Millet J, Ferrero A, Cebrian A, Canoves J, Martínez A..
Efecto del estiramiento miocárdico sobre las frecuencias de activación determinadas mediante análisis espectral durante la fibrilación ventricular..
Rev Esp Cardiol, 55 (2002), pp. 1143-50
[21]
Beaumont J, Davidenko N, Davidenko JM, Jalife J..
Spiral waves in two-dimensional models of ventricular muscle: formation of a stationary core..
[22]
Beaumont J, Jalife J..
Rotors and spiral waves in two dimensions. En: Zipes DP, Jalife J, editors. Cardiac electrophysiology from cell to bedside. Philadelphia: Saunders.
Rotors and spiral waves in two dimensions. En: Zipes DP, Jalife J, editors. Cardiac electrophysiology from cell to bedside. Philadelphia: Saunders, (2000), pp. 327-35
[23]
Moe GK..
On the multiple wavelet hypothesis of atrial fibrillation..
Arch Int Pharmacodyn Ther, 140 (1962), pp. 183-8
[24]
Karma A..
Electrical alternans and spiral wave breakup in cardiac tissue..
Chaos, 4 (1994), pp. 461-72
[25]
Garfinkel A, Kim YH, Voroshilovsky O, Qu Z, Kil JR, Lee MH, et al..
Preventing ventricular fibrillation by flattening cardiac restitution..
Proc Natl Acad Sci USA, 97 (2000), pp. 6061-6
[26]
Riccio ML, Koller ML, Gilmour RF..
Electrical restitution and spatiotemporal organization during ventricular fibrillation..
Circ Res, 84 (1999), pp. 955-63
[27]
Gray RA, Pertsov AM, Jalife J..
Spatial and temporal organization during cardiac fibrillation..
Nature, 392 (1998), pp. 75-8
[28]
Jalife J, Berenfeld O, Skanes A, Mandapati R..
Mechanisms of atrial fibrillation: mother rotors or multiple daughter wavelets, or both?.
J Cardiovasc Electrophysiol, 9 (1998), pp. S2-12
[29]
Weidmann S..
The electrical constants of Purkinje fibres..
J Physiol, 118 (1952), pp. 348-60
[30]
Mandapati R, Asano Y, Baxter WT, Gray R, Davidenko J, Jalife J..
Quantification of effects of global ischemia on dynamics of ventricular fibrillation in isolated rabbit heart..
Circulation, 98 (1998), pp. 1688-96
[31]
Coraboeuf E, Deroubaix E..
Shortening effect of tetrodotoxin on action potentials of the conducting system in the dog heart..
J Physiol, 280 (1978), pp. P24
[32]
Cabo C, Pertsov AM, Baxter WT, Davidenko JM, Gray RA, Jalife J..
Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle..
Circ Res, 75 (1994), pp. 1014-28
[33]
Krinsky VI, Efimov IR, Jalife J..
Vortices with linear cores in excitable media..
Proc R Soc Lond, 437 (1992), pp. 645-55
[34]
Kwan YY, Fan W, Hough D, Lee JJ, Fishbein MC, Karagueuzian HS, et al..
Effects of procainamide on wave-front dynamics during ventricular fibrillation in open-chest dogs..
Circulation, 97 (1998), pp. 1828-36
[35]
Starmer CF, Lastra AA, Nesterenko VV, Grant AO..
Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments..
Circulation, 84 (1991), pp. 1364-77
[36]
Akiyama T..
Intracellular recording of in situ ventricular cells during ventricular fibrillation..
Am J Physiol, 240 (1981), pp. H465-71
[37]
Zhou X, Guse P, Wolf PD, Rollins DL, Smith WM, Ideker RE..
Existence of both fast and slow channel activity during the early stages of ventricular fibrillation..
Circ Res, 70 (1992), pp. 773-86
[38]
Duff HJ, Sheldon RS, Cannon NJ..
Tetrodotoxin: sodium channel specific anti-arrhythmic activity..
Cardiovasc Res, 22 (1988), pp. 800-7
[39]
Starmer CF, Lancaster AR, Lastra AA, Grant AO..
Cardiac instability amplified by use-dependent Na channel blockade..
Am J Physiol, 262 (1992), pp. H1305-10
[40]
Herre JM, Titus C, Oeff M, Eldar M, Franz MR, Griffin JC, et al..
Inefficacy and proarrhythmic effects of flecainide and encainide for sustained ventricular tachycardia and ventricular fibrillation..
Ann Intern Med, 113 (1990), pp. 671-6
[41]
Balke CW, Marban E, O'Rourke B..
Calcium channels: structure, function and regulation. En: Zipes DP, Jalife J, editors. Cardiac electrophysiology. From cell to bedside. Philadelphia: Saunders.
Calcium channels: structure, function and regulation. En: Zipes DP, Jalife J, editors. Cardiac electrophysiology. From cell to bedside. Philadelphia: Saunders, (2000), pp. 8-21
[42]
Noguchi K, Masumiya H, Takahashi K, Kaneko K, Higuchi S, Tanaka H, et al..
Comparative effects of gallopamil and verapamil on the mechanical and electrophysiological parameters of isolated guinea-pig myocardium..
Can J Physiol Pharmacol, 75 (1997), pp. 1316-21
[43]
Watanabe T, Gray RA, Mandapati R, Asano T, Jalife J..
Verapamil converts fibrillation into sustained monomorphic tachycardia in the isolated rabbit heart..
Pacing Clin Electrophysiol, 20 (1997), pp. 1136
[44]
Samie FH, Mandapati R, Gray RA, Watanabe Y, Zuur C, Beaumont J, et al..
A mechanism of transition from ventricular fibrillation to tachycardia: effect of calcium channel blockade on the dynamics of rotating waves..
Circ Res, 86 (2000), pp. 684-91
[45]
Choi BR, Nho W, Liu T, Salama G..
Life span of ventricular fibrillation frequencies..
Circ Res, 91 (2002), pp. 339-45
[46]
Wu TJ, Lin SF, Weiss JN, Ting CT, Chen PS..
Two types of ventricular fibrillation in isolated rabbit hearts: importance of excitability and action potential duration restitution..
Circulation, 106 (2002), pp. 1859-66
[47]
Wagner JA, Weisman HF, Levine JH, Snowman AM, Snyder SH..
Differential effects of amiodarone and desethylamiodarone on calcium antagonist receptors..
J Cardiovasc Pharmacol, 15 (1990), pp. 501-7
[48]
Omichi C, Zhou S, Lee MH, Naik A, Chang CM, Garfinkel A, et al..
Effects of amiodarone on wave front dynamics during ventricular fibrillation in isolated swine right ventricle..
Am J Physiol Heart Circ Physiol, 282 (2002), pp. H1063-70
[49]
Chorro FJ, Canoves J, Guerrero J, Mainar L, Sanchis J, Such L, et al..
Alteration of ventricular fibrillation by flecainide, verapamil, and sotalol: an experimental study..
Circulation, 101 (2000), pp. 1606-15
[50]
Andersen HR, Wiggers H, Knudsen LL, Simonsen I, Thomsen PE, Christiansen N..
Dofetilide reduces the incidence of ventricular fibrillation during acute myocardial ischaemia. A randomised study in pigs..
Cardiovasc Res, 28 (1994), pp. 1635-40
[51]
Xue Y, Yamada C, Chino D, Hashimoto K..
Effects of azimilide, a KV(r) and KV(s) blocker, on canine ventricular arrhythmia models..
Eur J Pharmacol, 376 (1999), pp. 27-35
[52]
Dorian P, Newman D..
Tedisamil increases coherence during ventricular fibrillation and decreases defibrillation energy requirements..
Cardiovasc Res, 33 (1997), pp. 485-94
[53]
Choi BR, LIu T, Salama G..
The distribution of refrachory periods influence the dynamics of ventricular fibrillation..
Circ Res, 88 (2001), pp. E49
[54]
Qi XQ, Newman D, Dorian P..
Azimilide decreases defibrillation voltage requirements and increases spatial organization during ventricular fibrillation..
J Interv Card Electrophysiol, 3 (1999), pp. 61-7
[55]
Uchida T, Yashima M, Gotoh M, Qu Z, Garfinkel A, Weiss JN, et al..
Mechanism of acceleration of functional reentry in the ventricle: effects of ATP-sensitive potassium channel opener..
Circulation, 99 (1999), pp. 704-12
[56]
Chi L, Uprichard AC, Lucchesi BR..
Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death..
J Cardiovasc Pharmacol, 15 (1990), pp. 452-64
[57]
Robert E, Delye B, Aya G, Peray P, Juan JM, Sassine A, et al..
Comparison of proarrhythmogenic effects of two potassium channel openers, levcromakalim and nicorandil: a high-resolution mapping study on rabbit heart..
J Cardiovasc Pharmacol, 29 (1997), pp. 109-18
[58]
Pertsov AM, Panfilov AV, Medvedeva FU..
Instabilities of autowaves in excitable media associated with critical curvature phenomena..
Biofizika, 28 (1983), pp. 100-2
[59]
Nichols CG, Lopatin AN..
Inward rectifier potassium channels..
Annu Rev Physiol, 59 (1997), pp. 171-91
[60]
Yang J, Jan YN, Jan LY..
Control of rectification and permeation by residues in two distinct domains in an inward rectifier K+ channel..
Neuron, 14 (1995), pp. 1047-54
[61]
Samie FH, Berenfeld O, Anumonwo J, Mironov SF, Udassi S, Beaumont J, et al..
Rectification of the background potassium current: a determinant of rotor dynamics in ventricular fibrillation..
Circ Res, 89 (2001), pp. 1216-23
[62]
Warren M, Guha PK, Berenfeld O, Zaitsev A, Anumonwo JM.B, Dhamoon AS, et al..
Blockade of the inward rectifying potassium current terminates ventricular fibrillation in the guinea pig heart..
J Cardiovasc Electrophysiol, 14 (2003), pp. 621-31
[63]
Dhamoon AS, Bagwe S, Guha P, Anumonwo JM, Taffet SM, Jalife J..
Differential expression and whole-cell current rectification profiles of guinea pig Kir2.x channels..
Biophys J, 82 (2002), pp. 587a
[64]
Kubo Y, Baldwin TJ, Jan YN, Jan LY..
Primary structure and functional expression of a mouse inward rectifier potassium channel..
Nature, 362 (1993), pp. 127-33
[65]
Dorian P, Penkoske PA, Witkowski FX..
Order in disorder: effect of barium on ventricular fibrillation..
Can J Cardiol, 12 (1996), pp. 399-406
[66]
Kudenchuk PJ, Cobb LA, Copass MK, Cummins RO, Doherty AM, Fahrenbruch CE, et al..
Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation..
N Engl J Med, 341 (1999), pp. 871-8
[67]
Ramírez CJ, Rodríguez DA, Velasco VM, Rosas F..
Distrofia miotónica y taquicardia ventricular por reentrada rama-rama..
Rev Esp Cardiol, 55 (2002), pp. 1093-7
[68]
Zaitsev AV, Guha PK, Sarmast F, Kolli A, Berenfeld O, Pertsov AM, et al..
Wavebreak formation during ventricular fibrillation in the isolated, regionally ischemic pig heart..
[69]
Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al..
ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation..
J Am Coll Cardiol, 38 (2001), pp. 1231-66
[70]
Atarashi H, Inoue H, Hiejima K, Hayakawa H..
Conversion of recent-onset atrial fibrillation by a single oral dose of pilsicainide. The PSTAF Investigators..
Am J Cardiol, 78 (1996), pp. 694-7
Idiomas
Revista Española de Cardiología (English Edition)

Subscribe to our newsletter

Article options
Tools
es en

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

es en
Política de cookies Cookies policy
Utilizamos cookies propias y de terceros para mejorar nuestros servicios y mostrarle publicidad relacionada con sus preferencias mediante el análisis de sus hábitos de navegación. Si continua navegando, consideramos que acepta su uso. Puede cambiar la configuración u obtener más información aquí. To improve our services and products, we use "cookies" (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.