(Circulation. 1999;99:2219-2222.)
© 1999 American Heart Association, Inc.
Correspondence |
Is the Antiarrhythmic Effects of PA Related to Wavelength?
Institute for Heart Research Slovak Academy of Sciences, Bratislava, Slovak Republic
Department of Physiology and Pharmacology Tel-Aviv University Medical School, Tel-Aviv, Israel
To the Editor:
In their excellent article,1 Kwan et al found that (1) the antiarrhythmic effect of procainamide (PA) could not be attributed to the alteration in wavelength because it did not significantly affect wavelength during ventricular fibrillation (VF), and (2) the ability of PA to decrease the number of wavelets by preventing spontaneous wave breaks can represent a novel mechanism of antiarrhythmic drug action. Because PA antiarrhythmic and defibrillating effects in rats2 and guinea pigs3 cannot be explained by prolongation of wavelength, and the mechanisms of preventing wave break are not clear, let us discuss briefly the features required for antiarrhythmic defibrillating compounds.
In an attempt to clarify the mechanisms underlying the maintenance of VF, we examined4 the factors involved in transient VF (TVF) versus sustained VF (SVF). No differences were found between cardiac muscle mass, heart rate, action potential duration, and effective refractory period of animals that exhibited TVF versus SVF. Similar to Kwan et al1 (Figure 8), TVF exhibited slow and synchronized electrical fibrillating activity, with a large part of ventricular mass acting in synchrony, whereas SVF exhibited unorganized, less synchronized electrical activity at a higher rate, with small local fibrillating areas. Untreated VF starts as an organized electrical activity resembling TVF, which becomes faster, less organized, and unsynchronized within a few seconds owing to "spontaneous wave break." "Synchronized" fibrillation may occur only in hearts with good functional cell-to-cell coupling, ensuring continuous propagation of electrical signals through the myocardium in a manner that brings the viable cardiomyocytes to act almost in unison. Attenuation of spatial and transmural inhomogeneity of gap junctional alteration by enhancement of intercellular coupling can facilitate conversion of SVF into TVF by preventing spontaneous wave break and decreasing the number of reentry circles via synchronization of small local circles into bigger ones. Spontaneous defibrillation occurs when the viable myocardium acts as a functional syncytium and the majority of myocardial cells are simultaneously in the refractory period.4
Fast (fibrillating) cellular activity associated with temporary hypoxia or ischemia increases junctional resistance, decreases gap junctional conduction, and causes intercellular uncoupling, most likely owing to an increase in cytoplasmic free Ca2+ concentration ([Ca2+]i) and/or alteration in intercellular cAMP gradient.5 An excess of diastolic [Ca2+]i downregulates intercellular communication, impairs intercellular coupling, and thus increases the number of fibrillating microareas by spontaneous wave break.
Following this assumption, we hypothesized6 that an antiarrhythmic defibrillating drug should prevent intercellular desynchronization. It should decrease the number of fibrillating circles and thereby slow down the fibrillating rate. It should prevent or attenuate [Ca2+]i overload-induced electrical uncoupling and thereby enhance or reestablish intercellular coupling and synchronization. It should increase gap junctional conductance, should not decrease conduction velocity, and should preserve excitation-contraction coupling.
Recently, it was found2 3 that PA possesses 1 of the main antiarrhythmic effects: it prevents Ca overload and decreases previously enhanced [Ca2+]i toward its normal level. In this way, PA prevents spontaneous wave break, decreases the number of reentrant waves, and synchronizes fibrillating activity, thereby exhibiting antiarrhythmic effects unrelated, at least directly, to wavelength.
References
1.
Kwan YY, Fan W, Hough D, Lee JJ, Fishbein
MC, Karagueuzain HS, Chen P-H. Effects of procainamide on
wave-front dynamics during ventricular fibrillation in open
chest dogs. Circulation. 1998;97:1828–1836.
2. Zaugg CE, Wu ST, Kojima S, Wikman-Coffelt J, Parmley WW, Buser PT. Role of intracellular calcium in the antiarrhythmic effect of procainamide during ventricular fibrillation in rat hearts. Am Heart J. 1995;130:351–358.[Medline] [Order article via Infotrieve]
3. Tribulova N, Varon D, Polak-Charcon S, Slezak J, Manoach M. Aged heart as a model for prolonged atrial fibrillo-flutter. Exp Clin Cardiol. In press.
4. Manoach M, Varon D, Newman M, Netz H. Spontaneous termination and initiation of ventricular fibrillation as a function of heart size, age, autonomic autoregulation, and drugs: a comparative study on different species of different age. Heart Vessels. 1987;2(suppl 2):56–68.
5. Podzuweit T. Early arrhythmias resulting from acute myocardial ischemia: possible role of cAMP. In: Parratt JR, ed. Early Arrhythmias Resulting From Myocardial Ischemia. London, UK: Macmillan Press; 1983:171–198.
6. Manoach M, Watanabe Y. How can we facilitate spontaneous termination of ventricular fibrillation and prevent sudden cardiac death? A working hypothesis. J Cardiovasc Electrophysiol. 1995;6:584–590.[Medline] [Order article via Infotrieve]
Response
Division of Cardiology, Department of Medicine
Department of Pathology Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, Calif
We appreciate the comments of Drs Tribulova and Manoach. Very interestingly, the authors found that similar to its effects on canine ventricular fibrillation (VF), procainamide also decreases the complexities of VF in smaller hearts (rat and guinea pig) by a mechanism that is also independent of wavelength prolongation. The proposed mechanism(s) of procainamide-induced increase of cell-to-cell coupling as a basis for the prevention of spontaneous wave break is interesting, but we do not think that this is a unique mechanism for the prevention of wave break. We have shown in an in vitro swine model of stable VF (ie, perfusion maintained during the VF through the coronary artery1 ) that in spite of good perfusion, procainamide reversibly regularized VF by preventing spontaneous wave break. We think that active regenerative cellular properties, including dynamic action potential duration (APD) restitution,2 3 may be involved. Although the wavelength (product of APD and conduction velocity) remains unchanged after procainamide, the drug tends to flatten the APD restitution curve and prevents the generation of action potentials with short duration during VF. Our working hypothesis is that activation with short APD is intrinsically a weak stimulus that undergoes block (wave break). By preventing the initiation of activation with shorter APD, procainamide might prevent spontaneous wave break.4 We therefore think that in addition to the possible passive mechanism (increased intercellular coupling resistance) of wave-front breakups, as proposed by Drs Tribulova and Manoach, there also exists the distinct possibility of active cellular properties (APD restitutional properties during VF) that act in concert to either prevent or promote spontaneous wave breaks.
References
1. Kim Y-H, Yashima M, Wu T-J, Garfinkel A, Weiss JN, Karagueuzian HS, Chen P-S. Effects of procainamide on action potentials and wavefront dynamics during ventricular fibrillation. Circulation. 1997;96(suppl I):I-123. Abstract.
2. Karma A. Electrical alternans and spiral wave breakup in cardiac tissue. Chaos. 1994;4:461–472.[Medline] [Order article via Infotrieve]
3. Garfinkel A, Chen P-S, Walter DO, Karagueuzian HS, Kogan B, Evans SJ, Karpoukhin M, Hwang C, Uchida T, Gotoh M, Nwasokwa O, Sager P, Weiss JN. Quasiperiodicity and chaos in cardiac fibrillation. J Clin Invest. 1997;99:305–314.[Medline] [Order article via Infotrieve]
4. Weiss JN, Garfinkel A, Karagueuzian HS, Qu Z, Chen P-S. Chaos and the transition to ventricular fibrillation: a new approach to antiarrhythmic drug evaluation. Circulation. In press.
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