Showing papers by "Charles Antzelevitch published in 1991"
TL;DR: In spite of important advances in cardiology in recent years, pharmacological control of cardiac arrhythmias in the clinic remains an experiment conducted on a patient-by-patient basis using a trial and error approach tempered by good clinical judgment.
Abstract: In spite of important advances in cardiology in recent years, pharmacological control of cardiac arrhythmias in the clinic remains an experiment conducted on a patient-by-patient basis using a trial and error approach tempered by good clinical judgment. Treatment, especially of life-threatening ventricular arrhythmias, remains largely empiric today because of our lack of understanding of the complex pathophysiological processes that give rise to cardiac rhythm disturbances. The problem is compounded by our incomplete understanding of the mechanisms by which antiarrhythmic agents act to suppress and in some cases aggravate arrhythmias. Also confounding is the lack of criteria that can be applied to the differential diagnosis of specific arrhythmia mechanisms in the clinic. Differential diagnosis of cardiac arrhythmias requires an understanding of basic mechanisms and establishment of mechanism-specific electrophysiological criteria. Both in turn depend on our knowledge of the basic electrophysiological characteristics of the cells and tissues of the heart and the extent to which heterogeneity or specialization exists. Our ability to design specific drug treatments also depends on our understanding and awareness of differences in the pharmacological responsiveness of diverse cell types within the heart. Until recently, most investigations of the electrophysiology and pharmacology of the ventricles focused on two main cell types, namely, ventricular myocardium and Purkinje fibers (or conducting tissues). Recent studies have provided data supporting the existence of at least four functionally distinct cell types in the canine ventricle, each with a characteristic electrophysiological and pharmacological pro-
747 citations
TL;DR: Evidence is presented for the existence of a unique subpopulation of cells in the deep subepicardial layers of the canine left and right ventricles with electrophysiological features intermediate between those of conducting and myocardial cells that may facilitate conduction in epicardium and are likely to influence or mediate the manifestation of electrocardiographic J waves, T waves, U waves, and long QT intervals.
Abstract: Recent studies have shown that canine ventricular epicardium and endocardium differ with respect to electrophysiological characteristics and pharmacological responsiveness and that these differences are in large part due to the presence of a prominent transient outward current Ito and a spike-and-dome morphology of the action potential in epicardium but not endocardium. In attempting to quantitate these differences and assess their gradation across the ventricular wall, we encountered a subpopulation of cells in the deep subepicardial layers with electrophysiological characteristics different from those of either epicardium or endocardium. These cells, which we have termed M cells, display a spike-and-dome morphology typical of epicardium but a maximal rate of rise of the action potential upstroke that is considerably greater than that of either epicardium or endocardium. Using the restitution of the amplitude of phase 1 of the action potential as a marker for the reactivation of Ito, we showed M cells to possess a prominent 4-aminopyridine-sensitive Ito with a reactivation time course characterized by two components with fast and slow time constants. The rate dependence of action potential duration of M cells was considerably more accentuated than that of epicardium or endocardium and more akin to that of Purkinje fibers (not observed histologically in this region). Phase 4 depolarization was never observed in M cells, not even after exposure to catecholamines and/or low [K+]o. In summary, our study presents evidence for the existence of a unique subpopulation of cells in the deep subepicardium of the canine left and right ventricles with electrophysiological features intermediate between those of conducting and myocardial cells. Although their function is unknown, M cells may facilitate conduction in epicardium and are likely to influence or mediate the manifestation of electrocardiographic J waves, T waves, U waves, and long QT intervals and contribute importantly to arrhythmogenesis.
513 citations
TL;DR: The data indicate that propranolol, TTX, and flecainide, via their action to block sodium current, may exert opposite effects on action potential duration and refractoriness in cells spanning the ventricular wall.
Abstract: Using microelectrode techniques we compared the effects of tetrodotoxin (TTX, 2-3 microM), DL-propranolol (1-3 micrograms/ml), and flecainide acetate (10-15 microM) on isolated canine ventricular epicardial (epicardium) and endocardial (endocardium) tissues. Propranolol, TTX, and flecainide decreased Vmax and phase 0 amplitude in a use-dependent manner in both tissues. The effects of propranolol were slow to develop and wash out. TTX and propranolol always abbreviated action potential duration in endocardium. Action potential duration was abbreviated by 23.8 +/- 5.6 msec after propranolol (1 microgram/ml, basic cycle length [BCL] = 1,000 msec) and 10.8 +/- 12.9 msec after TTX (2 microM, BCL = 1,000 msec). In epicardium, the reduction of phase 0 and 1 amplitudes led to a slowing of the second action potential upstroke and an increase in the amplitude of phase 2. This accentuation of the notch resulted in a paradoxical prolongation of the epicardial action potential. Action potential duration was prolonged 34.4 +/- 11.3 msec after 4 hours of exposure to propranolol (1 microgram/ml, BCL = 1,000 msec), 11.1 +/- 6.3 msec after 15 minutes of exposure to TTX (2 microM, BCL = 1,000 msec), and 19.9 +/- 8.2 msec after 25-45 minutes of exposure to flecainide (15 microM, BCL = 500 msec). With stronger sodium block, phase 1 terminated at more negative potentials, the second upstroke often failed to appear, and an all-or-none repolarization ensued causing a marked abbreviation of the epicardial action potential. In some epicardial preparations, we observed marked abbreviation at some sites but prolongation at other sites after sodium blockade with flecainide. The dispersion of repolarization was often attended by reentrant activity. The differential response of epicardium and endocardium to sodium blockade was not observed when the preparations were pretreated with 4-aminopyridine or ryanodine, agents known to diminish the transient outward current and epicardial notch. Acceleration-induced prolongation of refractoriness was observed after sodium blockade in epicardium but not in endocardium. Postrepolarization refractoriness also occurred in epicardium but not in endocardium after TTX, propranolol, or flecainide exposure. The data indicate that propranolol, TTX, and flecainide, via their action to block sodium current, may exert opposite effects on action potential duration and refractoriness in cells spanning the ventricular wall. The presence of the transient outward current in epicardium but not in endocardium appears to contribute importantly to these differences.(ABSTRACT TRUNCATED AT 400 WORDS)
154 citations
TL;DR: The data indicate that EADs, Dads, and triggered activity produced by digitalis and Bay K 8644 are limited to or more readily induced in the deep subepicardial cell layers of the canine ventricle (M cells).
Abstract: Early afterdepolarizations (EADs) are membrane oscillations that interrupt or retard the repolarization phase of the cardiac action potential, whereas delayed afterdepolarizations (DADs) are oscillations that arise after full repolarization. When EADs and DADs are sufficiently large to depolarize the cell membrane to its voltage threshold, they give rise to triggered action potentials, which are believed to underlie some forms of extrasystolic activity and tachyarrhythmias. EAD- and DAD-induced triggered activity have been described and well characterized in isolated Purkinje fibers exposed to a wide variety of drugs, but are rarely seen in syncytial preparations of ventricular myocardium. These results are inconsistent with those of in vivo studies or experiments involving enzymatically dissociated myocytes. In the present study, we used the cardiotonic agent acetylstrophanthidin (AcS) and the calcium channel agonist Bay K 8644 to provide evidence in support of the hypothesis that induction of prominent EADs, DADs, and triggered activity occurs in a select population of cells in ventricular myocardium. The data indicate that EADs, DADs, and triggered activity produced by digitalis and Bay K 8644 are limited to or more readily induced in the deep subepicardial cell layers of the canine ventricle (M cells). Afterdepolarization-induced triggered activity was never observed in the epicardial or endocardial layers.
74 citations
01 Jan 1991
TL;DR: The results indicate that physiologically relevant variability of heart rate can result in electrocardiographic patterns of modulated parasystole in which entrainment of the ectopic pacemaker by the sinus rhythm is not as readily apparent.
Abstract: Modulated Parasystole. A mathematical model of modulated parasystole was used to study the characteristics of entrainment of a ventricular ectopic pacemaker by ventricular activations of sinus nodal origin under conditions of constant and variable heart rate. To mimic physiological fluctuations in heart rate due to sympathetic and parasympathetic influences, the sinus nodal cycle length was modulated by three sinusoidal waves of different frequencies simultaneously (0.025, 0.1, and 0.25 Hz). To simulate the electrotonic influence of ventricular activity on the cycling of the parasystolic pacemaker, the pacemaker was modulated according to biphasic phase-response relationships characterized by an early delay phase and a late acceleration phase. A wide range of intrinsic sinus nodal cycle length to ectopic pacemaker cycle length ratios was examined. Each simulation run consisted of the computation of 1,000 pacemaker firings. Entrainment (periodic firing, sometimes combined with a periodic manifest arrhythmia) was classified into four categories: simple entrainment (periodic pacemaker firing pattern accompanied by a periodic manifest arrhythmia), complex entrainment (similar, but with a periodic manifest arrhythmia covering more than one basic firing pattern), concealed entrainment (periodic firing, no periodic manifest arrhythmia), and no entrainment. The results indicate that physiologically relevant variability of heart rate can result in electrocardiographic patterns of modulated parasystole in which entrainment of the ectopic pacemaker by the sinus rhythm is not as readily apparent. With increased variability of heart rate, simple entrainment may convert into complex, complex into concealed, and concealed entrainment into patterns that show no entrainment at all. The data should aid in our understanding and ability to recognize the various electrocardiographic manifestations of modulated parasystole. (J Cardiovasc Electrophysiol, El. 2, pp. 34-44, February 1991)
4 citations