Serge Sicouri

Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells.

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-

Clinical relevance of cardiac arrhythmias generated by afterdepolarizations : role of M cells in the generation of U waves, triggered activity and torsade de pointes

Recent findings point to an important heterogeneity in the electrical behavior of cells spanning the ventricular wall as well as important differences in the response of the various cell types to cardioactive drugs and pathophysiologic states. These observations have permitted a fine tuning and, in some cases, a reevaluation of basic concepts of arrhythmia mechanisms. This brief review examines the implications of some of these new findings within the scope of what is already known about early and delayed afterdepolarizations and triggered activity and discusses the possible relevance of these mechanisms to clinical arrhythmias.

A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle : The M cell.

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.

Cellular basis for QT dispersion

The cellular basis for the dispersion of the QT interval recorded at the body surface is incompletely understood. Contributing to QT dispersion are heterogeneities of repolarization time in the three-dimensional structure of the ventricular myocardium, which are secondary to regional differences in action potential duration (APD) and activation time. While differences in APD occur along the apicobasal and anteroposterior axes in both epicardium and endocardium of many species, transitions are usually gradual. Recent studies have also demonstrated important APD gradients along the transmural axis. Because transmural heterogeneities in repolarization time are more abrupt than those recorded along the surfaces of the heart, they may represent a more onerous substrate for the development of arrhythmias, and their quantitation may provide a valuable tool for evaluation of arrhythmia risk. Our data, derived from the arterially perfused canine left ventricular wedge preparation, suggest that transmural gradients of voltage during repolarization contribute importantly to the inscription of the T wave. The start of the T wave is caused by a more rapid decline of the plateau, or phase 2 of the epicardial action potential, creating a voltage gradient across the wall. The gradient increases as the epicardial action potential continues to repolarize, reaching a maximum with full repolarization of epicardium; this juncture marks the peak of the T wave. The next region to repolarize is endocardium, giving rise to the initial descending limb of the upright T wave. The last region to repolarize is the M region, contributing to the final segment of the T wave. Full repolarization of the M region marks the end of the T wave. The time interval between the peak and the end of the T wave therefore represents the transmural dispersion of repolarization. Conditions known to augment QTc dispersion, including acquired long QT syndrome (class IA or III antiarrhythmics) lead to augmentation of transmural dispersion of repolarization in the wedge, due to a preferential effect of the drugs to prolong the M cell action potential. Antiarrhythmic agents known to diminish QTc dispersion, such as amiodarone, also diminish transmural dispersion of repolarization in the wedge by causing a preferential prolongation of APD in epicardium and endocardium. While exaggerated transmural heterogeneity clearly can provide the substrate for reentry, a precipitating event in the form of a premature beat that penetrates the vulnerable window is usually required to initiate the reentrant arrhythmia. In long QT syndrome, the trigger is thought to be an early afterdepolarization (EAD)-induced triggered beat. The likelihood of developing EADs and triggered activity is increased when repolarizing forces are diminished, making for a slower and more gradual repolarization of phases 2 and 3 of the action potential, which translates into broad, low amplitude and sometimes bifurcated T waves in the electrocardiogram. Our findings suggest that regional differences in the duration of the M cell action potential may be the basis for QT dispersion measured at the body surface under normal and long QT conditions. The data indicate that the interval delimited by the peak and the end of the T wave represents an accurate measure of regional dispersion of repolarization across the ventricular wall and as such may be a valuable index for assessment of arrhythmic risk. The presence of low amplitude, broad and/or bifurcated T waves, particularly under conditions of long QT syndrome, is indicative of diminished repolarizing forces and may represent an independent variable of arrhythmic risk, forecasting the development of EAD-induced triggered beats that can precipitate torsade de pointes. Although the QT interval, QT dispersion, the T wave peak-to-end interval, and the width and amplitude of the T wave often change in parallel, they contain different information and should not be expected to be e

Electrophysiologic basis for the antiarrhythmic actions of ranolazine

Ranolazine is a Food and Drug Administration-approved antianginal agent. Experimental and clinical studies have shown that ranolazine has antiarrhythmic effects in both ventricles and atria. In the ventricles, ranolazine can suppress arrhythmias associated with acute coronary syndrome, long QT syndrome, heart failure, ischemia, and reperfusion. In atria, ranolazine effectively suppresses atrial tachyarrhythmias and atrial fibrillation (AF). Recent studies have shown that the drug may be effective and safe in suppressing AF when used as a pill-in-the pocket approach, even in patients with structurally compromised hearts, warranting further study. The principal mechanism underlying ranolazines antiarrhythmic actions is thought to be primarily via inhibition of late I(Na) in the ventricles and via use-dependent inhibition of peak I(Na) and I(Kr) in the atria. Short- and long-term safety of ranolazine has been demonstrated in the clinic, even in patients with structural heart disease. This review summarizes the available data regarding the electrophysiologic actions and antiarrhythmic properties of ranolazine in preclinical and clinical studies.

Distribution of M Cells in the Canine Ventricle

Distribution of M Cells. Introduction: M cells and transitional cells residing in the deep structures of the ventricular free walls are distinguished by the ability of their action potentials to prolong disproportionately to those of other ventricular cells at relatively slow rates. This feature of the M cell due, at least in part, to a smaller contribution of the slowly activating component of the delayed rectifier current (Iks) is thought to contribute to the unique pharmacologic responsiveness of M cells, making them the primary targets in ventricular myocardium lor agents that cause action potential prolongation and induce early and delayed afterdepolarizations and triggered activity. Previous studies dealt exclusively with the characteristics and distribution of M cells in the canine right and left ventricular free wall near the base of the ventricles. The present study uses standard microelectrode techniques to define their behavior and distribution in the apical region of the ventricular wall as well as in the endocardial structures of the ventricle, including the interventricular septum, papillary muscles, and trabeculae.

Antiarrhythmic effects of ranolazine in canine pulmonary vein sleeve preparations

BACKGROUND Ectopic activity arising from the pulmonary veins (PV) plays a prominent role in the development of atrial fibrillation (AF). OBJECTIVE This study sought to determine the electrophysiological effects of ranolazine in canine PV sleeve preparations. METHODS Transmembrane action potentials were recorded from canine superfused left superior or inferior PV sleeves using standard microelectrode techniques. Acetylcholine (ACh, 1 microM), isoproterenol (1 microM), high calcium ([Ca(2+)](o) = 5.4 mM) or a combination was used to induce early or delayed afterdepolarizations (EADs or DADs) and triggered activity. RESULTS Ranolazine (10 microM) significantly accentuated use-dependent depression of maximal rate of increase of action potential upstroke (V(max)). Reducing basic cycle length (BCL) from 2000 to 200 ms resulted in a decrease of V(max) from 279 +/- 58 to 146 +/- 23 V/s (47.7%) in control subjects and from 241 +/- 71 to 72 +/- 63 V/s (70.2%) after 10 microM ranolazine (n = 4, P <.05). Ranolazine slightly abbreviated action potential duration, but induced significant rate-dependent prolongation of effective refractory period due to development of postrepolarization refractoriness (n = 6, P <.05). Ranolazine (10 microM) caused loss of excitability resulting in 2:1 activation failure at BCLs <or= 200 ms (n = 3) and suppressed late phase 3 EADs, DADs, and triggered activity elicited by exposure of the PV sleeves to Ach + isoproterenol, or high [Ca(2+)](o) + rapid pacing (n = 11). CONCLUSION Ranolazine causes marked use-dependent inhibition of sodium channel activity leading to prolongation of effective refractory period, conduction slowing, and block as well as suppression of late phase 3 EAD and DAD-mediated triggered activity in canine PV sleeves. Our data suggest that ranolazine may be useful in suppressing AF triggers arising from the PV sleeves.

Synergistic Effect of the Combination of Ranolazine and Dronedarone to Suppress Atrial Fibrillation

OBJECTIVES The aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF). BACKGROUND Safe and effective pharmacological management of AF remains one of the greatest unmet medical needs. METHODS The electrophysiological effects of dronedarone (10 μmol/l) and a relatively low concentration of ranolazine (5 μmol/l) separately and in combination were evaluated in canine isolated coronary-perfused right and left atrial and left ventricular preparations as well as in pulmonary vein preparations. RESULTS Ranolazine caused moderate atrial-selective prolongation of action potential duration and atrial-selective depression of sodium channel-mediated parameters, including maximal rate of rise of the action potential upstroke, leading to the development of atrial-specific post-repolarization refractoriness. Dronedarone caused little or no change in electrophysiological parameters in both atrial and ventricular preparations. The combination of dronedarone and ranolazine caused little change in action potential duration in either chamber but induced potent use-dependent atrial-selective depression of the sodium channel-mediated parameters (maximal rate of rise of the action potential upstroke, diastolic threshold of excitation, and the shortest cycle length permitting a 1:1 response) and considerable post-repolarization refractoriness. Separately, dronedarone or a low concentration of ranolazine prevented the induction of AF in 17% and 29% of preparations, respectively. In combination, the 2 drugs suppressed AF and triggered activity and prevented the induction of AF in 9 of 10 preparations (90%). CONCLUSIONS Low concentrations of ranolazine and dronedarone produce relatively weak electrophysiological effects and weak suppression of AF when used separately but when combined exert potent synergistic effects, resulting in atrial-selective depression of sodium channel-dependent parameters and effective suppression of AF.

Evidence for the Presence of M Cells in the Guinea Pig Ventricle

M Cells in the Guinea Pig. Introduction: Recent studies have described the presence of M cells in the deep layers of the canine and human ventricle displaying electrophysiologic and pharmacologic features different from those of epicardial (EPI) and endocardial (ENDO) cells. The M cell is distinguished electrophysiologically by the ability of its action potential to prolong disproportionately to that of other myocardial cells with slowing of the stimulation rate and pharmacologically by its unique sensitivity to Class III antiarrhythmic agents. The present study was designed to test the hypothesis that similar cells are present in the guinea pig ventricle.

Electrophysiologic characteristics of M cells in the canine left ventricular free wall.

Characteristics of M Cells. Introduction: Recent studies have described the existence of M cells in the deep structures of the canine and human ventricle. The present study was designed to further characterize the M cell with respect to its distribution across the canine left ventricular free wall and the dependence of its action potential on [K+]0.