The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart.

The discovery and characterization of the M cell, a unique cell type residing in the deep layers of the ventricular myocardium, has opened a new door in our understanding of the electrophysiology and pharmacology of the heart in both health and disease. The hallmark of the M cell is the ability of its action potential to prolong much more than that of other ventricular myocardial cells in response to a slowing of rate and/or in response to agents that act to prolong action potential duration. Our goal in this review is to provide a comprehensive characterization of the M cell, its contribution to transmural heterogeneity, and its role in the normal electrical function of the heart, in the inscription of the ECG (particularly the T wave), and in the development of QT dispersion, T wave alternans, long QT intervals, and cardiac arrhythmias, such as torsades de pointes. Our secondary goal is to address the controversy that has arisen relative to the functional importance of the M cell in the normal heart. The controversy derives largely from the failure of some investigators to demonstrate transmural heterogeneity of repolarization in the dog in vivo under control conditions and after administration of quinidine. The inability to demonstrate transmural heterogeneity under these conditions may be due to the use of bipolar recording techniques that, in our experience, seriously underestimate transmural dispersion of repolarization (TDR). The use of sodium pentobarbital and alpha-chloralose as anesthesia also is problematic, because these agents reduce or eliminate TDR by affecting a variety of ion channel currents. Finally, attempts to amplify transmural dispersion of repolarization with an agent such as quinidine must take into account that relatively high concentrations can result in effects opposite to those desired due to drug inhibition of multiple ion channels. These observations may explain the inability of earlier studies to detect the M cell.

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

Chronic amiodarone reduces transmural dispersion of repolarization in the canine heart.

INTRODUCTION: Amiodarone is a potent antiarrhythmic agent used in the management of both atrial and ventricular arrhythmias. In addition to its beta-blocking properties, amiodarone is known to block the sodium, potassium, and calcium channels in the heart. Its complex electropharmacology notwithstanding, the reasons for the high efficacy of the drug remain unclear. Also not well understood is the basis for the low incidence of proarrhythmia seen with amiodarone relative to other agents with Class III actions. The present study was designed to examine the effects of chronic amiodarone in epicardial, endocardial, and M cells of the canine left ventricle. METHODS AND RESULTS: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle. Tissues were obtained from mongrel dogs receiving amiodarone orally (30 to 40 mg/kg per day) for 30 to 45 days or from untreated controls. Chronic amiodarone produced a greater prolongation of action potential duration in epicardium and endocardium, but less of an increase, or even a decrease at slow rates, in the M region, thereby reducing transmural dispersion of repolarization. In addition, chronic amiodarone therapy suppressed the ability of the IKr blocker, d-sotalol, to induce a marked dispersion of repolarization or early afterdepolarization activity. CONCLUSION: Our data demonstrate for the first time a direct effect of chronic amiodarone treatment to differentially alter the cellular electrophysiology of ventricular myocardium so as to produce an important decrease in transmural dispersion of repolarization, especially under conditions in which dispersion is exaggerated. These results may contribute to our understanding of the effectiveness of amiodarone in the treatment of life-threatening arrhythmias as well as to our understanding of the low incidence of proarrhythmia attending therapy with chronic amiodarone in comparison with other Class III agents.

Effects of sodium channel block with mexiletine to reverse action potential prolongation in in vitro models of the long term QT syndrome.

INTRODUCTION: Recent clinical studies have reported a greater effectiveness of sodium channel block with mexiletine to abbreviate the QT interval in patients with the chromosome 3 variant (SCN5A, LQT3) of the long QT syndrome (LQTS) than those with the chromosome 7 form of the disease (HERG, LQT2), suggesting the possibility of gene-specific therapy for the two distinct forms of the congenital LQTS. Experimental studies using the arterially perfused left ventricular wedge preparation have confirmed these clinical observations on the QT interval but have gone on to further demonstrate a potent effect of mexiletine to reduce dispersion of repolarization and prevent torsades de pointes (TdP) in both LQT2 and LQT3 models. A differential action of sodium channel block on the three ventricular cell types is thought to mediate these actions of mexiletine. This study provides a test of this hypothesis by examining the effects of mexiletine in isolated canine ventricular epicardial, endocardial, and M region tissues under conditions that mimic the SCN5A and HERG gene defects. METHODS AND RESULTS: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle. d-Sotalol, an IKr blocker, was used to mimic the HERG defect (LQT2), and ATX-II, which increases late Na channel current, was used to mimic the SCN5A defect (LQT3). d-Sotalol (100 microM) preferentially prolonged the action potential of the mid-myocardial M cell (APD90 increased from 340 +/- 65 to 623 +/- 203 msec) as did ATX-II (10 to 20 nM; APD90 increased from 325 +/- 51 to 580 +/- 178 msec; basic cycle length = 2000 msec), thus causing a marked increase in transmural dispersion of repolarization (TDR). Mexiletine (2 to 20 microM) dose-dependently reversed the ATX-II-induced prolongation of APD90 in all three cell types. Mexiletine also reversed the d-sotalol-induced prolongation of the M cell action potential duration (APD), but had little effect on the action potential of epicardium and endocardium. Due to its preferential effect to abbreviate the action potential of M cells, mexiletine reduced the dispersion of repolarization in both models. Low concentrations of mexiletine (5 to 10 microM) totally suppressed early afterdepolarization (EAD) and EAD-induced triggered activity in both models. CONCLUSIONS: Our results indicate that the actions of mexiletine are both cell and model specific, but that sodium channel block with mexiletine is effective in reducing transmural differences in APD and in abolishing triggered activity induced by d-sotalol and ATX-II. The data suggest that mexiletine's actions to reduce TDR and prevent the induction of spontaneous and programmed stimulation-induced TdP in these models are due to a preferential effect of the drug to abbreviate the APD of the M cell and to suppress the development of EADs. The data provide further support for the hypothesis that block of the late sodium current may be of value in the treatment of LQT2 as well as LQT3 and perhaps other congenital and acquired (drug-induced) forms of LQTS.

d-Sotalol Induces Marked Action Potential Prolongation and Early Afterdepolarizations in M but Not Empirical or Endocardial Cells of the Canine Ventricle.

BACKGROUND: Despite its class III antiarrhythmic actions, experimental and clinical studies have shown that d-sotalol can also be proarrhythmic; a recent clinical trial that evaluated d-sotalol in postmyocardial patients (SWORD) had to be prematurely interrupted because of the excess mortality in the treated group. Previous studies have demonstrated the existence of a marked heterogeneity across the ventricular wall; epicardial, endocardial, and M cells have been shown to display distinct electrophysiologic characteristics and pharmacologic behavior. The present study was designed to test the hypothesis that M cells are the primary target for the class III actions of d-sotalol in canine ventricular myocardium and may contribute to its proarrhythmic effects. METHODS AND RESULTS: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, midmyocardial, and transmural strips, isolated from the canine left ventricle. d-Sotalol (100 µM, 60 minutes of exposure, [K(+)]o = 4 mM) prolongs the action potential in the three cell types, but more so in M than epicardial or endocardial cells, especially at the slower rates. At a basic cycle length of 2000 ms, action potential duration after 90% repolarization increases from 199 +/- 20 to 247.5 +/- 28 ms in epicardium (n = 10), from 212 +/- 26 to 274 +/- 27 ms in endocardium (n = 11), and from 309 +/- 65 to 533 +/- 207 ms in M cells (n = 13). d-Sotalol produces a marked steepening of action potential duration-rate relationships of M cells and an upward shift of restitution of action potential duration curves, more accentuated in M cells. Early afterdepolarizations were observed at slow rates (basic cycle lengths > 1000 ms) in 7 of 13 M cell preparation s(54%) but not in endocardial or epicardial preparations. A sudden acceleration of the rate could also induce a transient prolongation of the action potential and early afterdepolarization activity. CONCLUSION: In canine ventricular tissues, d-sotalol manifests its class III effects preferentially in the M cells, leading to the development of early afterdepolarizations and a marked increase in transmural dispersion of repolarization. The data suggest an important role of M cells in the proarrhythmic effects of the drug.

Evidence for the presence of M cells in the guinea pig ventricle.

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. METHODS AND RESULTS: We used a dermatome to obtain-thin strips of left ventricular free wall from the hearts of guinea pigs (8 to 14 weeks old) and standard microelectrode techniques to record transmembrane activity. Action potential duration measured at 90% repolarization (APD90) was significantly longer in mid-myocardial (MID) cells than in surface EPI or ENDO cells at all basic cycle lengths (BCLs) tested. At a BCL of 300 msec, APD90 was 102 +/- 21,136 +/- 9, and 95 +/- 15 msec in EPI, MID, and ENDO cells (mean +/- SD; n = 12). At a BCL of 5000 msec, APD90 was 133 +/- 14, 185 +/- 24, and 135 +/- 13 msec in EPI, MID, and ENDO cells ([K+]o = 4 mM). Thus, APD-rate relations were more pronounced in the MID cells. MID cells were also more sensitive to agents with Class III actions (e.g., d,I-sotalol: 10 to 100 microM), exhibiting a greater APD prolongation than EPI or ENDO. d,I-Sotalol also induced early afterdepolarizations in MID cells but not in EPI or ENDO cells. The rate of rise of the action potential upstroke (Vmax) was significantly greater in MID cells: 129 +/- 13, 240 +/- 42, and 192 +/- 28 V/sec in EPI, MID, and ENDO cells (n = 10 to 18). CONCLUSION: Our results demonstrate the existence of important transmural electrical heterogeneity in guinea pig ventricular myocardium. The study provides data in support of the existence of M cells in the mid-myocardial layers of the guinea pig ventricle exhibiting longer APDs and a greater sensitivity to agents with Class III antiarrhythmic action.

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

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+]o. METHODS AND RESULTS: We used standard microelectrode techniques to record transmembrane activity from deep subepicardial or transmural strips isolated from the canine left ventricular free wall near the base as well as subendocardial Purkinje fibers. M cells behavior (steep APD-rate relation) was observed at depths of 1 to 7 mm from the epicardial surface (deep subepicardium to mid-myocardium). M cells were found to be distributed uniformly in the deep subepicardium and did not appear in discrete bundles. We observed transitional behavior throughout the wall. The maximum rate of rise of the action potential upstroke, Vmax, increased sharply between epicardium and deep subepicardium (176 +/- 13 to 332 +/- 61 V/sec), remained high throughout the mid-myocardium and deep subendocardium, and returned to lower values only in the superficial layers of the endocardium (205 +/- 21 V/sec). The relationship between Vmax and takeoff potential in the M cell was fit by a Boltzmann equation with a V0.5 of -68.6 +/- 1.5 mV and k of 3.4 +/- 0.5. The relationship between resting membrane potential (RMP) and [K+]o in the M cell was exponential from 8 to 20 mmol/L (58 mV change in RMP per 10-fold change in [K+]o), deviating from K+ electrode behavior at [K+]o < 8 mmol/L. RMP in M cells continued to hyperpolarize at [K+]o < 2.5 mmol/L, reaching potentials of approximately -110 mV at [K+]o of 1 mmol/L. In contrast, subendocardial Purkinje fibers depolarized at these low levels of [K+]o. Unlike endocardium and epicardium, M cells developed early afterdepolarizations at low [K+]o and slow rates. CONCLUSIONS: Our data indicate that the M cells are widely distributed in the intramural layers of the canine left ventricular free wall. M cells and transitional cells occupy 30% to 40% of the left ventricular wall and an estimated 20% to 40% of the mass of the ventricles of the normal canine heart. They display characteristics common to both myocardial and specialized conducting cells. Like Purkinje fibers, M cells exhibit a relatively large Vmax and steep APD-rate relations that are modulated by [K+]o. Unlike Purkinje fibers, M cells do not appear in bundles, they do not depolarize at [K+]o < 2.5 mmol/L, nor do they exhibit phase 4 depolarization.

Distribution of M cells in the canine ventricle.

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 for 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. METHODS AND RESULTS: Action potentials recorded from the M region (deep subepicardium) displayed similar characteristics (steep action potential duration [APD]-rate relations) in the base and apex. However, important differences were apparent in the other regions. In epicardium, the spike and dome morphology of the action potential was less accentuated and the rate dependence of APD more pronounced in the apex versus the base. In endocardium, and especially deep subendocardium, rate dependence of APD was considerably more pronounced in the apex. Transmembrane recordings from the subsurface layers of the septum, trabeculae, and papillary muscles revealed M cell behavior (steep APD-rate relations) in the deep subendocardium. Epicardial and transitional behavior were also observed in the deep layers of these endocardial structures. CONCLUSION: Our results indicate that M cells reside throughout the deep subepicardial layers of the free wall of the canine left ventricle as well as in the deep subendocardial layers of the septum, papillary muscles, and trabeculae. The data also demonstrate prominent transmural as well as apicobasal gradients of phase 1 and phase 3 repolarization. These findings may have implications relative to our understanding of the electrocardiographic J wave, T wave, U wave, and long QTU intervals.

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.

Drug-induced afterdepolarizations and triggered activity occur in a discrete subpopulation of ventricular muscle cells (M cells) in the canine heart: quinidine and digitalis.

INTRODUCTION: Oscillations of membrane potential that attend or follow the cardiac action potential and depend on preceding transmembrane activity for their manifestation are known as afterdepolarizations. Early afterdepolarizations (EADs) interrupt or retard repolarization of the cardiac action potential, whereas delayed afterdepolarizations (DADs) arise after full repolarization. EADs and DADs can give rise to spontaneous action potentials or triggered activity believed to be responsible for a variety of cardiac arrhythmias. Recent studies from our laboratory have highlighted differences in the electrophysiology and pharmacology of three functionally distinct myocardial cell types found in the canine ventricle. Epicardial, M region, and endocardial tissues and cells show distinct, sometimes opposite, responses to a variety of drugs, including those capable of inducing EADs and DADs. METHODS AND RESULTS: In the present study, we used standard microelectrode techniques to examine the pharmacologic response of these cellular subtypes to therapeutic levels of quinidine and toxic levels of digitalis. Quinidine readily produced prominent EADs and EAD-induced triggered activity in tissue preparations from the M region (deep subepicardium), but not in those from epicardium, endocardium, or deep subendocardium of the canine ventricle. Acetylstrophanthidin produced prominent DADs in M cell preparations and subendocardial Purkinje fibers but only minute DADs, if any, in epicardium, endocardium, or deep subendocardium. DAD-induced triggered activity was observed to arise only in Purkinje and M cells and never in myocardial tissues from the epicardial, endocardial, or deep subendocardial regions of the ventricular wall. CONCLUSION: We conclude that EADs, DADs, and triggered activity caused by therapeutic levels of quinidine and toxic levels of digitalis are limited to or much more readily induced in a select population of cells in the deep subepicardial (M cell) region of the canine ventricle in addition to the Purkinje system of the heart.

Afterdepolarizations and triggered activity develop in a select population of cells (M cells) in canine ventricular myocardium: the effects of acetylstrophanthidin and Bay K 8644.

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.

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.

Electrical uncoupling and impulse propagation in isolated sheep Purkinje fibers.

Alterations in electrical coupling may have a major role in the development of cardiac rhythm and conduction disturbances. We have used microelectrodes and linear Purkinje fibers to analyze the relative importance of cell-to-cell coupling on action potential propagation and to study the changes in the relationship between conduction velocity (theta) and upstroke velocity (Vmax) induced by three agents (heptanol, hypertonic solution, and ouabain) known to alter gap junction resistance. Heptanol superfusion (1.5-3.0 mM) reversibly led to a major decrease in theta and ultimately to block at a time when Vmax had been reduced by approximately 38%. Conduction delay was closely correlated with an increase in intracellular resistance (Ri), calculated as the sum of myoplasmic and junctional resistances, assuming a one-dimensional cable model. Qualitatively similar results were obtained by superfusion with 0.1-0.5 mM ouabain or hypertonic Tyrode solution (up to 600 mM sucrose added) instead of heptanol. In contrast, when the Vmax vs. theta relationship was studied by changing the KCl from 4 to 20 mM, decreases in Vmax correlated well with changes in theta. No significant effects on Ri were observed during KCl superfusion. Finally, we developed a computer model of action potential propagation along a one-dimensional strand of 90 electrically coupled heart cells. By changing systematically the degree of electrical coupling or the maximum sodium conductance in the model and by studying the effects of these changes on propagation and Vmax, we obtained strong evidence supporting the validity of our experimental results. The overall data provide testable predictions regarding the role of electrical uncoupling on abnormal impulse propagation.

Modulated parasystole as a mechanism of ventricular ectopic activity leading to ventricular fibrillation.

The electrocardiograms of 2 patients with frequent premature ventricular complexes characterized by variable coupling intervals and fusions with sinus activations were analyzed according to the modulated parasystole and reflection hypotheses of Moe et al. In addition, the ectopic activity was associated with couplets, tachycardia and ventricular fibrillation. Departures from the "classic" criteria of parasystole could not be explained satisfactorily if a completely protected (insulated) pacemaker was assumed. In each instance a triphasic response curve could be constructed, suggesting that modulated parasystole was the mechanism common to both patients. Couplets and runs of ventricular tachycardia were ascribed to single and repetitive reflection, respectively, in the presence of supernormal excitability of the ectopic pacemaker, the ventricle or both. In these patients, fibrillation probably resulted from spatial nonuniformity of the ventricular response to the reflected event during a phase of vulnerability. This study suggests that modulated parasystole in the presence of supernormal excitability may lead to very severe arrhythmias and trigger ventricular fibrillation. In the clinical setting, such patients may be misdiagnosed because of atypical features.

Chronic idiopathic idioventricular tachycardia caused by slow response automaticity.

A 22-year-old female, asymptomatic and without any evidence of cardiac disease, was found to have a persistent idioventricular tachycardia (IVT). Sinus rhythm and IVT rates were similar and showed parallel changes in successive resting electrocardiograms. Both IVT and sinus rhythm were transiently slowed or suppressed by vagal stimulation and accelerated by sympathetic stimulation. Long periods of atrial overdrive pacing, at a rate 62% faster than the spontaneous rate of IVT, depressed both ectopic and sinus activity. Fast channel blocking agents (lidocaine, disopyramide), and digoxin and amiodarone failed to modify IVT significantly. Verapamil, a calcium channel blocking drug, allowed total control of the arrhythmia. These electrophysiologic and pharmacologic responses suggest that the IVT may relate to the automatic activity of a ventricular focus of the "slow response" type, functionally resembling an "additional" sinus node with preserved innervation. During an 88-month follow-up, the patient continued to be asymptomatic, warning arrhythmias were never found and the features of IVT remained unmodified.