The enigmatic ECG manifestation of Brugada syndrome.
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Adult↗
Biomedical subjects
C Antzelevitch
Publications and source records attributed to C Antzelevitch.
Sodium channel block with mexiletine is effective in reducing dispersion of repolarization and preventing torsade des pointes in LQT2 and LQT3 models of the long-QT syndrome.
BACKGROUND: This study examines the contribution of transmural heterogeneity of transmembrane activity to phenotypic T-wave patterns and the effects of pacing and of sodium channel block under conditions mimicking HERG and SCN5A defects linked to the congenital long-QT syndrome (LQTS). METHODS AND RESULTS: A transmural ECG and transmembrane action potentials from epicardial, M, and endocardial or Purkinje cells were simultaneously recorded in an arterially perfused wedge of canine left ventricle. d-Sotalol was used to mimic LQT2, whereas ATX-II mimicked LQT3. d-Sotalol caused a preferential prolongation of the M cell action potential duration (APD90, 291+/-14 to 354+/-35 ms), giving rise to broad and sometimes low-amplitude bifurcated T waves and an increased transmural dispersion of repolarization (TDR, 51+/-15 to 72+/-17 ms). QT interval increased from 320+/-13 to 385+/-37 ms. ATX-II produced a preferential prolongation of the M cell APD90 (280+/-25 to 609+/-49 ms) and caused a marked delay in the onset of the T wave and a sharp rise in TDR (40+/-5 to 168+/-40 ms). QT-, APD90-, and dispersion-rate relations were much steeper in the ATX-II than in the d-sotalol model. Mexiletine (2 to 20 micromol/L) dose-dependently abbreviated the QT interval and APD90 of all cell types, more in the ATX-II than in the d-sotalol model, but decreased TDR equally in the two models. Mexiletine 2 to 5 micromol/L totally suppressed spontaneous torsade de pointes (TdP) and reduced the vulnerable window during which single extrastimuli could induce TdP in both models. Higher concentrations of mexiletine (10 to 20 micromol/L) totally suppressed stimulation-induced TdP. CONCLUSIONS: Our results suggest that although pacing and sodium channel block are very effective in abbreviating the QT interval and TDR in LQT3, these therapeutic approaches may also be valuable in reducing the incidence of arrhythmogenesis in LQT2.
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Are M cells present in the ventricular myocardium of the pig? A question of maturity.
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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.
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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.
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Sodium effects on 4-aminopyridine-sensitive transient outward current in canine ventricular cells.
Tetrodotoxin (TTX) or substitution of external Na+ reduces the 4-aminopyridine-sensitive transient outward current (Ito1) in rat ventricular myocytes. We investigated the outcome of reducing external sodium on the kinetics, gating, and selectivity of Ito1 with a dual-patch electrode technique to record whole cell currents and transmembrane potentials independently of the voltage clamp in canine midmyocardial cells. Steps from -80 to 0 mV produced overlapping inward sodium and outward potassium currents, accompanied by a loss of voltage control associated with activation of INa. Substitution of external Na+ or application of TTX abolished INa, restored voltage control, and reduced Ito1. Inactivation of INa with a 10-ms prestep to -45 mV decreased Ito1 to the same extent as external Na+ substitution. The kinetics, gating, and selectivity of Ito1 recorded after inactivation of INa were unaffected by drastic reductions in external Na+. Our findings suggest that a larger Ito1 in the presence of normal external Na+ is due to 1) transient loss of voltage control and concomitant changes in activation of Ito1 and/or 2) facilitation of an outward current by intracellular Na+. We conclude that reduction of external sodium has no direct effect on the kinetics or gating of Ito1, non does Na+ contribute to current flow through Ito1 channels in canine midmyocardial cells.
4-Aminopyridine↗
Cellular basis for the electrocardiographic J wave.
BACKGROUND: The J wave is a deflection that appears in the ECG as a late delta wave following the QRS or as a small secondary R wave (R'). Also referred to as an Osborn wave, the J wave has been observed in the ECG of animals and humans for more than four decades, yet the mechanism underlying its manifestation is poorly understood. The present study investigates the cellular basis for the J wave using an isolated arterially perfused preparation consisting of a wedge of canine right or left ventricle. METHODS AND RESULTS: A 12-lead ECG was initially recorded in vivo. After isolation and arterial perfusion of the right or left ventricular wedge, transmembrane action potentials were simultaneously recorded from epicardial, M region, and endocardial transmural sites with three floating microelectrodes. A transmural ECG was recorded concurrently. A J wave was observed at the R-ST junction of the ECG in 17 of 20 adult dogs, usually in leads II, III, aVR, and aVF and the mid to lateral precordial leads. The J wave in the transmural ECG recorded across the wedge was closely associated with the presence of a prominent action potential notch in epicardium but not endocardium. The shape and amplitude of the J wave were found to depend on (1) the transmural distribution of the action potential notch amplitude, (2) the relative time course of the early phases of the action potential (width of notch) at different sites within the wall, (3) sequence of activation, and (4) conduction time across the wall. A highly significant correlation was demonstrated between the amplitude of the epicardial action potential notch and the amplitude of the J wave recorded during interventions that alter the appearance of the electrocardiographic J wave, including hypothermia, premature stimulation, and block of the transient outward current by 4-aminopyridine. Ventricular activation from endocardium to epicardium, with epicardium activated last, was also an important prerequisite for the appearance of the J wave. This sequence permits the establishment of a voltage gradient of the early phases of the action potential after activation (ie, the QRS) is complete. CONCLUSIONS: Our results provide the first direct evidence in support of the hypothesis that heterogeneous distribution of a transient outward current-mediated spike-and-dome morphology of the action potential across the ventricular wall underlies the manifestation of the electrocardiographic J wave. The presence of a prominent action potential notch in epicardium but not endocardium is shown to provide a voltage gradient that manifests as a J (Osborn) wave or elevated J-point in the ECG.
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Cellular and ionic mechanisms underlying erythromycin-induced long QT intervals and torsade de pointes.
OBJECTIVES: This study sought to elucidate the cellular and ionic basts for erythromycin-induced long QT syndrome. BACKGROUND: Erythromycin is known to produce long QTU intervals on the electrocardiogram (ECG) and to be associated with the development of torsade de pointes (TdP). The mechanisms responsible for the adverse effects of this widely used antibiotic are not well defined. METHODS: The present study used microelectrode and whole-cell patch-clamp techniques to assess the effects of erythromycin on epicardial, endocardial and M cells in transmural strips, arterially perfused wedges and single myocytes isolated from the canine left ventricle. RESULTS: In isolated strips, erythromycin (10 to 100 micrograms/ml) produced a much more pronounced prolongation of the action potential duration (APD) in M cells than in endocardial and epicardial cells, resulting in the development of a large dispersion of repolarization across the ventricular wall at slow stimulation rates. Erythromycin (50 to 100 micrograms/ml) induced early after depolarizations (EADs) in cells in the M (20%) but not epicardial or endocardial regions in transmural strips of ventricular free wall. Erythromycin (100 micrograms/ml) also caused APD prolongation and a transmural dispersion of repolarization, but not EADs, in intact arterially perfused wedges of canine left ventricle. These changes were attended by the development of a long QT interval on the transmural ECG. A polymorphic ventricular tachycardia closely resembling TdP was readily and reproducibly induced after erythromycin but not before. Whole-cell patch-clamp techniques, used to examine the effects of erythromycin on myocytes isolated from the M region, showed a potent effect of the drug to inhibit the rapidly activating component (IK(r)) but not the slowly activating component (IKs) of the delayed rectifier potassium current (IK). The inward rectifier current (IK1) was unaffected. CONCLUSIONS: Our data demonstrate a preferential response of M cells to the class III actions of erythromycin, due principally to the effect of the drug to inhibit IK(r) in a population of cells largely devoid of IKs. Our findings indicate that erythromycin thus produces long QT intervals as well as a prominent dispersion of repolarization across the ventricular wall, setting the stage for induction of TdP-like tachyarrhythmias displaying characteristics typical of reentry.
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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.
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I(to) and action potential notch are smaller in left vs. right canine ventricular epicardium.
Transmural heterogeneities of repolarizing currents underlie prominent differences in the electrophysiology and pharmacology of ventricular epicardial, endocardial, and M cells in a number of species. The degree to which heterogeneities exist between the right and left ventricles is not well appreciated. The present study uses standard microelectrode and whole cell patch-clamp techniques to contrast the electrophysiological characteristics and pharmacological responsiveness of tissues and myocytes isolated from right (RVE) and left canine ventricular epicardium (LVE). RVE and LVE studied under nearly identical conditions displayed major differences in the early repolarizing phases of the action potential. The magnitude of phase 1 in RVE was nearly threefold that in LVE: 28.7 +/- 6.2 vs. 10.6 +/- 4.1 mV (basic cycle length = 2,000 ms). Phase 1 in RVE was also more sensitive to alterations of the stimulation rate and to 4-aminopyridine (4-AP), suggesting a much greater contribution of the transient outward current (I(to) 1) in RVE than in LVE. The combination of 4-AP plus ryanodine, low chloride, or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (chloride channel blocker) completely eliminated the notch and all rate dependence of the early phases of the action potential, making RVE and LVE indistinguishable. At +70 mV, RVE myocytes displayed peak I(to) 1 densities between 28 and 37 pA/pF. LVE myocytes included cells with similar I(to) 1 densities (thought to represent subsurface cells) but also cells with much smaller current levels (thought to represent surface cells). Average peak I(to) 1 density was significantly smaller in LVE than in RVE at voltages more than or equal to +10 mV. Our data point to prominent differences in the magnitude of the I(to) 1-mediated action potential notch in cells at the surface of RVE compared with the LVE and suggest that important distinctions may exist in the response of these two tissues to pharmacological agents and pathophysiological states, as previously demonstrated for epicardium and endocardium. Our findings also suggest that a calcium-activated outward current contributes to the early repolarization phase in RVE and LVE and that the influence of this current, although small, is more important in the left ventricle.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Phase 2 reentry as a mechanism of initiation of circus movement reentry in canine epicardium exposed to simulated ischemia.
OBJECTIVES: Myocardial ischemia results in an early phase of arrhythmias that primarily involves reentrant mechanisms. However, the trigger that initiates reentry remains unknown. We studied the initiation of reentry attending the development of electrical heterogeneity during simulated ischemia in isolated canine right ventricular subepicardium. METHODS: Preparations consisted of thin epicardial sheets in which action potentials were recorded at 4 sites with intracellular microelectrodes. Tissues were superfused with a hyperkalemic, hypoxic and acidotic 'ischemic' solution. RESULTS: Simulated ischemia produced a 40-70% abbreviation of the action potential at some epicardial sites but not others, primarily by suppressing development of the action potential plateau (or dome). This typically created a marked dispersion of repolarization within the preparation. Local re-excitation ensued when the action potential dome propagated from sites where it was maintained to sites where it was abolished. This mechanism, termed 'phase 2 reentry', produced an extrasystole which then initiated one or more cycles of circus movement reentry. Tachycardias consisting of repetitive reentry occurred in larger tissues. The window for reentry occurred over a range of stimulation rates that shifted to faster rates as ischemia progressed. The transient outward current blocker, 4-aminopyridine, restored the dome at all sites by reversing the ischemia-induced abbreviation of the action potential. Thus, block of the transient outward current restored electrical homogeneity and abolished all reentrant activity within the epicardial preparations. CONCLUSION: Our results implicate phase 2 reentry as a new mechanism for genesis of extrasystoles during simulated ischemia and identify this mechanism as a trigger of circus movement reentry. Validation of this hypothesis awaits the results of future studies using high-resolution recording techniques.
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Role of M cells in acquired long QT syndrome, U waves, and torsade de pointes.
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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.
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Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell.
Recent studies have described regional differences in the electrophysiology and pharmacology of ventricular myocardium in canine, feline, rat, guinea pig, and human hearts. In this study, we use standard microelectrode and whole-cell patch-clamp techniques to examine the characteristics of the action potential and the delayed rectifier K+ current (IK) in epicardial, M region (deep subepicardial to midmyocardial), and endocardial cells isolated from the canine left ventricle. Cells from the M region displayed much longer action potential durations (APDs) at slow rates. At a basic cycle length of 4 s, APD measured at 90% repolarization was 358 +/- 16 (mean +/- SEM), 262 +/- 12, and 287 +/- 11 ms in cells from the M region, epicardium, and endocardium, respectively. Steady state APD-rate relations were steeper in cells from the M region. In complete Tyrode's solution, IK was smaller in myocytes from the M region when compared with those isolated from the epicardium or endocardium. Further characterization of IK was conducted in a Na(+)-, K(+)-, and Ca(2+)-free bath solution to isolate the slowly activating component of the delayed rectifier (IKs) from the rapidly activating component (IKr). IKs was significantly smaller in M cells than in epicardial and endocardial cells. With repolarization to -20 mV, IKs tail current density was 1.99 +/- 0.30 pA/pF (mean +/- SEM) in epicardial cells, 1.83 +/- 0.18 pA/pF in endocardial cells, and 0.92 +/- 0.14 pA/pF in M cells. Voltage dependence and time course of activation and deactivation of IKs were similar in the three cell types. The relative contribution of IKr and IKs among the three cell types was examined by using 6 mmol/L [K+]o Tyrode's solution with and without E-4031, a highly selective blocker of IKr. An E-4031-sensitive current was observed in the presence but not in the absence of extracellular K+. This rapidly activating component showed characteristics similar to those of IKr as described in rabbit and cat ventricular cells. Deactivation of IKr was significantly slower than that of IKs. IKr (E-4031-sensitive component) tail current density was similar in the three cell types, whereas IKs (E-4031-insensitive component) tail current density was significantly smaller in the M cells. Our results suggest that the distinctive phase-3 repolarization features of M cells are due in part to a lesser contribution of IKs and that this distinction may also explain why M cells are the main targets for agents that prolong APD in ventricular myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)
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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.
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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.
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