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(Circulation. 1996;93:372-379.)
© 1996 American Heart Association, Inc.

Articles

Cellular Basis for the Electrocardiographic J Wave

Gan-Xin Yan, MD, PhD; Charles Antzelevitch, PhD

From the Masonic Medical Research Laboratory, Utica, NY.

Correspondence to Dr Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker St, Utica, NY 13504.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
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.

Key Words: electrophysiology • electrocardiography • action potentials • arrhythmia • reentry

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
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 the Osborn wave, the J wave or elevated J-point has been described in the ECG of animals and humans for more than four decades,¹ since Osborn's observation in the early 1950s.² In humans, the appearance of a prominent J wave in the ECG is considered pathognomonic of hypothermia^{3 4 5 6} and hypercalcemia.^{7 8} A distinct J wave or elevated J-point has been described in subjects completely recovered from hypothermia^{9 10} or those predisposed to early repolarization syndrome,^{11 12} but it is otherwise rarely observed in humans under normal conditions. In animals, a distinct J wave is commonly observed in the ECG of some species, including baboons and dogs, under baseline conditions and is greatly amplified under hypothermic conditions.^{13 14 15} An elevated J-point is commonly encountered in humans and some animal species under normal conditions.

A more prominent I_to-mediated spike-and-dome action potential morphology in ventricular epicardium than in endocardium has been proposed as the cellular electrophysiological basis for the J wave. The more conspicuous notched configuration of the epicardial response is thought to produce a transmural voltage gradient during ventricular activation that manifests as a J wave or J-point elevation in the ECG.^{16 17 18 19} Direct evidence in support of the hypothesis, however, has been lacking.

Recently, we developed an isolated, arterially perfused preparation consisting of a wedge of canine ventricle from which one can simultaneously record transmembrane activity from several sites across the ventricular wall together with a transmural ECG. In the present study, we use this preparation to test the hypothesis that the electrocardiographic J wave and elevated J-point are products of a heterogeneous distribution of an I_to-mediated spike-and-dome morphology of the action potential in canine ventricular myocardium.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Arterially Perfused Wedge of Canine Left or Right Ventricle
Dogs weighing 20 to 25 kg were anticoagulated with heparin and anesthetized with pentobarbital (25 mg/kg IV). A 12-lead ECG was obtained (Schiller AG). The chest was opened via a left thoracotomy, and the heart was excised, placed in a cardioplegic solution consisting of cold (4°C) Tyrode's solution containing 8.5 mmol/L [K⁺]_o, and transported to a dissection tray. Transmural wedges with dimensions of approximately 1x1x0.8 or 0.8x0.8x0.4 cm³ were dissected from the left or right ventricles, respectively. The tissue was cannulated via a small (diameter, 100 µm) branch of the left anterior descending artery or another coronary artery and perfused with cardioplegic solution. The total period of time from excision of the heart to cannulation and perfusion of the artery was less than 4 minutes. Unperfused tissue was carefully removed with a razor blade. The preparation was then placed in a small tissue bath and arterially perfused with Tyrode's solution of the following composition (mmol/L): NaCl 129, KCl 4, NaH₂PO₄ 0.9, NaHCO₃ 20, CaCl₂ 1.8, MgSO₄ 0.5, glucose 5.5, and insulin 1 U/L, buffered with 95% O₂/5% CO₂ (36±1°C). The perfusate was delivered to the artery by a roller pump (Cole Parmer Instrument Co). Perfusion pressure was monitored with a pressure transducer (World Precision Instruments, Inc) and maintained between 40 and 50 mm Hg by adjustment of the perfusion flow rate. The preparations remained immersed in the arterial perfusate, which was allowed to rise to a level 2 to 3 mm above the tissue surface (36±1°C).

Recording of the Transmural ECG and Transmembrane Action Potentials
The ventricular wedges were allowed to equilibrate in the tissue bath until electrically stable, usually 1 hour. The preparations were stimulated at basic cycle lengths ranging from 500 to 4000 ms with bipolar silver electrodes insulated except at the tips and applied to the endocardial surface.

A transmural ECG signal was recorded with extracellular silver/silver chloride electrodes placed near the epicardial and endocardial surfaces of the preparation plugged into a differential DC amplifier. Transmembrane action potentials were recorded simultaneously from the epicardial, endocardial, and M regions by three separate intracellular floating microelectrodes (DC resistance, 10 to 20 M) filled with 2.7 mol/L KCl and connected to a high-input impedance amplifier. Impalements were obtained from the cut surface of the preparation at positions approximating the transmural axis of the ECG recording. Amplified signals were digitized, stored on magnetic media and CD-ROM, and analyzed by Spike 2 (Cambridge Electronic Designs). The amplitude of the action potential notch was measured as the voltage difference between the end of phase 1 and the peak of phase 2 (dome).

Statistics
Statistical analysis of the data was performed with Student's t test for paired data. When possible, the data are presented as mean±SD.

	Results

Top Abstract Introduction Methods Results Discussion References

 
A prominent J wave was observed in the ECGs of 17 of 20 dogs from which a 12-lead body surface ECG was recorded in vivo. A J wave or J-point elevation was most readily apparent in leads II, III, aVR, aVF, and the precordial leads (V₃ through V₆). The ECG recorded from the left (lateral) precordial leads usually corresponded well with the transmural ECG recorded from the left ventricular wedge preparations isolated from the same heart, as illustrated in Fig 1. ECG₂, recorded in vivo from lead V₅, displays a J wave (arrow) similar to that observed in the transmural ECG (ECG₁ ) recorded across the arterially perfused left ventricular wedge isolated from the same heart (Fig 1). A prominent spike-and-dome morphology of the transmembrane action potential in epicardium is coincident with the appearance of a J wave at the R-ST junction.

View larger version (16K): [in this window] [in a new window]   Figure 1. Tracings showing relation between the spike-and-dome morphology of the epicardial action potential and the appearance of the J wave. ECG2 is a lead V5 ECG recorded from the dog in vivo. ECG1 is a transmural ECG recorded across the arterially perfused left ventricular wedge isolated from the heart of the same dog. Both display a prominent J wave at the R-ST junction (arrows). The two upper traces are transmembrane action potentials simultaneously recorded from the epicardial (Epi) and M regions with floating microelectrodes. The preparation was paced at a basic cycle length of 4000 ms. The sinus cycle length at the time ECG2 was recorded was 500 ms. The electrocardiographic J wave is temporally coincident with the notch of the epicardial action potential. Although the M cell action potential also exhibits a prominent notch, it occurs too early to exert an important influence on the manifestation of the J wave.

The accentuation or appearance of a J wave is a typical feature of the ECG in humans^{3 6 10 20 21} and animals^{13 14 15} exposed to cold accidentally or as part of a clinical or experimental surgical procedure. To examine the relation between alterations of the electrocardiographic J wave and the configuration of the action potentials of cells spanning the ventricular wall, we exposed arterially perfused wedges of canine left ventricle to hypothermia. In the example illustrated in Fig 2, only an elevated J-point is observed under normothermic (36°C) conditions (Fig 2A). The notched configuration of the action potential is considerably more prominent in the epicardial response (top) than in the endocardial action potential. Moreover, the end of phase 1 of the epicardial action potential is coincident with the peak of the J-point elevation in the ECG. A decrease in the temperature of the perfusate and bath to 29°C yields a distinct and prominent J wave, whose appearance is clearly associated with an increase in the amplitude and width of the action potential notch in epicardium but not endocardium (Fig 2B). The effect of hypothermia was reversible. Rewarming of the preparation leads to a parallel reduction in the amplitude of the J wave and that of the notch of the epicardial action potential (Fig 2C).

View larger version (13K): [in this window] [in a new window]   Figure 2. Effect of hypothermia on action potential and ECG morphology. Each panel shows transmembrane recordings obtained from the epicardial (Epi) and endocardial (Endo) regions of an isolated arterially perfused canine left ventricular wedge and a transmural ECG recorded simultaneously. A, A small but distinct action potential notch in epicardium but not in endocardium is associated with an elevated J-point at the R-ST junction (arrow) under normothermic conditions (36°C). B, A decrease in the temperature of the perfusate and bath to 29°C results in an increase in the amplitude and width of the action potential notch in epicardium but not in endocardium, leading to a prominent J wave on the transmural ECG (arrow). C, Rewarming to a temperature of 34°C is attended by a parallel reduction in the amplitude and width of the J wave and epicardial action potential notch.

The coincident timing of the epicardial notch and electrocardiographic J wave suggests that the J wave is caused by a transmural voltage gradient created by the presence of a notch in the epicardial but not endocardial layers. As a further test of this hypothesis, we examined these relations under conditions in which the I_to-mediated spike-and-dome morphology of the epicardial action potential is reduced. Fig 3 shows the effect of premature stimulation, and Fig 4 illustrates direct block of I_to with 4-AP.

View larger version (19K): [in this window] [in a new window]   Figure 3. Effect of premature stimulation on the relation between epicardial action potential notch amplitude and J wave amplitude. A, Simultaneous recording of a transmural ECG and transmembrane action potentials from the epicardial (Epi) and endocardial (Endo) regions of an isolated arterially perfused right ventricular wedge. A significant action potential notch in epicardium is associated with a prominent J wave (arrow) during basic stimulation (S1-S1: 4000 ms). Premature stimulation (S1-S2: 300 ms) causes a parallel decrease in the amplitude of the epicardial action potential notch and that of the J wave (arrow). B, Plot of the amplitudes of the epicardial action potential notch () and J wave () as a function of the S1-S2 interval. The amplitude of the epicardial action potential notch and that of the J wave are normalized to the value recorded at an S1-S2 interval of 900 ms.

View larger version (17K): [in this window] [in a new window]   Figure 4. . Effect of the Ito blocker 4-AP on epicardial action potential and ECG. Simultaneous recording of a transmural ECG and transmembrane action potentials from the epicardial (Epi) and endocardial (Endo) regions of an isolated arterially perfused left ventricular wedge obtained under control conditions (shaded traces) and after 10 minutes of 4-AP (5 mmol/L; solid traces). 4-AP greatly diminished the notch of the epicardial action potential and the J wave in the ECG.

Due to the slow reactivation kinetics of I_to, premature stimulation of canine ventricular epicardium results in a diminution of the action potential notch. In the example illustrated in Fig 3A, the smaller notch of the premature beat is shown to be attended by a parallel decrease in the magnitude of the J wave (arrows). Fig 3B plots normalized values of the two parameters, recorded with premature stimuli applied at S₁-S₂ intervals ranging between 250 and 900 ms. The progressive decrease in the amplitude of the action potential notch observed at shorter S₁-S₂ intervals is accompanied by a similar decrease in the amplitude of the corresponding J wave. Similar correspondence was observed in five other preparations in which premature stimulation was used.

In another series of experiments (n=9), we used 4-AP (5 mmol/L) to directly inhibit I_to and thus abolish or markedly reduce the action potential notch. Fig 4 shows a representative example in which reduction of the epicardial notch is accompanied by a corresponding reduction in the magnitude of the J wave. It is also noteworthy that 4-AP produces a prolongation of the APD in endocardium, principally by its action to inhibit the delayed rectifier current. In contrast, 4-AP produces little change in the APD of epicardium because it blocks both I_to and delayed rectifier current in this tissue; these actions are known to produce opposing effects on APD in canine epicardium.²² The result is a wider T wave and a prolonged QT interval. The prominent J waves that appear during hypothermia are also largely abolished by 5 mmol/L 4-AP (data not shown).

Fig 5 presents a correlation of the changes in action potential notch and J wave amplitudes recorded during the various interventions described above (hypothermia, premature stimulation, and 4-AP). One representative plot is shown for each intervention (three different preparations). Linear regression reveals a highly significant correlation (r=.99) between the two parameters when the S₁-S₂ interval or temperature is varied. Average data for each intervention are shown in the Table. The average regression slope was 0.017 for 4-AP, 0.010 for the S₁-S₂ protocol, and 0.009 for the temperature protocol.

View larger version (24K): [in this window] [in a new window]   Figure 5. . Graph showing correlation between amplitude of J wave of transmural ECG and amplitude of epicardial action potential notch recorded at different S1-S2 intervals () and temperatures (29°C to 36.5°C, ) and in the absence and presence of 5 mmol/L 4-AP (). Three separate preparations. Basic cycle length was 4000 ms. In the case of the hypothermia and restitution plots, the solid lines were obtained by linear regression (r2=.99 for both).

View this table: [in this window] [in a new window]   Table 1. Average J Wave Amplitudes and Epicardial Action Potential Notch Amplitudes Recorded From Arterially Perfused Canine Ventricular Wedge Preparations at Different S1-S2 Intervals and Temperatures (29°C and 36°C) and in the Absence and Presence of 4-AP 5 mmol/L

Role of the Different Cell Types
A spike-and-dome morphology of the action potential is clearly present in other than epicardial cells. Cells displaying a prominent notched configuration have been described in the deep layers of the endocardial structures of the ventricles of the heart, including the septum, papillary muscles, and trabeculae, as well as in cells residing in the deep structures of the free wall, particularly in the M region.^{23 24 25} Those residing in the endocardial layers cannot contribute to the J wave because their action potential notch normally occurs during activation of the ventricular wall and thus is embedded in the QRS complex. Cells in the M region could contribute to the J wave, depending on phase relationships and activation vectors. With an endocardial-to-epicardial transmural activation sequence, M cells in the deep subepicardial layers are likely to contribute to the manifestation of a J wave in the ECG. The notch of M cells located deeper in the midmyocardial layers would be expected to contribute to the voltage gradients and electromotive forces generated during the QRS and therefore are not likely to influence the appearance of the J wave. The early repolarization phase of these midmyocardial cells could theoretically contribute to the J wave if their action potential notch were able to clear the QRS complex.

To test this hypothesis, we recorded from an arterially perfused transmural wedge of canine left ventricle with the wall intact and the endocardial layers removed (Fig 6). Fig 6A shows a transmural ECG and three transmembrane traces recorded simultaneously from the endocardial, M, and epicardial regions of an intact left ventricular wedge preparation. The notch of the epicardial action potential is temporally aligned with a prominent J wave in the ECG (arrow). The notch of the M cell action potential, however, coincides with the QRS and thus contributes little if at all to the J wave. The traces in Fig 6B were recorded 60 minutes after 4 mm of the endocardial surface was removed with a sharp razor blade. The stimulating electrodes were applied to the new endocardial (midmyocardial) surface, and epicardial and M cell recordings were obtained from approximately the same sites. The transmural ECG displays a QRS 35% briefer than in the intact preparation followed by two J waves, one corresponding to the notch in the M cell action potential and the other corresponding to the notch in the epicardial response (arrows). The appearance of the first J wave seems to be due to the shorter transmural activation as well as to the widening and accentuation of the notch of the M cell action potential. The accentuation of the notch and prolongation of the M cell action potential are both expected as a consequence of the removal of the electrotonic influences of endocardium (because the intrinsic action potential of endocardium is relatively brief and largely devoid of a notch).

View larger version (20K): [in this window] [in a new window]   Figure 6. . Role of M cells in the generation of the J wave. A, Transmural ECG and transmembrane action potentials from endocardial (Endo), M region (M), and epicardial (Epi) sites were recorded simultaneously from an isolated arterially perfused canine left ventricular wedge. The action potential notch in epicardium but not endocardium or M region was associated with the appearance of a prominent J wave in the ECG (arrow). B, Recordings obtained from the same epicardial and M region sites 1 hour after a segment of the endocardial surface 4 mm thick was excised. Transmural activation time was abbreviated, resulting in a 35% narrower QRS and the appearance of two J waves (arrows). The first J wave is associated with the notch of the action potential recorded from the M region. In the intact preparation (A), the notch of the M cell is not apparent in the ECG because of its occurrence during the QRS. The second J wave is coincident with the notch of the epicardial response. It is noteworthy that the spike-and-dome morphology of the M cell action potential is greatly augmented after the endocardium is removed, indicating an intrinsically larger notch in the M region.

It is of interest that despite the presence of a more accentuated notch in epicardium, the corresponding J wave (second arrow) recorded after removal of endocardium is small compared with that recorded in the intact preparation (compare Fig 6B with Fig 6A). This observation serves to highlight the fact that the amplitude of the J wave is not determined by the amplitude of the spike and dome alone but rather by the voltage gradient that develops across the ventricular wall. With endocardium missing, the voltage gradient between epicardial and M regions was small because of the presence of an action potential notch in both, resulting in a small J wave.

The importance of the activation sequence is illustrated in Fig 7. Recordings are from an arterially perfused canine left ventricular wedge preparation. With an endocardial-to-epicardial activation sequence, a prominent J wave, temporally aligned with the notch of the epicardial action potential, is apparent in the transmural ECG (Fig 7A). When the sequence is reversed, the notch of the epicardial response is coincident with the QRS, and a J wave is not observed (Fig 7B).

View larger version (15K): [in this window] [in a new window]   Figure 7. . Effect of activation sequence on the appearance of the J wave in the ECG. Simultaneous recordings of a transmural ECG and transmembrane action potentials from the epicardial (Epi) and endocardial (Endo) regions of an isolated arterially perfused left ventricular wedge are shown. A, The preparation was stimulated from the endocardial surface; a prominent J wave, temporally aligned with the notch of the epicardial action potential, is apparent in the ECG. B, The preparation was stimulated from the epicardial surface; the notch of the epicardial response is coincident with the QRS, and a J wave is no longer observed. Basic cycle length, 2000 ms.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Using a newly developed arterially perfused canine ventricular wedge preparation, we provide, for the first time, direct evidence in support of the hypothesis that heterogeneous distribution of an I_to-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 at the R-ST junction of the ECG.

The ECG waveform is known to depend on the properties of the generator (action potential), the spread of excitation, and the characteristics of the volume conductor.²⁶ Consistent with these basic principles, 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) the sequence of activation, and (4) the conduction time across the wall.

Our data demonstrate a highly significant correlation between the amplitude of the epicardial action potential notch and that of the J wave recorded during interventions that alter the appearance of the electrocardiographic J wave, including hypothermia, premature stimulation, and block of I_to by 4-AP (Figs 1 through 5).

Ventricular activation from endocardium to epicardium, with epicardium activated last, was 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 of the preparation (ie, the QRS) is complete, that is, in the absence of other voltage gradients or electromotive forces. Accordingly, stimulation of the preparation from an epicardial site did not produce a J wave despite the maintenance of cellular differences in the morphology of the action potential (Fig 7).

Conduction time across the wall is another determining factor. Removal of the endocardial layers abbreviated the QRS and allowed expression of the notch of the midmyocardial M cells as a J wave in the ECG (Fig 6). This finding also suggests that ECG expression of the notch in regions of the myocardium such as right ventricular epicardium (where the action potential notch is most prominent^{27 28} ) may be obscured. Consistent with previous studies, we found the spike-and-dome morphology of right ventricular epicardial action potentials to be more accentuated than that of left ventricular epicardium. Despite the larger notch, right ventricular epicardium might be expected to make only a minor contribution to the J wave under normal conditions. Because of a thinner ventricular wall and a briefer activation time, the right ventricular epicardial action potential notch occurs during the QRS generated by the heart as a whole. The prominent early repolarization and secondary depolarization phase (notch) of the right ventricular epicardial response therefore occur during a time when large electromotive forces and dipoles are generated as a result of continued spread of excitation in other parts of the heart. Thus, during normal excitation, these cells would be expected to contribute little to the manifestation of the J wave.

Taken together, these observations argue for the manifestation of the J wave in ECG leads in which the mean vector axis is transmurally oriented across the left ventricle and septum. It is therefore not surprising that the J wave in the dog is most prominent in leads II, III, aVR, aVF, and mid to left precordial leads V₃ through V₆. A similar picture is seen in the human ECG.^{3 6 8} Moreover, vectorcardiography indicates that the J wave forms an extra loop that occurs at the junction of the QRS and T loops.²⁹ It is directed leftward and anteriorly, which explains its prominence in leads associated with the left ventricle.

The electrocardiographic J wave was first noted in animal experiments involving hypercalcemia conducted in the 1920s.⁷ The first extensive description and characterization appeared 30 years later in a study by Osborn involving experimental hypothermia in dogs.² As a consequence, this wave, which appears at the R-ST junction, is often referred to as either a J wave or an Osborn wave. Other less frequently used terms include J deflection, camel hump, and elevated J-point.

Earlier studies attributed the J wave to a variety of factors, including anoxia, injury current, acidosis, delayed ventricular depolarization, and early ventricular repolarization.^{30 31} In the late 1980s, Litovsky and Antzelevitch and colleagues^{16 32 33} proposed a difference in the electrophysiology of ventricular epicardium and endocardium as the basis for the electrocardiographic J wave. The ionic mechanism underlying the J wave has not been fully elucidated but has been attributed largely to the presence of a 4-AP–sensitive I_to in some myocardial cells but not others, giving rise to a heterogeneous distribution of a spike-and-dome morphology of the action potential.^{18 33 34} The presence of a prominent I_to is largely responsible for the relatively large phase 1 and the characteristic spike-and-dome (notched) configuration of the epicardial action potential. The absence of a prominent notch in the endocardial action potential is correlated with a much smaller I_to. These regional differences in the contribution of I_to, first suggested on the basis of action potential data,¹⁶ have now been demonstrated with whole-cell patch-clamp techniques in feline,³⁵ rabbit,³⁶ canine,³⁴ and human³⁷ ventricular myocytes.

The spike-and-dome morphology of the epicardial action potential is absent in canine neonates, gradually appearing over the first few months of life.¹⁸ The progressive development of the notch is paralleled by the appearance of I_to.^{18 38 39} It is therefore not surprising that a J wave is not observed in neonatal dogs (C.A. et al, unpublished observations).

In humans, the appearance of a prominent J wave has been typically associated with pathophysiological conditions such as hypothermia^{3 6} and hypercalcemia,^{7 8} although a small J wave is observed in some patients who have completely recovered from hypothermia^{9 10} or those predisposed to early repolarization syndrome.^{11 12} Our results suggest that the very prominent J wave induced by hypothermia is the result of a marked accentuation of the spike-and-dome morphology of the action potential of M and epicardial cells (ie, an increase in both width and amplitude of the notch). It is tempting to speculate that this is due to the effect of cold temperatures to slow the kinetics of activation of I_to less than the kinetics of the I_Ca. This hypothesis remains to be tested. In addition to inducing a more prominent notch, hypothermia produces marked slowing of conduction velocity. The additional conduction delay from endocardium to epicardium together with the widening of the epicardial action potential notch can serve to unmask a latent J wave by moving it out of the QRS complex (Fig 2).

Association of hypercalcemia with the appearance of the J wave^{7 8} can also be explained on the basis of an accentuation of the spike-and-dome morphology of the epicardial action potential.⁴⁰ This effect of hypercalcemia is thought to be due to an increase in the net outward current during the early phases of the action potential, possibly due to an increase in calcium-activated chloride current and a decrease in I_Ca (more rapid inactivation). The presence of a prominent I_to in epicardium sensitizes that tissue to the effects of high calcium concentration.⁴⁰

Clinical Implications
The presence of a prominent notch has been shown to predispose canine ventricular epicardium to all-or-none repolarization and phase 2 reentry (see References 18, 33, and 41 for reviews). Under ischemic conditions and in response to a variety of drugs, canine ventricular epicardium exhibits an all-or-none repolarization at the end of phase 1 of the action potential. Failure of the dome to develop results in a marked (40% to 70%) abbreviation of the action potential. Under these conditions, the action potential plateau (dome) is usually abolished at some epicardial sites but not others, causing a marked dispersion of repolarization. Propagation of the action potential dome from sites at which it is maintained to sites at which it is abolished can cause local reexcitation of the preparation. This mechanism, called phase 2 reentry, produces extrasystolic activity, which can then initiate one or more cycles of circus movement reentry.⁴² Electrical heterogeneity leading to phase 2 reentry has been demonstrated in canine epicardium exposed to (1) K⁺ channel openers such as pinacidil,⁴³ (2) sodium channel blockers such as flecainide,⁴⁴ (3) increased [Ca²⁺]_o,⁴⁰ (4) metabolic inhibition,¹⁹ and (5) simulated ischemia.⁴² I_to blockade restores electrical homogeneity and abolishes reentrant activity in all cases.

Because the J wave provides an index of the prominence of the spike-and-dome morphology of the epicardial response, it may prove to be of diagnostic or prognostic value in identifying subjects predisposed to phase 2 reentry or individuals who may be inclined to develop various forms of early repolarization syndrome.

The idiopathic J wave has been linked to life-threatening ventricular arrhythmias such as the Brugada syndrome.^{45 46 47 48 49} The Brugada syndrome is characterized by a persistent ST-segment elevation in leads V₁ through V₃ (unrelated to ischemia, electrolyte abnormalities, or structural heart disease), normal QT interval, and sudden cardiac death.⁴⁶ Apparent right bundle branch block is also present in many but not all cases. Recent data point to similarities between the conditions that predispose to phase 2 reentry and those that attend the appearance of the Brugada syndrome. Loss of the action potential dome (plateau) in epicardium but not endocardium causes elevation of the ST segment or early repolarization syndrome, similar to that found in patients with the Brugada syndrome.¹⁹ Because loss of the dome is caused by an outward shift in the balance of currents active at the end of phase 1 of the action potential (principally I_to and I_Ca), autonomic neurotransmitters like acetylcholine facilitate loss of the action potential dome⁵⁰ by suppressing I_Ca, whereas ß-adrenergic agonists restore the dome by augmenting I_Ca. Sodium channel blockers also facilitate loss of the canine right ventricular action potential dome as a result of a negative shift in the voltage at which phase 1 begins.^{44 51} Accentuation of the ST-segment elevation in patients with the Brugada syndrome after vagal maneuvers or class I antiarrhythmic agents and reduction of ST-segment elevation after ß-adrenergic agents are consistent with these experimental findings. The appearance of the ST-segment elevation only in right precordial leads is also consistent with the observation that loss of the action potential is usually observed in right but not left ventricular epicardium.^{19 52} These observations point to a depressed right ventricular epicardial action potential dome as the basis for the ST-segment elevation and phase 2 reentry as a trigger for episodes of ventricular fibrillation in patients with the Brugada syndrome. These hypotheses remain to be investigated.

	Selected Abbreviations and Acronyms

 

4-AP = 4-aminopyridine APD = action potential duration ICa = inward calcium current Ito = transient outward current

	Acknowledgments

 
This study was supported by grant HL-47678 from the National Institutes of Health; a fellowship award from the American Heart Association, New York State Affiliate, to Dr Yan; and a grant from the Seventh Manhattan Masonic District Association. We are grateful to Drs Weissenburger and Di Diego for their helpful discussions. We also gratefully acknowledge the expert technical assistance of Judy Hefferon, Tengxian Liu, and Robert Goodrow.

Received May 31, 1995; revision received August 14, 1995; accepted September 11, 1995.

	References

Top Abstract Introduction Methods Results Discussion References

 

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