Role of M cells in acquired long QT syndrome, U waves, and torsade de pointes

Journal of Electrocardiology Vol. 28 Supplement

Role of M Cells in Acquired Long QT Syndrome, U Waves, and Torsade de Pointes

Charles Antzelevitch, PhD, Vladislav V. Nesterenko, PhD, and Gan-Xin Yah, MD, PhD

trolyte imbalances, usually coupled with bradycardia or long pauses. Most agents capable of prolonging the QTU interval appear to be capable of causing TdP. They include widely prescribed antibiotics, antihistaminics, antifungal agents, and antiarrhythmic drugs (principally those that cause prolongation of the action potential, class Ia and class HI antiarrhythmics). The most notable examples of TdP have occurred in patients on quinidine who also develop hypokalemia and present with slow heart rates or long pauses. Such a combination of predisposing factors is not uncommon. These conditions are similar to those under which quinidine and other agents induce early afterdepolarizations (EADs) and triggered activity in isolated Purkinje fibers and M cells. These and other observations have suggested a role for EADs in the development of long QT intervals, U waves, and TdP; however, the role of EADs and triggered activity in the genesis and maintenance of TdP remains to be fully elucidated. Some authors have suggested that TdP at times m a y be initiated and maintained by triggered activity simultaneously originating at two independent foci, while others have suggested that TdP m a y be initiated by a triggered beat but maintained by a circus m o v e m e n t reentry mechanism. 2 There is fairly good agreement that the initiating event is an hAD-induced triggered response, but still in question is the origin of the triggered beats (Purkinje vs M cells). Among those who agree that reentry is responsible for the maintenance of TdP, there is no clear consensus as to the substrate responsible for the development of reentry and the nature of the reentrant arrhythmia. Corollary issues that need to be addressed include: w h a t is responsible for the long QT interval, the accentuation of the U wave, and the marked dispersion of repolarization that accompany TdR While prolonged responses and triggered activity arising in Purkinje fibers can account for the generation of a triggered response, they cannot readily account for these other ECG manifestations that attend the development of TdP. Recent work has uncovered a population of ceils in the deep structures of canine and h u m a n ventricles that dis-

Regional differences in the electrophysiologic and pharmacologic properties of ventricular myocardium have been delineated in a growing n u m b e r of studies. 14 Several investigations have highlighted the electrophysiologic differences between ventricular endocardium and epicardium, demonstrating different, and sometimes opposite, responses of these two cell types to pharmacologic agents and pathophysiologic states in a number of species?-n Other studies have described differences in the electrophysiologic characteristics and pharmacologic responsiveness of M cells located in the deep structures of the canine, guinea pig, and h u m a n ventricles. 2,14-x9Epicardial, endocardial, and M ceil action potentials differ principally with respect to repolarization characteristics. Ventricular epicardium and M cells commonly display action potentials with a prominent spike-and-dome morphology, which is small or lacking in endocardium. M cells are distinguished chiefly by the ability of their action potentials to prolong disproportionately to the other cell types with slowing of rate. In this study, we reviewed the characteristics of the M cells and describe their possible role in acquired long QT syndrome and torsade de pointes (TdP). Torsade de pointes is an atypical polymorphic ventricular tachycardia most often associated with prolongation of the QTU interval in the electrocardiogram (ECG). A congenital variety of the long QTU interval manifests in several forms, differing from the acquired type with respect to cycle length dependence and sympathetic nervous system involvement. The onset of TdP in congenital long QTU syndrome is thought to be more adrenergic dependent, whereas the acquired form is believed to be more pause dependent. The acquired form is often associated with a variety of pharmacologic agents and elec-

From Masonic Medical Research Laboratory, Utica, New York.

Supported by grants HL37396 and EIL47678 from the National Institutes of Health and a Grant-in-Aid from the American Heart Association, NYS Affiliate. Reprint requests: Dr. Charles Antzelevitch, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13504.

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132 Journalof ElectrocardJologyVol. 28 Supplement play electrical characteristics and responsiveness to drugs that are consistent with the ECG manifestations that attend the development of long QT intervals and TdP. M cells differ front epicardial and endocardial cells with respect to phase 3 repolarization, displaying a much greater action potential duration (APD) at slow rates, s,4,1~,2° They are widely distributed and, together x~th transitional cells, comprise 30 to 40% of the ventricular wall. They reside in the deep subepicardial to midmyocardial layers in the ventricular free wall and in the deep subendocardial layers of endocardial structures, including the septum, papillary muscles, and trabeculae. ~8,2~Evidence for the existence of M cells in the h u m a n heart was recently provided by Drouin et al. ~9 using transmural tissue slices from explanted normal h u m a n hearts. The rate dependence of APD in the M region is considerably more accentuated than that of epicardium and endocardium and more similar to that of Purkinje fibers (Fig. 1). The ionic basis for the longer action potential of M cells clearly involves a diminished net repolarizing current. The delayed rectifier current (IK) together with the transient outward current (Ira) and inward rectifier current (IK~) are generally thought to contribute to the regulation of APD.=,23 In the canine ventricle, the magnitude of Ii
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(Fig. 2). Zto plays an important role in phase 1 repolarization, but because of its rapid activation and inactivation kinetics, Ito has little, if any, effect on phase 3 repolarization in the canine ventricle. 1~,24It is also noteworthy that M cells displaying steep APD-rate relations possess levels of Ito similar to those found in epicardial cells displaying Httle rate dependence of APD. Thus, differences in IK! and [to do not appear to account for the marked heterogeneity of repolarization characteristics observed among cells spanning the canine ventricular wall. Recent findings suggest a weaker I~
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Fig. 2. (A) Action potentials recorded from myocytes isolated from the epicardial, endocardial, and M regions of the canine left ventricle. (B) Transient outward current (Ito) recorded from the three cell types (current traces recorded during depolarizing steps from a holding potential of - 8 0 mV to test potentials ranging between -20 and +70 mV). (C) Voltage-dependent activation of the slowly activating component of the delayed rectifier K + current (IKs) (currents were elicited by the voltage pulse protocol shown in the inset; Na +-, K ÷-, and Ca 2+free solution). (D) Current-voltage relationships for I m in epicardial, endocardial, and M region myocytes. (E) The average peak current-voltage relationship for Ito for each of the three cell types. Values are m e a n ± SD. (F) Voltage dependence of Ii¢s (current remaining after exposure to E-4031) and Im (E-4031-sensitive current). Values are mean _+SE. P < .05 compared with Epi or Endo. Modified from Liu and Antzelevitch} ~ With permission.

region is increased and a slight resistive barrier is imposed around the M region. The computer model also predicts the development of an "apparent" EAD in monophasic action potential recordings under these conditions2 ~.4° The apparent EAD is a reflection of the delayed repolarization of the M cells in the deep struCtures of the wall. The c o m p u t e r m o d e l consists of 3,000 x 1,800 myocardial cells representing a two-dimensional transmural slice (3 x 1.8 cm) across the left ventricuiar free wall. The transmembrane activity of each cell is simulated using the Luo and Rudy modeP 1 and all cells are connected through Iow-resistance gap junctions (Fig. 3). The delayed rectifier current, Ix<, is increased linearly from the endocardium to the epicardium to simulate the transmural gradient of APD. Action potential duration of cells in the midmyocardium (M cell region, ranging from 40 to 80% of the transmural width) are further prolonged by an additional decrease of I~c Propagated electrical activity is initiated by stimulating the endocardiaI side of the preparation (Fig. 3A). Figure 3B illustrates the

transmembrane potentials of individual cells along the transmural line designated N-R W h e n the myocardial cells are electrically coupled, the resultant distribution of APD across the wall is much smoother than the distribution of intrinsic APD (Fig. 3B, C). Under conditions of homogeneous myocardial resistivity, the simulated ECG shows a monotonic T wave whose peak coincides with repolarization of the epicardial action potential and whose termination coincides with repolarization of the endocardial response (Fig. 3D). W h e n myocardial resistivity at the borders of the M region is slightly elevated, a distinct U wave appears in the simulated ECG (Fig. 3D). Under these conditions, the QTU interval extends b e y o n d the repolarization of the epicardial and endocardial action potentials, but is consistent with the repolarization of cells in the M region. The amplitude and direction of the U wave and its separation from the T wave are influenced by: (1) the size of the M region, (2) the total barrier resistance, (3) the magnitude and direction of the APD gradient in the M

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Fig. 3. Computer simulation of the ECG in a transmural slice of the left ventricular free wall. (A) Geometry of the simulated preparation showing the distribution of epicardiat, M, and endocardial regions. The model consists of 3,000 x 1,800 myocardial cells representing a two-dimensional transmural slice (3 x 1.8 cm) across the wall. All cells are electrically connected and the transmembrane activity of each cell is simulated using the Luo and Rudy model. ~ (B) Electrical activity of individual cells along the transmural line designated N-P (see A) without (1) and with (2) resistive barriers introduced at the borders of the M region. (C) Distribution of action potential duration (APD) across the ventricular wall: 1, no resistive barriers; 2, with resistive barriers; 3, intrinsic APD (no electrical coupling). (D) Simulated ECG showing the absence of a U wave w h e n myocardial resistivity is homogeneous across the ventricular wall (trace 1) and the presence of a distinct U wave w h e n the resistance at the borders of the M region (single gap junctions) is increased from 2 to 15 g2.cm2 (trace 2).

region, (4) the average APD of M cells, and (5) the average myocardial resistivity in the M region. Different morphologies of the T-U complex can be simulated by combining these five factors (Fig. 4). Thus, the phenotypic appearance of the T-U complex is a function of the distribution of myocardial resistivity and repolarization gradients across the ventricular wall. The computer model also provides an explanation for the appearance of inverted or negative U waves. A negative U wave is generated simply by reversing the APD gradient within the M region, which can occur as a result of ischemia or other insults. 42 Further evidence in support of the hypothesis that the M cell underlies or contributes prominently to the U wave and long QTU interval derives from the concordance between the rate-dependent repolarization characteristics of the M cells and the appearance of the U wave 4~ (Fig. 5). Direct lines of evidence in support of the hypothesis are available as well. These derive from in vivo studies in

which transmural activity is measured using transmural monophasic action potential electrodes and from studies involving arterially perfused preparations consisting of a wedge of canine left ventricle from which we simultaneously record transmembrane activity and a transmural ECG44 (Fig. 6). The wedge is perfused with Tyrodes solution through a branch of the left anterior descending coronary artery and t r a n s m e m b r a n e responses are recorded along the cut surface from cells spanning the left ventricular free wall. Epicardial, M, and endocardial or Purkinje fiber action potentials are simultaneously recorded using several floating microelectrodes. Addition of dl-sotaloI (100 gM) to the perfusate results in a much greater prolongation of APD in midmyocardial M cells than in epicardial or endocardial ceils. Drug-induced prolongation of APD in M cells is attended by the appearance of a U wave or a bifid or notched T wave in the EGG. Repolarization of the epicardial response is coincident with the peak of the T wave, whereas repolarization of the M cell is always coincident with the end of the QTU

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Fig. 4. Phenotypic appearance of the T-U complex in a simulated transmural ECG of the left ventricular free wall. (A) Effect of increasing coupling resistance at the borders of the M region: 1, homogeneous resistivity throughout the wall; 2-6, progressive increase in barrier resistance (2-10 times normal). (B) Effect of prolonging the action potential duration (APD) in the M region: 1, no prolongation of APD in the M region; 2-6, progressive increase in APD (G~¢ [maximal conductance of delayed rectifier potassuim channel] decreased by 0.05 to 0.25 mS/cm2). (C) Effect of varying the width of the M region: l, M region extends from 40 to 50% of the transmural width of the left ventricular free wall; 2, 40 to 60%; 3, 40 to 70%; 4, 40 to 80%; 5, 30 to 80%; 6, 20 to 80%. (D) Effect of the magnitude and direction of the APD gradient in the M region with APD at the center of the M region fixed: l, APD gradient in the M region is 5 times that of the normal ventricular APD gradient between the endocardium and epicardium; 2, APD gradient in the M region is 2 times normal; 3, APD gradient in the M region is the same as the normal epicardial-endocardial APD gradient (as shown in Fig. 3B, trace 3); 4, no APD gradient in the M region (APD of M cells is prolonged but constant throughout the M region); 5, APD gradient in the M region is opposite to that of the epicardial-endocardiaI gradient; 6, APD gradient in the M region is opposite and twice as steep as the normal epicardial-endocardial gradient. Data in B-D were simulated using a barrier resistance of 15 f~.cm at the borders of the M region.

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Fig. 5. M ceils as the basis for the U wave. Upper trace: Transmembrane activity recorded simuhaneously from endocardia! (Endo), deep subepicardial (M cell), and epicardial (Epi) tissues obtained by successive dermatome shavings made parallel to the epicardial surface (canine left ventricular free wall). The M cell action potential, free of the electrotonic influence of epicardium and endocardium, shows a dramatic prolongation of the action potential as the basic cycle length is increased from 1,000 to 2,000 ms. Lower trace: Hoher recording (equivalent to lead V 1 or V2) from a patient on amiodarone who died of torsade de pointes that degenerated into ventricular fibrillation shortly after this trace was recorded. The trace shows dramatic rate-dependent changes in the QTU interval, with a "giant U wave" apparent following a pause of 1,900 ms. The ratedependent changes in the action potential duration of the M cell correlate well with the manifestation of the U wave in the ECG. QTU and RR measurements are in milliseconds. The clinical trace is courtesy of R. Acunzo and M. B. Rosenbaum. From Antzelevitch and Sicouri. 2 With permission.

Fig. 6. Relationship between the QTU interval and repo!arization of epicardial (Epi), M region (M), and subendocardial Purkinje fiber action potentials during programmed stimulation. The three transmembrane traces and the transmural ECG were simultaneously recorded from an arterially perfused left ventricular free wall preparation. The left ventricular wedge was perfused ~Mth Tyrodes solution via a small native branch of the left descending coronary artery and stimulated from the endocardial surface at a basic cycle length of 5,000 ms. The transmembrane action potentials were simultaneously recorded from epicardial (Epi), M region (M), and subendocardial Purkinje (Purkinje) fiber action potentials using three floating microelectrodes. The transmural ECG was recorded concurrently using silver electrodes placed in the tissue bath near the epicardial and endocardial surfaces of the preparation. The traces were obtained 30 minutes after addition of 100 ~tM dl-sotalol to the perfusate. The end of the QTU complex during basic (S1) and premature ($2) stimulation was always coincident with repolarization of the M cells. Repolarization of Purkinje fibers always outlasted the QTU interval, failing to register on the ECG.

complex. Action potentials of subendocardial Purkinje fibers usually outlast those of the M cells, but their repolarizations do not register on the transmural ECG (Fig. 6). These data provide the first direct line of evidence in support of the hypothesis that M cells underlie the ECG U wave, bifid T wave, and long QTU interval. Delayed repolarization of M cells thus contributes to the U wave by creating a dispersion of repolarization within ventricular myocardium. Dispersion of repolarization is thought to be a key component in the development of TdP, an atypical tachycardia that often attends the appearance of U waves and long QT intervals in the ECG. M cells may contribute to the development of TdP in several ways. One possible scheme is as follows. The greater prolongation of the M cell action potential in

response to agents and conditions that predispose to TdP could create a c o l m n n of functional refractoriness in the midmyocardial layers of the ventricular wall. A premature beat, in the form of a triggered or automatic response, would propagate along the edges of the column, reentering the M region only after expiration of refractoriness in this region. Retrograde conduction of the wave would be limited to the M region since the bordering regions are n o w refractory. As functional refractoriness of the borders dissipates, the excitation wave would exit and once again travel anterogradely, circumscribing the M region. Repetition of this type of circus m o v e m e n t with progressively shifting sites of reentry would then yield the electrical migration characteristics seen with TdP.4.43 This hypothesis remains to be tested.

M Cells

References 1. Antzelevitch C, Sicouri S, Litovsky SH et al: Heterogeneity within the ventricular wall: electrophysioIogy and pharmacology of epicardial, endocardial and M cells. Circ Res 69:1427, 1991 2. Antzelevitch C, Sicouri S: Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: the role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am ColI Cardiol 23:259, 1994 3. Antzelevitch C, Sicouri S, Lukas A et al: Clinical implications of electrical heterogeneity in the heart. The electrophysiology and pharmacology of epicardial, M and endocardial ceils, p. 88. In Podrid P J, Kowey PR (eds): Cardiac arrhythmia: mechanism, diagnosis and m a n a g e m e n t . William & Wilkins, Baltimore, 1994 4. Antzelevitch C, Sicouri S, Lukas A et al: Regional differences in the electrophysiology of ventricular cells: physiological and clinical implications, p. 228. In Zipes DP, Jalife J (eds): Cardiac electrophysioiogy: from cell to bedside. WB Saunders, Philadelphia, 1994 5. Gilmour RE Zipes DP: Different electrophysiologicaI responses of canine e n d o c a r d i u m and epicardium to combined hyperkalemia, hypoxia, and acidosis. Circ Res 46:814, 1980 6. Litovsky SH, Antzelevitch C: Transient o u t w a r d c u r r e n t p r o m i n e n t in canine v e n t r i c u l a r epicardium but not endocardium. Circ Res 62:116, 1988 7. Bridge JH, Cabeen R, Jr, Langer GA, Reeder S: Sodium efflux in rabbit myocardium: relationship to sodium-calcium exchange, d Physiol (Lond) 316:555, 1981 8. Fedida D, Giles WR: Regional variations in action potentials a n d t r a n s i e n t o u t w a r d c u r r e n t in myocytes isolated from rabbit left ventricle. J Physiol (Lond) 442:191, 1991 9. Krishnan SC, Antzelevitch C: FIecainide-induced a r r h y t h m i a in canine ventricular epicardium: phase 2 reentry? Circulation 87:562, 1993 10. Di Diego JM, Antzelevitch C: Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues: does activation of ATPregulated potassimn current promote phase 2 reentry? Circulation 88:1177, 1993 11. Liu DW, Gintant GA, Antzelevitch C: Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res 72:671, 1993 12. Lukas A, Antzelevitch C: Differences in the electrophysiological response of canine ventricular epicardium and e n d o c a r d i u m to ischemia: role of the transient o u t w a r d current. Circulation 88:2903, 1993

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13. Di Diego JM, Antzelevitch C: High [Ca2+]-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium: phase 2 reentry. Circulation 89:1839, 1994 14. Sicouri S, Antzelevitch C: A subpopulation of cells with unique electrophysiological properties in the deep subepicardium of the canine ventricle: the M cell. Circ Res 68:1729, I991 15. Sicouri S, Antzelevitch C: Drug-induced afterdepolarizations and triggered activity occur in a discrete subpopulation of ventricular muscle cell (M cells) in the canine heart: quinidine and digitalis. J Cardiovasc Electrophysiol 4:48, 1993 16. Sicouri S, Antzelevitch C: Distribution of M cells in the canine ventricle. (abstract) PACE 16:898, 1993 17. Liu DW, Gintant GA, Antzelevitch C: Electrophysiologic characteristics of myocytes from epicardium, m i d m y o c a r d i u m and endocardium of the canine left ventricle. (abstract) PACE 15:537, 1992 18. Sicouri S, Antzelevitch C: Electrophysiologic characteristics of M cells in the canine left ventricular free wall. J Cardiovasc Electrophysiol 6:591, 1995 19. Drouin E, Charpentier F, Gauthier C et al: Evidence for the presence of M cells in the h u m a n ventricle. Abstract PACE 16:876, 1993 20. Katz AM: T wave "memory": possible casual relationship to stress-induced changes in cardiac ion channels? J Cardiovasc Electrophysiol 3:150, I992 21. Sicouri S, Antzelevitch C: Distribution of M cells in the canine ventricle. J Cardiovasc Electrophysiol 5:824, 1994 22. Carmeliet E: K+ channels and control of ventricular repolarization in the heart. F u n d a m Clin Pharmacol 7:19, 1993 23. Gintant CA, Cohen IS, Datyner NB, Kline RP: Time d e p e n d e n t o u t w a r d currents in the heart, p. 1121. In Fozzard HA, Jennings RB, Haber E et al. (eds): The heart and cardiovascular system. Raven Press, New York, 1991 24. Tseng GN, Hoffman BF: Two components of transient o u t w a r d c u r r e n t in canine v e n t r i c u l a r myocytes. Circ Res 64:633, 1989 25. Liu DW, Antzelevitch C: 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. Circ Res 76:351, 1995 26. Noble D, Tsien RW: Outward m e m b r a n e currents activated in the plateau range of potentials in cardiac Purkinje fibers. J Physiol (Lond) 200:205, 1969 27. B e u c k e l m a n n D J, Nabauer M, E r d m a n n E: Alterations of K+ currents in isolated h u m a n ventricular myocytes from patients with terminal heart failure. Circ Res 73:379, 1993 28. Wang Z, Fermini B, Nattel S: Delayed rectifier outw a r d current and repolarization in h u m a n atrial myocytes. Circ Res 73:276, 1993

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29. Sanguinetti MC, Jurkiewicz NK: Two components of cardiac delayed rectifier K+ current. J Gen Physiol 96:195, I990 30. Sanguinetti MC, Jurkiewicz NK: Delayed rectifier outward K+ current is composed of two currents in guinea pig atrial cells. Am J PhysioI 260:H393, 1991 31. F u r u k a w a T, Kimura S, F u r u k a w a N e t al: Potassium rectifier currents differ in myocytes of endocardial and epicardial origin. Circ Res 70:91, 1992 32. Giles WR, Imaizumi Y: Comparison of potassium currents in rabbit atrial and ventricular cells. J Physiol (Lond) 405:123, i988 33. Hume JR, Uehara A: Ionic basis of the different action potential configurations of single guinea-pig atrial and ventricular myocytes. J Physiol (Lond) 368:525, I985 34. Hiraoka M, Kawano S: Mechanism of increased amplitude and duration of the plateau with sudden shortening of diastolic intervals in rabbit ventricular ceils. Circ Res 60:14, 1987 35. Josephson JR, Sanchez Chapula J, Brown AM: Early o u t w a r d current in rat single ventricular cells. Circ Res 54:157, 1984 36. Balser JR, Bennett PB, Roden DM: T i m e - d e p e n d e n t o u t w a r d c u r r e n t in g u i n e a - p i g v e n t r i c u l a r myocytes. J Gen Physiol 96:835, 1990 37. Nesterenko VV, Antzelevitch C: Simulation of the electrocardiographic U wave in h e t e r o g e n e o u s myocardium: effect of the local junctional resistance, p. 43. In Computers in cardiology. IEEE C o m p u t e r Society Press, Los Alamitos, CA, i992

38. Nesterenko VV, Antzelevitch C: M cells as the basis for the electrocardiographic U wave. (abstract) Circulation 86:I-302, 1992 39. Nesterenko VV, Antzelevitch C: Monophasic action p o t e n t i a l (MAP) recordings display "apparent" early a f t e r d e p o l a r i z a t i o n s (EAD) w h e n action potentials of deep myocardial cells are prolonged: a computer simulation study. (abstract) Circulation 90:I- 183, 1994 40. Nesterenko VV, Antzelevitch C: Factors responsible for "apparent" early afterdepolarizations (EAD) in monophasic action potential (MAP) recordings: a model study. (abstract) PACE 18:II-830, i995 4!. Luo C, Rudy Y: A model of the ventricular cardiac action potential: depolarization, repolarization and their interaction. Circ Res 68:1501, 1991 42. Nesterenko VV, Antzelevitch C: Morphologic diversity of the electrocardiographic T-U complexmyocardial cells: a model study. (abstract) PACE 18:II896, 1995 43. Antzelevitch C, Di Diego JM, Sicouri S, Lukas A: Selective pharmacological modification of repolarizing currents: antiarrhythmic and proarrhythmic actions of agents that influence repolarization in the heart, p. 57. In Breithardt J (ed): Antiarrhythmic drugs: mechanisms of antiarrhythmic and proarrhythmic actions. Springer-Verlag, Berlin, 1995 44. Yan G-X, Antzelevitch C: Contribution of M cells to the electrocardiographic U wave: direct evidence from arterially p e r f u s e d canine left ventricle. (abstract) PACE 18:II-993, 1995

D i f f e r e n t Circadian B e h a v i o r of t h e A p e x a n d t h e E n d of t h e T Wave

P. Coumel, MD, FESC,* P. Maison-Blanche, MD,* D. Catuli, MD,* N. Neyroud, MS,* J. Fayn, PhD,-t- and P. Rube], PhD~-

Ventricular repoiarization duration is an important electrophysiologic parameter that is poorly investigated in conventional electrocardiography. Heart rate (HR) and

From *H~pital Lariboisi~re, Paris, and -]-Inserm U121, Lyon, France.

Supported by grants from F~deration Fran~aise de Cardiologie, Association Fran~aise contre les Myopathies, Fondation pour la Recherche M~dicale. Reprint requests: Dr. Philippe Coumel, H~pital Lariboisiere, 2, rue Ambroise-Pard, 75010, Paris, Prance.

the autonomic nervous system (ANS) are responsible for its variations. The approach of static QT measurement on the surface electrocardiogram (ECG) and its correction using Bazett's formula are inadequate tools. Holter recordings and their computerized analysis are much better adapted to assess QT dynamics. Measuring the QT interval exactly has always been a difficult problem, but evaluating its variations rather than its absolute value can be done with a precision on the order of 1 ms. Yet, assessing tiny variations of the QT