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Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome
Journal of Electrocardiology Vol. 32 Supplement 1999
Cellular Basis for Long QT, Transmural Dispersion of Repolarization, and Torsade de Pointes in the Long QT Syndrome
Wataru Shimizu, MD, PhD,* and Charles Antzelevitch, PhD t
Abstract: Genetic studies have identified four forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes located on chromosomes 3 (LQT3), 7 (LQT2), 11 (LQT1), and 21 (LQTS). Preliminary clinical studies have reported different phenotypic electrocardiographic patterns and different sensitivity to pacing or pharmacological therapy for each genotype. A transmural electrocardiogram and transmembrane action potentials from epicardial, M, and endocardial cells were simultaneously recorded from an arterially perfused wedge of canine left ventricle. Isoproterenol (100 nmol/L) in the presence of chromano1293B (30 p,mol/L), an IKs blocker (LQT1 model), produced a preferential prolongation of M-cell action potential duration (APD), resulting in an increase in transmural dispersion of repolarization (TDR) and a broad-based T wave, as commonly seen in LQT1 patients. D-Sotalol (100/~mol/L), an IKr blocker (LQT2 model), and ATX-II (20 nmol/L), an agent that augments late INa (LQT3 model), also produced a preferential prolongation of M-cell APD, an increase in TDR, and low-amplitude T wave with a bifurcated appearance (LQT2), and late-appearing T wave (LQT3), respectively. APD-, QT-, and TDR-rate relations were much steeper in the LQT3 model than in either the LQT1 or LQT2 model, whereas the rate relations in the LQT1 and LQT2 models were both steeper than those u n d e r control conditions. Spontaneous and programmed electrical stimulation-induced torsade de pointes (TdP) were observed in all 3 models. Propranolol (1 /~mol/L), a beta blocker, completely prevented the effect of isoproterenol to persistently or transiently increase TDR and to induce TdP in the LQT1 and LQT2 models, but facilitated TdP in the LQT3 model. Mexiletine, a class IB Na + channel blocker, dose-dependently (2-20 p,mol/L) abbreviated the QT and APD more in the LQT3 model, but decreased TDR and suppressed TdP in the 3 models. K e y w o r d s : long QT syndrome, arrhythmias, KvLQT1, HERG, SCN5A, KCNE 1, M cell, heterogeneity.
From the * Department of Internal Medicine, National Cardiovascular Center, Osaka, Japan; and l- Masonic Medical Research Laboratory, Utica, NK
Supported by grant HL47678 from the National Institutes of Health (C. Antzelevitch) and grants from Medtronic Japan (W. Shimizu), American Heart Association (W. Shimizu) Suzuken Memorial Foundation (W. Shimizu), and the Sixth, Seventh, and Eighth Manhattan Masonic Districts and NYS and Florida Grand Lodges F. & A.M. Reprint requests: Wataru Shimizu, MD, PhD, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka 565-8565 Japan. Copyright © 1999 by Churchill Livingstone ® 0022-0736/991320S-0035510.00/0
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The long QT syndrome (LQTS) is characterized by long QT intervals, an atypical polymorphic ventricular arrhythmia known as torsade de pointes (TdP), and a high risk for sudden cardiac death (1-5). In the congenital form of the LQTS, an imbalance between left and right stellate inputs to the heart was first suggested to underlie LQTS in 1975 ( 1). However, the sympathetic imbalance hypothesis as a primary cause lost ground when recent genetic linkage analysis uncovered four gene mutations responsible for ion channel defects (6-15). Genetic linkage analysis has identified four forms of congenital LQTS caused by mutations in ion channel genes located on chromosomes 3, 7, 11, and 21 (6-10). Chromosome l l linked LQT1 is assodated with a mutation in KvLQT1 which encodes for the slowly activating delayed rectifier potassium currents (IKs) (11,12), and chromosome 21-1inked LQT5 is the result of a mutation in KCNE 1 (minK) whose product coassembles with that of KvLQT1 to form the IKs channel (I 3). Chromosome 7-1inked LQT2 is caused by mutations in HERG, a gene that encodes for the channel that carries the rapidly activating delayed rectifier potassium currents (IKr) (7), whereas chromosome 3-1inked LQT3 is related to mutations in SCN5A, a gene that encodes for the alpha subunit of the sodium channel in heart (6). More recently, the autosomal recessive form of Jervell and Lange-Nielsen syndrome, characterized by marked QT prolongation and deafness, is reported to arise in individuals who inherit abnormal KvLQT1 or KCNE 1 alleles from both parents (14,15). Our studies employed arterially-perfused canine left ventricular preparations from which we are able to simultaneously record transmembrane activity from epicardial, M, and endocardial or subendocardial Purkinje sites along the transmural surface of the ventricular wall using floating glass microelectrodes (16-21). A pseudo-electrocardiogram (ECG) recorded concurrently along the same vector permits correlation of transmembrane and electrocardiographic activity. The wedge is capable of developing and sustaining a variety of arrhythmias, including ventricular premature beats and TdP. This review summarizes the results of studies designed to probe the cellular basis of the long QT interval, phenotypic appearance of abnormal T waves, the mechanisms of TdP as well as possible therapeutic approaches in congenital LQTS.
Phenotypic Appearance of Abnormal T Waves In 1995, Moss and coworkers demonstrated a correlation between the phenotypic appearance of
abnormal T waves and the 3 genotypes of congenital LQTS (22). LQT1 patients with IKs defect were found to display broad-based prolonged T waves, whereas LQT2 patients with IKr defect showed low-amplitude, moderately delayed T waves with a notched or bifurcated appearance. LQT3 patients with sodium channel (INa) defect displayed distinctive late-appearing T waves. We hypothesized that the interaction of the 3 electrically distinct cells types encountered across the ventricular wall (epicardium, M, and endocardium) is responsible for the different morphologies of the T wave and that the preferential prolongation of M cells by the ion channel mutations underlies LQTS, contributing to the development of long QT intervals and TdP. M ceils are known to display electrical characteristics and responses to drugs consistent with the ECG manifestations that attend the development of long QT and TdP (23-27). Data form the arterially perfused left ventricular wedge preparation suggest that the morphology of the T wave is a function of 2 opposing transmural currents, due to the development of opposing voltage gradients during repolarization: between epicardium and the M-cell region, and between the M-cell region and endocardium. The presence of a high level of tissue resistivity between the epicardium and the M region also serves to modulates the intensity of the transmural currents (16-21) (Figs. 1 and 2). The peak of the T wave in the ECG is always coincident with the repolarization of the shortest epicardial action potential, whereas the end of the T wave coincides with repolarization of the longest M-cell action potential. Repolarization of endocardial action potentials is usually intermediate between that of the M cells and the epicardial cells. In contrast, repolarization of subendocardial Purkinje fibers always outlasts that of the M cells, suggesting that repolarization of Purkinje cells fails to contribute to the manifestation of the T waves. Thus, the transmural dispersion of repolarization (TDR) across the ventricular wall is defined by the difference in repolarization time (activation time + action potential duration [APD]) between the M cell and the epicardial cell.
LQT1 Syndrome Chromanol 293B, a relatively specific IKs blocker, mimics the LQT1 (and LQT5) syndrome (17); it produces a homogeneous prolongation of APD across the ventricular wall but fails to widen the T wave or increase the TDR (Fig. 1B). Beta-adrenergic stimulation with isoproterenol increases transmural
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200 msec Fig. 1. Transmembrane action potentials and transmural electrocardiogram (ECG) in the LQTI model of arterially perfused canine left ventricular wedge preparations. All traces depict action potentials simultaneously recorded from endocardial (Endo), M, and epicardial (Epi) sites together with a transmural ECG. Basic cycle length = 2,000 ms. (A) Control. (B) Chromanol 293B (30 #mol/L) prolonged the action potentials of the three cell types and the QT interval, but did not increase transmural dispersion of repolarization (42 to 46 ms) or widen the T wave. (C) Isoproterenol (100 nmol/L) in the continued presence of chromanol 293B abbreviated the action potential of epicardial and endocardial cells, but not that of the M cell, resulting in an accentuated transmural dispersion of repolarization (85 ms) and broad-based T waves as commonly seen in LQT1 patients. (Reprinted with permission (17).)
dispersion of repolarization as a result of an abbreviation of the APD of epicardial a n d endocardial cells but not by a prolongation of that of M ceils, resulting in a long QT interval with a b r o a d - b a s e d T w a v e (Fig. 1C), as c o m m o n l y seen in patients afflicted with the LQT1 s y n d r o m e . The differential response of the 3 cell types to isoproterenol m a y be explained by intrinsic differences in IKs a m o n g the 3 cell types. A larger a u g m e n t a t i o n of a n y r e m a i n i n g IKs by isoproterenol in epicardial and endocardial cells t h a n in M cells, w h e r e IKs is intrinsically weak, w o u l d be expected to abbreviate the epicardial a n d endocardial responses but not that of the M cell, giving rise to a b r o a d - b a s e d T w a v e and a large TDR.
LQT2 Syndrome D-Sotalo1, an IKr blocker, mimics LQT2 as well as acquired (drug-induced) forms of LQTS (16). DSotalol especially in the presence of low p o t a s s i u m
(2 m m o l / L ) produces a preferential prolongation of the M-cell APD and a v e r y significant slowing of phase 3 repolarization of the 3 cell types, resulting in a prolonged QT interval, an increased t r a n s m u r a l dispersion of repolarization a n d low amplitude T w a v e s with a deeply n o t c h e d or bifurcated appearance (Fig. 2D), as often seen in patients with the LQT2 syndrome.
LQT3 Syndrome ATX-II, an agent that a u g m e n t s late sodium current (INa), mimics the LQT3 s y n d r o m e (I6). ATX-II m a r k e d l y prolongs the QT interval, widens the T wave, a n d causes a sharp rise in TDR as a result of a greater prolongation of the APD of the M cell in w h i c h late INa is m o r e p r o m i n e n t . ATX-II also produces a m a r k e d delay in onset of the T w a v e due to relatively large effects of the drug o n epicardial and endocardial APD (Fig. 2F), consistent w i t h the
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Fig. 2. Transmembrane action potentials and transmural electrocardiogram (ECG) in the LQT2 model in normal (A and B) or low potassium (C and D), and in the LQT3 model (E and F) of arterially perfused canine left ventricular wedge preparations. All traces depict action potentials simultaneously recorded from endocardial (Endo), M, and epicardial (Epi) sites together with a transmural ECG. Basic cycle length = 2,000 ms. (B) D-Sotalo1 (100 /~mol/L) prolonged the QT interval, widened the T wave, and increased the transmural dispersion of repolarization as a result of a greater prolongation of the M-cell action potential. (D) D-Sotalol (100 /~mol/L) in the presence of low potassium (2 mmol/L) gave rise to low-amplitude T waves with a notched or bifurcated appearance due to a
Torsade de pointes (TdP) is an atypical p o l y m o r phic ventricular tachycardia often associated with QT p r o l o n g a t i o n in congenital LQTS. While there is general a g r e e m e n t that the initiating e v e n t in TdP is an early afterdepolarization (EAD)-induced triggered response (3,28-30), still in question is the origin of the triggered beats, Purkinje fibers or M cells. E1-Sherif a n d coworkers, using high-resolution 3-dimensional isochronal m a p s of activation and repolarization patterns, suggested that the initial beat of the TdP arises f r o m a focal subendocardial site, w h e r e a s s u b s e q u e n t beats are due to r e e n t r a n t excitation (31,32). Data f r o m the w e d g e h a v e provided further evidence of the m e c h a n i s m of TdP. TdP develops s p o n t a n e o u s l y in models of the LQT1 (LQT5), LQT2, a n d LQT3 s y n d r o m e s ( 16,17,19,21 ) (Figs. 3A a n d 3B). W h e n s p o n t a n e o u s TdP is not observed, it can be induced using a single extrastimulus applied to the epicardium, the site of shortest refractoriness (Fig. 3C). In all models, the first p r e m a t u r e beat that initiates TdP displays a relatively n a r r o w positive QRS deflection, similar to that of the basic beats that are stimulated f r o m the endocardial site, indicating that it originates in the deep s u b e n d o c a r d i u m either in the Purkinje cells or M cells (Figs. 3A a n d 3B). In contrast, s u b s e q u e n t TdP appears to be due to a r e e n t r a n t m e c h a n i s m , because (a) a large t r a n s m u ral dispersion of repolarization and refractoriness is required to induce TdP; (b) TdP is m o s t easily induced using a single extrastimulus introduced at the site of shortest repolarization (epicardium); (c) m a i n t a i n e d TdP can be induced only in larger preparations; and (d) several pharmacologic agents can suppress TdP by reducing the vulnerable wind o w during w h i c h an extrastimulus can induce
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very significant slowing of repolarization as commonly seen in LQT2 patients. (F) ATX-II (20 nmol/L) markedly prolonged the QT interval, widened the T wave, and caused a sharp rise in the transmural dispersion of repolarization. ATX-II also produced a marked delay in onset of the T wave due to relatively large effects of the drug on the epicardial and endocardial action potentials, consistent with the late-appearing T wave pattern observed in LQT3 patients. (Reprinted with permission (16).)
Cellular Basis for the Long QT Syndrome • A
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Fig. 3. Polymorphic ventricular tachycardia displaying features of torsade de pointes (TdP) in the LQTI (A), LQT2 (B), and LQT3 (C) models of arterially perfused canine left ventricular wedge preparations. Chromanol 293B + isoproterenol, D-Sotalo1, and ATX-II were used to mimic the 3 syndromes, respectively. Each trace shows action potentials simultaneously recorded from M and epicardial (Epi) cells together with a transmural ECG. The preparation was paced from the endocardial surface at a basic cycle length of 1,000 or 2,000 ms (S1). (A and B) Spontaneous TdP induced in the LQT1 and LQT2 models, respectively. In both models, first groupings show spontaneous ventricular premature beat (or couplet) that failed to induce TdP, and second groupings shown spontaneous premature beat that succeeded. Premature response appears to originate from deep subendocardium (M or Purkinje). (C) Programmed electrical stimulationinduced TdP in the LQT3 model. ATX-II produced very
The value of p a c e m a k e r t h e r a p y was discussed by Moss a n d coworkers for patients w i t h congenital LQTS resistant to beta blockers or left cervicothoracic s y m p a t h e t i c g a n g l i o n e c t o m y (33). M o r e recently, Schwartz et al. d e m o n s t r a t e d that increases in heart rate recorded during exercise testing or on Holter recording w e r e m o r e effective in abbreviating the QT interval in LQT3 patients t h a n in LQT2 patients (34). Using guinea pig ventricular m y o cytes, Priori et al. also d e m o n s t r a t e d greater pacinginduced abbreviation of APD in the LQT3 t h a n in the LQT2 (35). In contrast, Hirao a n d coworkers used m o n o p h a s i c action potential (MAP) recordings and atrial pacing, w h i c h is expected to h a v e little influence on s y m p a t h e t i c activity, a n d suggested that a t t e n u a t i o n of b o t h the QT interval and the MAP duration in response to increasing heart rate was m o r e p r o n o u n c e d in patients w i t h congenital LQTS t h a n in control patients (36). Most of their LQTS patients w e r e s u b s e q u e n t l y s h o w n to be linked to LQT1 or LQT2 genotypes (unpublished data). A m o n g the LQTS models created in the w e d g e preparation, APD-, QT- a n d TDR-rate relations are generally m u c h steeper in the LQT3 m o d e l t h a n in either LQT1 or LQT2 m o d e l ( 16,17), consistent w i t h the results of Schwartz a n d coworkers. However, the rate relations in the LQT1 and LQT2 models are b o t h steeper t h a n those u n d e r control conditions (16,17). In the clinic, long pauses, short-long-short sequences and other perturbations of rate h a v e b e e n s h o w n to relate to arrhythrnogenic consequences in patients w i t h congenital as well as acquired LQTS (37). Thus, constancy in the rate of ventricular activation w o u l d be expected to be favorable in m o s t patients with the LQTS. These results suggest that a l t h o u g h p a c e m a k e r t h e r a p y is likely to be m o s t effective in the LQT3 patients, its usefulness should not be discounted in the LQT1 and LQT2 as well as acquired LQTS.
4 significant dispersion of repolarization (first grouping). A single extrastimulus ($2) applied to the epicardial surface at an $1-S2 interval of 320 ms initiated TdP (second grouping). (Modified and reprinted with permission (16,17,27).)
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Fig. 4. Effect of mexiletine (Mex) on action potential duration (APD) and QT interval in the LQT2 (A) and LQT3 (B) models of arterially perfused canine left ventricular wedge preparations. All traces show superimposed action potentials recorded simultaneously from M and epicardial cells (Epi) together with a transmural electrocardiogram (ECG). Basic cycle length = 2,000 msec. In the LQT3 (ATX-II, 20 nmol/L) model, 2 to 20 /zmol/L mexiletine dose-dependently abbreviated the APD of both cells as well as the QT interval; 20/zmol/L mexiletine totally reversed the effects of ATX-II to prolong the APD and the QT interval, and to increase the transmural dispersion of repolarization (B). In contrast, in the LQT2 (D-sotalo1, 100/~mol/L) model, 20 #,mol/L mexiletine failed to totally reverse the actions of D-sotalol to prolong the APD and the QT interval. However, because mexiletine abbreviated the M-cell APD more than that of the epicardial cell, the transmural dispersion of repolarization was decreased to control values (A). (Reprinted with permission (16).)
Possible Pharmacologic Therapy A direct link of g e n e m u t a t i o n s to ion c h a n n e l d y s f u n c t i o n suggests the possibility of g e n e - s p e cific t h e r a p y for c o n g e n i t a l LQTS. S c h w a r t z a n d coworkers have shown that sodium channel block w i t h m e x i l e t i n e was m u c h m o r e effective in a b b r e v i a t i n g QT i n t e r v a l in LQT3 p a t i e n t s w i t h INa defect t h a n in e i t h e r LQT1 or LQT2 p a t i e n t s (34). C o m p t 0 n et al. h a v e s h o w n t h a t e x o g e n o u s l y a d m i n i s t e r e d p o t a s s i u m significantly s h o r t e n e d the QT i n t e r v a l in LQT2 p a t i e n t s w i t h IKr defect (38). Shimizu a n d c o w o r k e r s h a v e r e p o r t e d t h a t nicorandil, a K + c h a n n e l o p e n e r , significantly a b b r e v i a t e d the QT i n t e r v a l a n d MAP d u r a t i o n in the p r e s e n c e of e p i n e p h r i n e in LQT1 p a t i e n t s w i t h IKs defect (29). H o w e v e r , the effects of these a n t i a r r h y t h m i c agents to a b b r e v i a t e the QT interval a n d APD is n o t necessarily c o n g r u e n t w i t h their efficacy in decreasing a r r h y t h m i c risk or s u d d e n cardiac death.
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Beta blockers are widely reported to reduce the incidence of syncope a n d sudden cardiac death in patients with congenital LQTS (39). Vincent et al. d e m o n s t r a t e d that LQT1 patients w e r e m o s t responsive to beta blockers a m o n g the 3 forms of congenital LQTS (40). Recently, beta blockers w e r e reported to be effective to suppress cardiac events also in LQT2 s y n d r o m e (41). However, the effectiveness of beta blockers in patients with the LQT3 g e n o t y p e is u n k n o w n , largely because the LQT3 patients are very rare. In the LQTS m o d e l of the wedge, therapeutic concentrations of propranolol, a beta blocker, completely inhibit the influence of isoproterenol to increase TDR and to p r o d u c e s p o n t a n e o u s as well as stimulation-induced TdP in the LQT1 model, supporting the fact that beta blockers are dramatically effective in LQT1 patients (17,42). In the LQT2 model, p r o p r a n o l o l also suppressed the influence of isoproterenol to transiently increase the TDR and
Cellular Basis for the Long QT Syndrome
the incidence of TdP (42), indicating that beta blockers m a y be protective in patients with the LQT2 as well as the LQT1 syndrome. In contrast, propranolol totally suppressed the protective effect of isoproterenol to abbreviate the APD, to decrease the TDR and the d e v e l o p m e n t of TdP in the LQT3 model (42). These data suggest that lg-blockade m a y facilitate the long QT and the induction of TdP and m a y be contraindicated in patients with the LQT3 syndrome, a l t h o u g h further evaluation is needed. Na + Channel Blockers The class IB antiarrhythmic agent, mexiletine, is k n o w n to block the late INa at the level of the action potential plateau, a l t h o u g h its effects on fast INa and on n o r m a l c o n d u c t i o n are negligible. Preliminary clinical reports have suggested that mexiletine dramatically abbreviates the QT interval in LQT3 patients but not in LQT1 or LQT2 patients (34). Our data using the arterially perfused wedge preparations s h o w that mexiletine is more effective in abbreviating the QT interval in the LQT3 model t h a n in either LQT1 or LQT2 model (16), concordant with the results of Schwartz and coworkers (Fig. 4). However, mexiletine reduces transmural dispersion of repolarization and prevents the develo p m e n t of s p o n t a n e o u s and stimulation-induced TdP in the LQT1 and LQT2 models as well as in the LQT3 model, as a result of a greater abbreviation of APD in M cells in w h i c h late fNa is larger (16,17) (Fig. 4). These findings suggest that while Na + channel block with class IB a n t i a r r h y t h m i c agents is most effective in the LQT3 syndrome, Na + channel blockers in combination with beta blockers m a y w a r r a n t further consideration as a therapeutic approach in the t r e a t m e n t of the LQT1 and LQT2 syndromes. K + Channel Openers Our preliminary data involving the wedge preparations suggest that nicorandil is capable of abbreviating long QT, reducing TDR and preventing s p o n t a n e o u s and stimulation-induced TdP in the LQT1 and LQT2 models but not in the LQT3 model, although relatively high concentrations of nicorandil are required (43).
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18. Yan GX, Shimizu W, Antzelevitch C: The characteristics and distribution of M ceils in arterially-perfused canine left ventricular wedge preparations. Circulation 98:1921, 1998 19. Yan GX, Antzelevitch C: Cellular basis for the normal T wave and the electrocardiographic manifestations of the long QT syndrome. Circulation 98:1928, 1998 20. Shimizu W, Antzelevitch C: Cellular and ionic basis for T wave alternans under long QT syndrome conditions. Circulation 99:1499, 1999 21. Shimizu W, Antzelevitch C: Sodium pentobarbital reduces transmural dispersion of repolarization and prevents torsade de pointes in models of acquired and congenital long QT syndrome. J Cardiovasc Electrophysiol 10:154, 1999 22. Moss AJ, Zareba W, Benhorin J, et al: ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 92:2929, 1995 23. 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:i729, 1991 24. Antzelevitch C, Sicouri S, Litovsky SH, et al: Heterogeneity within the ventricular wall: electrophysiology and pharmacology of epicardial, endocardial and M cells. Circ Res 69:1427, 1991 25. Antzelevitch C, Sicouri S: Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: the role of M ceils in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol 23:259, 1994 26. Antzelevitch C, Shimizu W, Yan GX, et ah The M cell: its contribution to the ECG and to normal and abnormal function of the heart. J Cardiovasc Electrophysiol 10:1124, 1999 27. Antzelevitch C, Yan GX, Shimizu W, Burashnikov A: Electrical heterogeneity as the basis for the ECG and function of the heart in health and disease. In Zipes DP, Jalife J (eds): Cardiac electrophysiology: from cell to bedside, 3rd ed. WB Saunders, Philadelphia, 1999 (in press) 28. Shimizu W, Ohe T, Kurita T, et ah Effects of verapamil and propranolol on early afterdepolarizations and ventricular arrhythmias induced by epinephrine in congenital long QT syndrome. J Am Coll Cardiol 26:1299, 1995 29. Shimizu W, Kurita T, Matsuo K, et ah Improvement of repolarization abnormalities by a K + channel opener in the LQT1 form of congenital long QT syndrome. Circulation 97:1581, 1998 30. Vos MA, Verduyn SC, Gorgels APM, et al: Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by D-sotalo1 and pacing in the dog with chronic atrioventricular block. Circulation 91:864, 1995 31. E1-Sherif N, Caref EB, Yin H, Restivo M: The electro-
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physiological mechanism of ventricular arrhythmias in the long QT syndrome: tridimensional mapping of activation and recovery patterns. Circ Res 79:474, 1996 El-Sherif N, Chinushi M, Caref EB, Restivo M: Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long-QT syndrome. Detailed analysis of ventricular tridimensional activation patterns. Circulation 96:4392, 1997 Moss AJ, Liu JE, Gottlieb S, et ah Efficacy of permanent pacing in the m a n a g e m e n t of high-risk patients with long QT syndrome. Circulation 84:1524, i991 Schwartz PJ, Priori SG, Locati EH, et ah Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to NA + channel blockade and to increases in heart rate: implications for gene-specific therapy. Circulation 92:3381, 1995 Priori SG, Napolitano C, Cantu F, et ah Differential responses to NA + channel blockade, /3-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects present in the long-QT syndrome. Circ Res 78:1009, 1996 Hirao H, Shimizu W, Kurita T, et ah Frequencydependent electrophysiologic properties of ventricular repolarization in patients with congenital long QT syndrome. J Am Coll Cardiol 28:1269, 1996 Viskin S, Alla SR, Barron HL, et ah Mode of onset of torsade de pointes in congenital long QT syndrome. J Am Coll Cardiol 28:1262, 1996 Compton SJ, Lux RL, Ramsey MR, et ah Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation 94:1018, 1996 Moss AJ, Schwartz PJ, Crampton RS, et ah The long QT syndrome: prospective longitudinal study of 328 families. Circulation 84:1136, 1991 Vincent GM, Fox J, Zhang L, Timothy KW: Betablockers markedly reduce risk and syncope in KvLQT1 long QT patients (abstract). Circulation 94:I204, 1996 Wilde AAM, Jongbloed RJE, Doevendans PA, et al: Auditory stimuli as a trigger for arrhytbmic events differentiate HERG-related (LQT2) patients from KvLQTl-related patients (LQT1). J Am Coll Cardiol 33:327, 1999 Shimizu W, Antzelevitch C: Different effects of/3-adrenergic agonists and antagonists in LQTI, LQT2 and LQT3 models of the long QT syndrome. J Am Cell Cardiol (in press) Shimizu W, Antzelevitch C: Differential effects of a K + channel opener in reducing dispersion of repolarization and preventing torsade de pointes in LQT 1, LQT2 and LQT3 models of the long QT syndrome (abstract). PACE 21:II-846, 1998
Cellular Basis for Long QT, Transmural Dispersion of Repolarization, and Torsade de Pointes in the Long QT Syndrome
Wataru Shimizu, MD, PhD,* and Charles Antzelevitch, PhD t
Abstract: Genetic studies have identified four forms of congenital long QT syndrome (LQTS) caused by mutations in ion channel genes located on chromosomes 3 (LQT3), 7 (LQT2), 11 (LQT1), and 21 (LQTS). Preliminary clinical studies have reported different phenotypic electrocardiographic patterns and different sensitivity to pacing or pharmacological therapy for each genotype. A transmural electrocardiogram and transmembrane action potentials from epicardial, M, and endocardial cells were simultaneously recorded from an arterially perfused wedge of canine left ventricle. Isoproterenol (100 nmol/L) in the presence of chromano1293B (30 p,mol/L), an IKs blocker (LQT1 model), produced a preferential prolongation of M-cell action potential duration (APD), resulting in an increase in transmural dispersion of repolarization (TDR) and a broad-based T wave, as commonly seen in LQT1 patients. D-Sotalol (100/~mol/L), an IKr blocker (LQT2 model), and ATX-II (20 nmol/L), an agent that augments late INa (LQT3 model), also produced a preferential prolongation of M-cell APD, an increase in TDR, and low-amplitude T wave with a bifurcated appearance (LQT2), and late-appearing T wave (LQT3), respectively. APD-, QT-, and TDR-rate relations were much steeper in the LQT3 model than in either the LQT1 or LQT2 model, whereas the rate relations in the LQT1 and LQT2 models were both steeper than those u n d e r control conditions. Spontaneous and programmed electrical stimulation-induced torsade de pointes (TdP) were observed in all 3 models. Propranolol (1 /~mol/L), a beta blocker, completely prevented the effect of isoproterenol to persistently or transiently increase TDR and to induce TdP in the LQT1 and LQT2 models, but facilitated TdP in the LQT3 model. Mexiletine, a class IB Na + channel blocker, dose-dependently (2-20 p,mol/L) abbreviated the QT and APD more in the LQT3 model, but decreased TDR and suppressed TdP in the 3 models. K e y w o r d s : long QT syndrome, arrhythmias, KvLQT1, HERG, SCN5A, KCNE 1, M cell, heterogeneity.
From the * Department of Internal Medicine, National Cardiovascular Center, Osaka, Japan; and l- Masonic Medical Research Laboratory, Utica, NK
Supported by grant HL47678 from the National Institutes of Health (C. Antzelevitch) and grants from Medtronic Japan (W. Shimizu), American Heart Association (W. Shimizu) Suzuken Memorial Foundation (W. Shimizu), and the Sixth, Seventh, and Eighth Manhattan Masonic Districts and NYS and Florida Grand Lodges F. & A.M. Reprint requests: Wataru Shimizu, MD, PhD, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka 565-8565 Japan. Copyright © 1999 by Churchill Livingstone ® 0022-0736/991320S-0035510.00/0
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The long QT syndrome (LQTS) is characterized by long QT intervals, an atypical polymorphic ventricular arrhythmia known as torsade de pointes (TdP), and a high risk for sudden cardiac death (1-5). In the congenital form of the LQTS, an imbalance between left and right stellate inputs to the heart was first suggested to underlie LQTS in 1975 ( 1). However, the sympathetic imbalance hypothesis as a primary cause lost ground when recent genetic linkage analysis uncovered four gene mutations responsible for ion channel defects (6-15). Genetic linkage analysis has identified four forms of congenital LQTS caused by mutations in ion channel genes located on chromosomes 3, 7, 11, and 21 (6-10). Chromosome l l linked LQT1 is assodated with a mutation in KvLQT1 which encodes for the slowly activating delayed rectifier potassium currents (IKs) (11,12), and chromosome 21-1inked LQT5 is the result of a mutation in KCNE 1 (minK) whose product coassembles with that of KvLQT1 to form the IKs channel (I 3). Chromosome 7-1inked LQT2 is caused by mutations in HERG, a gene that encodes for the channel that carries the rapidly activating delayed rectifier potassium currents (IKr) (7), whereas chromosome 3-1inked LQT3 is related to mutations in SCN5A, a gene that encodes for the alpha subunit of the sodium channel in heart (6). More recently, the autosomal recessive form of Jervell and Lange-Nielsen syndrome, characterized by marked QT prolongation and deafness, is reported to arise in individuals who inherit abnormal KvLQT1 or KCNE 1 alleles from both parents (14,15). Our studies employed arterially-perfused canine left ventricular preparations from which we are able to simultaneously record transmembrane activity from epicardial, M, and endocardial or subendocardial Purkinje sites along the transmural surface of the ventricular wall using floating glass microelectrodes (16-21). A pseudo-electrocardiogram (ECG) recorded concurrently along the same vector permits correlation of transmembrane and electrocardiographic activity. The wedge is capable of developing and sustaining a variety of arrhythmias, including ventricular premature beats and TdP. This review summarizes the results of studies designed to probe the cellular basis of the long QT interval, phenotypic appearance of abnormal T waves, the mechanisms of TdP as well as possible therapeutic approaches in congenital LQTS.
Phenotypic Appearance of Abnormal T Waves In 1995, Moss and coworkers demonstrated a correlation between the phenotypic appearance of
abnormal T waves and the 3 genotypes of congenital LQTS (22). LQT1 patients with IKs defect were found to display broad-based prolonged T waves, whereas LQT2 patients with IKr defect showed low-amplitude, moderately delayed T waves with a notched or bifurcated appearance. LQT3 patients with sodium channel (INa) defect displayed distinctive late-appearing T waves. We hypothesized that the interaction of the 3 electrically distinct cells types encountered across the ventricular wall (epicardium, M, and endocardium) is responsible for the different morphologies of the T wave and that the preferential prolongation of M cells by the ion channel mutations underlies LQTS, contributing to the development of long QT intervals and TdP. M ceils are known to display electrical characteristics and responses to drugs consistent with the ECG manifestations that attend the development of long QT and TdP (23-27). Data form the arterially perfused left ventricular wedge preparation suggest that the morphology of the T wave is a function of 2 opposing transmural currents, due to the development of opposing voltage gradients during repolarization: between epicardium and the M-cell region, and between the M-cell region and endocardium. The presence of a high level of tissue resistivity between the epicardium and the M region also serves to modulates the intensity of the transmural currents (16-21) (Figs. 1 and 2). The peak of the T wave in the ECG is always coincident with the repolarization of the shortest epicardial action potential, whereas the end of the T wave coincides with repolarization of the longest M-cell action potential. Repolarization of endocardial action potentials is usually intermediate between that of the M cells and the epicardial cells. In contrast, repolarization of subendocardial Purkinje fibers always outlasts that of the M cells, suggesting that repolarization of Purkinje cells fails to contribute to the manifestation of the T waves. Thus, the transmural dispersion of repolarization (TDR) across the ventricular wall is defined by the difference in repolarization time (activation time + action potential duration [APD]) between the M cell and the epicardial cell.
LQT1 Syndrome Chromanol 293B, a relatively specific IKs blocker, mimics the LQT1 (and LQT5) syndrome (17); it produces a homogeneous prolongation of APD across the ventricular wall but fails to widen the T wave or increase the TDR (Fig. 1B). Beta-adrenergic stimulation with isoproterenol increases transmural
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dispersion of repolarization as a result of an abbreviation of the APD of epicardial a n d endocardial cells but not by a prolongation of that of M ceils, resulting in a long QT interval with a b r o a d - b a s e d T w a v e (Fig. 1C), as c o m m o n l y seen in patients afflicted with the LQT1 s y n d r o m e . The differential response of the 3 cell types to isoproterenol m a y be explained by intrinsic differences in IKs a m o n g the 3 cell types. A larger a u g m e n t a t i o n of a n y r e m a i n i n g IKs by isoproterenol in epicardial and endocardial cells t h a n in M cells, w h e r e IKs is intrinsically weak, w o u l d be expected to abbreviate the epicardial a n d endocardial responses but not that of the M cell, giving rise to a b r o a d - b a s e d T w a v e and a large TDR.
LQT2 Syndrome D-Sotalo1, an IKr blocker, mimics LQT2 as well as acquired (drug-induced) forms of LQTS (16). DSotalol especially in the presence of low p o t a s s i u m
(2 m m o l / L ) produces a preferential prolongation of the M-cell APD and a v e r y significant slowing of phase 3 repolarization of the 3 cell types, resulting in a prolonged QT interval, an increased t r a n s m u r a l dispersion of repolarization a n d low amplitude T w a v e s with a deeply n o t c h e d or bifurcated appearance (Fig. 2D), as often seen in patients with the LQT2 syndrome.
LQT3 Syndrome ATX-II, an agent that a u g m e n t s late sodium current (INa), mimics the LQT3 s y n d r o m e (I6). ATX-II m a r k e d l y prolongs the QT interval, widens the T wave, a n d causes a sharp rise in TDR as a result of a greater prolongation of the APD of the M cell in w h i c h late INa is m o r e p r o m i n e n t . ATX-II also produces a m a r k e d delay in onset of the T w a v e due to relatively large effects of the drug o n epicardial and endocardial APD (Fig. 2F), consistent w i t h the
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Fig. 2. Transmembrane action potentials and transmural electrocardiogram (ECG) in the LQT2 model in normal (A and B) or low potassium (C and D), and in the LQT3 model (E and F) of arterially perfused canine left ventricular wedge preparations. All traces depict action potentials simultaneously recorded from endocardial (Endo), M, and epicardial (Epi) sites together with a transmural ECG. Basic cycle length = 2,000 ms. (B) D-Sotalo1 (100 /~mol/L) prolonged the QT interval, widened the T wave, and increased the transmural dispersion of repolarization as a result of a greater prolongation of the M-cell action potential. (D) D-Sotalol (100 /~mol/L) in the presence of low potassium (2 mmol/L) gave rise to low-amplitude T waves with a notched or bifurcated appearance due to a
Torsade de pointes (TdP) is an atypical p o l y m o r phic ventricular tachycardia often associated with QT p r o l o n g a t i o n in congenital LQTS. While there is general a g r e e m e n t that the initiating e v e n t in TdP is an early afterdepolarization (EAD)-induced triggered response (3,28-30), still in question is the origin of the triggered beats, Purkinje fibers or M cells. E1-Sherif a n d coworkers, using high-resolution 3-dimensional isochronal m a p s of activation and repolarization patterns, suggested that the initial beat of the TdP arises f r o m a focal subendocardial site, w h e r e a s s u b s e q u e n t beats are due to r e e n t r a n t excitation (31,32). Data f r o m the w e d g e h a v e provided further evidence of the m e c h a n i s m of TdP. TdP develops s p o n t a n e o u s l y in models of the LQT1 (LQT5), LQT2, a n d LQT3 s y n d r o m e s ( 16,17,19,21 ) (Figs. 3A a n d 3B). W h e n s p o n t a n e o u s TdP is not observed, it can be induced using a single extrastimulus applied to the epicardium, the site of shortest refractoriness (Fig. 3C). In all models, the first p r e m a t u r e beat that initiates TdP displays a relatively n a r r o w positive QRS deflection, similar to that of the basic beats that are stimulated f r o m the endocardial site, indicating that it originates in the deep s u b e n d o c a r d i u m either in the Purkinje cells or M cells (Figs. 3A a n d 3B). In contrast, s u b s e q u e n t TdP appears to be due to a r e e n t r a n t m e c h a n i s m , because (a) a large t r a n s m u ral dispersion of repolarization and refractoriness is required to induce TdP; (b) TdP is m o s t easily induced using a single extrastimulus introduced at the site of shortest repolarization (epicardium); (c) m a i n t a i n e d TdP can be induced only in larger preparations; and (d) several pharmacologic agents can suppress TdP by reducing the vulnerable wind o w during w h i c h an extrastimulus can induce
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very significant slowing of repolarization as commonly seen in LQT2 patients. (F) ATX-II (20 nmol/L) markedly prolonged the QT interval, widened the T wave, and caused a sharp rise in the transmural dispersion of repolarization. ATX-II also produced a marked delay in onset of the T wave due to relatively large effects of the drug on the epicardial and endocardial action potentials, consistent with the late-appearing T wave pattern observed in LQT3 patients. (Reprinted with permission (16).)
Cellular Basis for the Long QT Syndrome • A
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Fig. 3. Polymorphic ventricular tachycardia displaying features of torsade de pointes (TdP) in the LQTI (A), LQT2 (B), and LQT3 (C) models of arterially perfused canine left ventricular wedge preparations. Chromanol 293B + isoproterenol, D-Sotalo1, and ATX-II were used to mimic the 3 syndromes, respectively. Each trace shows action potentials simultaneously recorded from M and epicardial (Epi) cells together with a transmural ECG. The preparation was paced from the endocardial surface at a basic cycle length of 1,000 or 2,000 ms (S1). (A and B) Spontaneous TdP induced in the LQT1 and LQT2 models, respectively. In both models, first groupings show spontaneous ventricular premature beat (or couplet) that failed to induce TdP, and second groupings shown spontaneous premature beat that succeeded. Premature response appears to originate from deep subendocardium (M or Purkinje). (C) Programmed electrical stimulationinduced TdP in the LQT3 model. ATX-II produced very
The value of p a c e m a k e r t h e r a p y was discussed by Moss a n d coworkers for patients w i t h congenital LQTS resistant to beta blockers or left cervicothoracic s y m p a t h e t i c g a n g l i o n e c t o m y (33). M o r e recently, Schwartz et al. d e m o n s t r a t e d that increases in heart rate recorded during exercise testing or on Holter recording w e r e m o r e effective in abbreviating the QT interval in LQT3 patients t h a n in LQT2 patients (34). Using guinea pig ventricular m y o cytes, Priori et al. also d e m o n s t r a t e d greater pacinginduced abbreviation of APD in the LQT3 t h a n in the LQT2 (35). In contrast, Hirao a n d coworkers used m o n o p h a s i c action potential (MAP) recordings and atrial pacing, w h i c h is expected to h a v e little influence on s y m p a t h e t i c activity, a n d suggested that a t t e n u a t i o n of b o t h the QT interval and the MAP duration in response to increasing heart rate was m o r e p r o n o u n c e d in patients w i t h congenital LQTS t h a n in control patients (36). Most of their LQTS patients w e r e s u b s e q u e n t l y s h o w n to be linked to LQT1 or LQT2 genotypes (unpublished data). A m o n g the LQTS models created in the w e d g e preparation, APD-, QT- a n d TDR-rate relations are generally m u c h steeper in the LQT3 m o d e l t h a n in either LQT1 or LQT2 m o d e l ( 16,17), consistent w i t h the results of Schwartz a n d coworkers. However, the rate relations in the LQT1 and LQT2 models are b o t h steeper t h a n those u n d e r control conditions (16,17). In the clinic, long pauses, short-long-short sequences and other perturbations of rate h a v e b e e n s h o w n to relate to arrhythrnogenic consequences in patients w i t h congenital as well as acquired LQTS (37). Thus, constancy in the rate of ventricular activation w o u l d be expected to be favorable in m o s t patients with the LQTS. These results suggest that a l t h o u g h p a c e m a k e r t h e r a p y is likely to be m o s t effective in the LQT3 patients, its usefulness should not be discounted in the LQT1 and LQT2 as well as acquired LQTS.
4 significant dispersion of repolarization (first grouping). A single extrastimulus ($2) applied to the epicardial surface at an $1-S2 interval of 320 ms initiated TdP (second grouping). (Modified and reprinted with permission (16,17,27).)
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Fig. 4. Effect of mexiletine (Mex) on action potential duration (APD) and QT interval in the LQT2 (A) and LQT3 (B) models of arterially perfused canine left ventricular wedge preparations. All traces show superimposed action potentials recorded simultaneously from M and epicardial cells (Epi) together with a transmural electrocardiogram (ECG). Basic cycle length = 2,000 msec. In the LQT3 (ATX-II, 20 nmol/L) model, 2 to 20 /zmol/L mexiletine dose-dependently abbreviated the APD of both cells as well as the QT interval; 20/zmol/L mexiletine totally reversed the effects of ATX-II to prolong the APD and the QT interval, and to increase the transmural dispersion of repolarization (B). In contrast, in the LQT2 (D-sotalo1, 100/~mol/L) model, 20 #,mol/L mexiletine failed to totally reverse the actions of D-sotalol to prolong the APD and the QT interval. However, because mexiletine abbreviated the M-cell APD more than that of the epicardial cell, the transmural dispersion of repolarization was decreased to control values (A). (Reprinted with permission (16).)
Possible Pharmacologic Therapy A direct link of g e n e m u t a t i o n s to ion c h a n n e l d y s f u n c t i o n suggests the possibility of g e n e - s p e cific t h e r a p y for c o n g e n i t a l LQTS. S c h w a r t z a n d coworkers have shown that sodium channel block w i t h m e x i l e t i n e was m u c h m o r e effective in a b b r e v i a t i n g QT i n t e r v a l in LQT3 p a t i e n t s w i t h INa defect t h a n in e i t h e r LQT1 or LQT2 p a t i e n t s (34). C o m p t 0 n et al. h a v e s h o w n t h a t e x o g e n o u s l y a d m i n i s t e r e d p o t a s s i u m significantly s h o r t e n e d the QT i n t e r v a l in LQT2 p a t i e n t s w i t h IKr defect (38). Shimizu a n d c o w o r k e r s h a v e r e p o r t e d t h a t nicorandil, a K + c h a n n e l o p e n e r , significantly a b b r e v i a t e d the QT i n t e r v a l a n d MAP d u r a t i o n in the p r e s e n c e of e p i n e p h r i n e in LQT1 p a t i e n t s w i t h IKs defect (29). H o w e v e r , the effects of these a n t i a r r h y t h m i c agents to a b b r e v i a t e the QT interval a n d APD is n o t necessarily c o n g r u e n t w i t h their efficacy in decreasing a r r h y t h m i c risk or s u d d e n cardiac death.
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Beta blockers are widely reported to reduce the incidence of syncope a n d sudden cardiac death in patients with congenital LQTS (39). Vincent et al. d e m o n s t r a t e d that LQT1 patients w e r e m o s t responsive to beta blockers a m o n g the 3 forms of congenital LQTS (40). Recently, beta blockers w e r e reported to be effective to suppress cardiac events also in LQT2 s y n d r o m e (41). However, the effectiveness of beta blockers in patients with the LQT3 g e n o t y p e is u n k n o w n , largely because the LQT3 patients are very rare. In the LQTS m o d e l of the wedge, therapeutic concentrations of propranolol, a beta blocker, completely inhibit the influence of isoproterenol to increase TDR and to p r o d u c e s p o n t a n e o u s as well as stimulation-induced TdP in the LQT1 model, supporting the fact that beta blockers are dramatically effective in LQT1 patients (17,42). In the LQT2 model, p r o p r a n o l o l also suppressed the influence of isoproterenol to transiently increase the TDR and
Cellular Basis for the Long QT Syndrome
the incidence of TdP (42), indicating that beta blockers m a y be protective in patients with the LQT2 as well as the LQT1 syndrome. In contrast, propranolol totally suppressed the protective effect of isoproterenol to abbreviate the APD, to decrease the TDR and the d e v e l o p m e n t of TdP in the LQT3 model (42). These data suggest that lg-blockade m a y facilitate the long QT and the induction of TdP and m a y be contraindicated in patients with the LQT3 syndrome, a l t h o u g h further evaluation is needed. Na + Channel Blockers The class IB antiarrhythmic agent, mexiletine, is k n o w n to block the late INa at the level of the action potential plateau, a l t h o u g h its effects on fast INa and on n o r m a l c o n d u c t i o n are negligible. Preliminary clinical reports have suggested that mexiletine dramatically abbreviates the QT interval in LQT3 patients but not in LQT1 or LQT2 patients (34). Our data using the arterially perfused wedge preparations s h o w that mexiletine is more effective in abbreviating the QT interval in the LQT3 model t h a n in either LQT1 or LQT2 model (16), concordant with the results of Schwartz and coworkers (Fig. 4). However, mexiletine reduces transmural dispersion of repolarization and prevents the develo p m e n t of s p o n t a n e o u s and stimulation-induced TdP in the LQT1 and LQT2 models as well as in the LQT3 model, as a result of a greater abbreviation of APD in M cells in w h i c h late fNa is larger (16,17) (Fig. 4). These findings suggest that while Na + channel block with class IB a n t i a r r h y t h m i c agents is most effective in the LQT3 syndrome, Na + channel blockers in combination with beta blockers m a y w a r r a n t further consideration as a therapeutic approach in the t r e a t m e n t of the LQT1 and LQT2 syndromes. K + Channel Openers Our preliminary data involving the wedge preparations suggest that nicorandil is capable of abbreviating long QT, reducing TDR and preventing s p o n t a n e o u s and stimulation-induced TdP in the LQT1 and LQT2 models but not in the LQT3 model, although relatively high concentrations of nicorandil are required (43).
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