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T wave alternans in an in vitro canine tissue model of Brugada syndrome

¹Krannert Institute of Cardiology, Indiana University School of Medicine and ²Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana

Submitted 29 November 2005 ; accepted in final form 16 February 2006

	ABSTRACT

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Macroscopic T wave alternans (TWA) associated with increased occurrence of ventricular arrhythmias has been reported in patients with Brugada syndrome. However, the mechanisms in this syndrome are still unclear. We evaluated the hypothesis that TWA in Brugada syndrome was caused by the dynamic instability and heterogeneity of action potentials (APs) in the right ventricle. Using an optical mapping system, we mapped APs on the epicardium or transmural surfaces of 28 isolated and arterially perfused canine right ventricular preparations having drug-induced Brugada syndrome (in µmol/l: 2.5–15 pinacidil, 5.0 terfenadine, and 5.0–13 pilsicainide). Bradycardia at cycle length (CL) of 2,632 ± 496 ms (n = 19) induced alternating deep and shallow T waves in the transmural electrocardiogram. Compared with the shallow T waves, deep T waves were associated with epicardial APs having longer durations and larger domes. Adjacent regions having APs with alternating domes, with constant domes, and without domes coexisted simultaneously in the epicardium and caused TWA. In contrast to the alternating epicardial APs, midmyocardial and endocardial APs did not change during TWA. Alternans could be terminated by rapid (CL: 529 ± 168 ms, n = 7) or very slow (CL: 3,000 ms, n = 7) pacing. The heterogeneic APs during TWA augmented the dispersion of repolarization both within the epicardium and from the epicardium to the endocardium and caused phase 2 reentry. In this drug-induced model of Brugada syndrome, heterogeneic AP contours and dynamic alternans in the dome of right ventricular epicardial, but not midmyocardial or endocardial, APs caused TWA and heightened arrhythmogenicity in part by increasing the dispersion of repolarization.

mapping; repolarization; ventricular arrhythmias; phase 2 reentry

	METHODS

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Arterially perfused right ventricular tissue preparations. The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication no. 85–23, revised 1996). We prepared tissues with procedures similar to those used previously (31–33, 36–38). In brief, we harvested hearts from 28 anesthetized (pentobarbital sodium at 30 mg/kg body wt) adult male mongrel dogs (25–30 kg) and immediately retrogradely perfused the hearts through the aorta with a cardioplegic solution (Tyrode's solution, see below, with 15 mmol/l KCl, 4°C) that washed out the blood and pentobarbital sodium and protected the hearts during the subsequent period of tissue isolation. We isolated tissues of two different sizes, 2.5 x 2.5 x 1.0 cm³ (free wall preparations, n = 18) and 0.8 x 2.5 x 1.0 cm³ (transmural preparations, n = 10), from the same region (0–35 mm from the pulmonary valves) in the right ventricular free wall to evaluate the epicardial and transmural distributions of APs, respectively. Only one preparation was harvested from each heart. Each preparation contained either two (free wall preparations) or one (transmural preparations) branch of the right coronary artery (diameter: 1 mm). We inserted separate perfusion and pressure-monitoring cannulas in the arteries, ligated major arterial leaks with silk sutures, and trimmed underperfused tissue from the preparations. The isolated tissues were mounted in a warmed chamber with the recording surface (the epicardium or cut-exposed transmural surface) up, perfused with Tyrode's solution (in mmol/l: 128.0 NaCl, 4.69 KCl, 22.0 NaHCO₃, 0.65 NaH₂PO₄, 0.50 MgCl₂, 11.1 dextrose, and 2.0 CaCl₂, and gassed with 95% O₂-5% CO₂, pH 7.4) at an arterial pressure of 40–50 mmHg at 36.5 ± 0.5°C, and immersed in the perfusion efflux.

Tissue preparations were perfused continuously and stained with di-4-ANEPPS (C₂₈H₃₆N₂O₃S; 4 µmol/l in perfusate; Molecular Probes, Eugene, OR), which is a membrane-potential-sensitive fluorescent dye having no known electrophysiological effects and used widely in optical mapping studies. Sufficient time was allowed for the tissues to recover from the cardioplegic and isolation processes, until their full stabilization [with consistent arterial resistance, contractions, action potential durations (APDs), velocity of conduction, and ECG for >10 min]. We evaluated the healthiness of the preparations as we have done previously (31–33, 36–38). Well-perfused preparations had a vivid reddish color, low-noise optical signals with normal APD, and strong contractions upon stimulation, in contrast to the short APD (or inactivation), dull color, weak contractions, or noisy optical signals (poor perfusion and dye staining) of ischemic preparations. Healthy preparations were immobilized with cytochalasin D (20–30 µmol/l; Sigma Chemical, St. Louis, MO), which depolymerizes cytoskeletal actin filaments and reduces the Ca²⁺ sensitivity of myofilaments (5) without affecting the shape of the canine ventricular AP, as we verified previously (4, 36). The immobilized tissue had no recordable pulsation in arterial pressure and no visible contraction during stimulation. Tissue immobilization eliminated motion artifacts in optically recorded APs and facilitated the identification of the AP dome and early afterdepolarizations. We verified that these procedures produced stable tissues having transmural dispersion of APD and conduction velocity (36) similar to in vivo observations (3, 17).

Electrophysiological recording. We paced the tissue preparations from the endocardium at a cycle length (CL) of 2,000 ms (2 ms duration, 2x diastolic current threshold, with a bipolar electrode). Two silver electrodes were placed in the bath, 5–10 mm away from the epicardium and endocardium, to register the transmural ECG. An optical mapping system (36) with a 256-element (16 x 16) photodiode camera (C4675; Hamamatsu) collected the fluorescence signals from a 19.5 x 19.5 mm² observation area (1.1 x 1.1 mm²/element) on the tissue surface and converted it to 256 channels of electrical signals (APs). A custom data acquisition system recorded the APs, ECG, and arterial pressure at 1,000 samples·channel^–1·s^–1.

Drugs and study protocols. Data were recorded at pacing CLs of 3,000, 2,000, 1,000, 600, and 400 ms, after the preparations were fully immobilized and stabilized (baseline recording). Brugada-type ECG (J-ST elevation with negative T wave) and TWA were induced with the perfusion of pinacidil (2.5–5 to 10–15 µmol/l; Sigma Chemical), pilsicainide (5–10 to 13 µmol/l; Dai-Ichi Suntry Pharma, Tokyo, Japan), and terfenadine (0–5 µmol/l; Sigma Chemical; see Ref. 2). The above data recordings were repeated after 20 min of stabilization after drug administration at each incremental concentration.

We measured APD from the interval between the maximum rate of depolarization (time of depolarization) and peak of the second-order derivative of AP (time of repolarization) as we have done previously (31–33, 36–38), as well as at 50% repolarization and at the peak of the AP dome when it was present. We mapped the distributions of APD on the epicardial surfaces of free wall preparations and designated Epi 1, Epi 2, and Epi 3 to the regions having APs with alternating domes, without a dome, and with constant domes, respectively. We statistically analyzed APDs at the recording sites along the epicardial, endocardial, and midmyocardial (half-wall-thickness) layers in the transmural preparations. We measured the QT interval and the depth of the negative T wave and S-T level at the J point in the transmural ECG and separated the changes in T wave into the following two categories: macro-TWA (1:1 alternating shallow and deep T waves) and random T wave changes (2 or 3 shallow T wave beats followed by a deep T wave; Fig. 1 and Ref. 1).

View larger version (17K): [in this window] [in a new window]   Fig. 1. Macroscopic T wave alternans (TWA, A) and random T wave changes (B and C) in transmural electrocardiogram (ECG) at pacing cycle lengths (CLs) of 2,000 (A), 600 (B), and 1,000 (C) ms in a preparation having ECG characteristics of Brugada syndrome (in µmol/l: 10 pinacidil, 5.0 terfenadine, and 5.0 pilsicainide). Shallow and deep T waves appeared alternately in A and randomly in B and C. Progressively deeper negative T waves initiated polymorphic ventricular tachycardia in C.

	RESULTS

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Onset of macro-TWA and random T wave changes in Brugada syndrome. We induced Brugada-type ECG (J-ST elevation with negative T wave) in all 28 tissues, macro-TWA in 19 tissues, and random T wave changes in 14 tissues (Tables 1–3). TWA and random T wave changes occurred at higher doses of pinacidil and pilsicainide than for just Brugada-type ECG (Table 1). Macro-TWA occurred as beat-to-beat alterations in the morphology of the T wave, especially in the depth of the T wave, at slower pacing rates (Tables 1 and 2, e.g., Fig. 1A). Although the QRS duration did not change, QT interval and S-T level changed along with the changing T waves (Tables 2 and 3). Increasing the pacing rate converted macro-TWA into random T wave changes (Tables 1 and 3, e.g., Fig. 1B) or eliminated macro-TWA (CL: 800 ± 219 ms, range: 1,000–600 ms, n = 5). Further increase in the pacing rate (CL: 529 ± 168 ms, range: 600–400 ms, n = 7) eliminated random T wave changes. Severe bradycardia (CL: 3,000 ms, n = 7) also diminished macro-TWA. All macro-TWA occurred within a window of activation CL of between 600 and 3,000 ms.

View larger version (35K): [in this window] [in a new window]   Fig. 2. Statistical transmural (A and C) and epicardial (B and D) distributions of action potential durations (APDs) during TWA (2 successive beats, CL: 2,000 ms) and during random T wave changes (RTWC, CL: 600 ms) in tissues having ECG characteristics of Brugada syndrome. Both TWA (A and B) and random T wave changes (C and D) have similar associations between the depth of T waves and the spatial heterogeneity and temporal dynamics of AP. APDs [especially the peak of the APD dome (APDdome)] were longer during the deep than during the shallow T waves in the epicardium (Epi) but were similar in the midmyocardium (Mid) and endocardium (Endo; A and C). Alternating APs (Epi 1) and nonalternating APs without (Epi 2) and with a dome (Epi 3) coexisted in the epicardium (B and D). There were 7, 12, 6, and 8 tissues in A, B, C, and D, respectively. APD50, 50% repolarization.

View larger version (29K): [in this window] [in a new window]   Fig. 3. Action potential (APs) alternans occurred in the epicardium, but not in the mid- and endocardium, during TWA in a transmural preparation having ECG characteristics of Brugada syndrome (in µmol/l: 15 pinacidil, 5.0 terfenadine, and 13 pilsicainide, CL: 2,000 ms). The TWA in ECG is demonstrated in A. Selected traces of two alternating successive APs on the cut-exposed transmural surface (from the dotted sites in D-F) and their corresponding ECG are shown in B. The alternans in ECG and epicardial APs are shown clearly in C, which is derived from B by superimposing the corresponding waveforms associated with the deep and shallow T waves. The transmural distributions of APDs during TWA (same beats as in B and C) are shown in D (the deep T wave, transmural dispersion: 128 ms) and E (the shallow T wave, transmural dispersion: 62 ms). F: map of APD differences (derived from D and E) showing the occurrence of AP alternans during TWA within the first 2–3 mm from the epicardium. APDdeep, APD at deep T waves; APDshallow, APD at shallow T waves.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Epicardial heterogeneity of AP alternans during TWA (A, CL: 2,000 ms) and during random T wave changes (B, CL: 600 ms) in a free wall preparation having ECG characteristics of Brugada syndrome (in µmol/l: 10 pinacidil, 5.0 terfenadine, and 10 pilsicainide). The maps of APD differences between the deep and shallow T wave beats (APDdeep – APDshallow), APs at the Epi 1 sites (), and ECGs are shown at left in A and B. Superimposed ECGs and APs of the deep and shallow T wave beats are shown at right in A and B. Alternating APs between those with and without domes (Epi 1) corresponded to the deep and shallow T waves and coexisted with stable APs without (Epi 2) or with (Epi 3) domes in the epicardium. Increasing pacing rate converted TWA (A) to random T wave changes (B). Top and right sides of the mapping region were next to the tricuspid valve and right ventricular outflow tract.

View larger version (51K): [in this window] [in a new window]   Fig. 5. An example of phase 2 reentry in the epicardium of a free wall preparation having ECG characteristics of Brugada syndrome (in µmol/l: 10 pinacidil, 5.0 terfenadine, and 10 pilsicainide, CL: 600 ms). A, left, shows ECG, AP in the Epi 1 region (site 1), and the epicardial distribution of activation time (in ms). The ECG and APs at sites 1–4 are enlarged in A, right. Regions having alternating domes and regions without and with AP domes (Epi 1–3) are separated by the lines of open squares in the map of activation time. B: epicardial distributions of membrane potential (lighter density representing higher potential) at 3 (a), 78 (b), 107 (c), and 152 (d) ms after the onset of phase 2 reentry. Phase 2 activation conducted counterclockwise (demonstrated by the movement of lighter density in B) from site 1, to sites 2, 3, and 4, and then reentered site 1 (along the dashed arrow line in the map and as indicated on the APs in A).

View larger version (55K): [in this window] [in a new window]   Fig. 6. Examples of blocked phase 2 conduction during TWA in a free wall preparation (A; in µmol/l: 10.0 pinacidil, 5.0 terfenadine, and 13.0 pilsicainide, CL: 2,000 ms) and in a transmural preparation (B; in µmol/l: 2.5 pinacidil, 5.0 terfenadine, and 5.0 pilsicainide, CL: 2,000 ms) having ECG characteristics of Brugada syndrome. A: free wall example. Activation times (in ms) within the epicardial mapping region are shown in a. APs at the Epi 1–3 sites () and ECG are shown in b. The sequential maps in c show the distribution of membrane potential (lighter density representing higher potential) at 23, 67, 92, and 160 ms after the onset of phase 2 activation. Prominent AP dome appeared at the 2nd beat in Epi 1 (b). Phase 2 activation conducted from the border of the Epi 1 region to the Epi 2 and Epi 3 regions made a figure-eight pattern around the Epi 1 region and then was blocked at the opposite border (still in refractory because of longer local APDs) of the Epi 1 region (a and c). The blocked phase 2 reentry produced a large biphasic T wave in the second beat in the ECG (b). B: transmural example. ECGs (top) and transmural distributions of APs (separated by the grid, bottom) during shallow (left) and deep (right) T wave beats. There was no extrasystole at the shallow T wave beat (left). The large AP domes initiated nonconducted phase 2 activation (see arrows) in the epicardium and produced a deep T wave in the ECG (right).

	DISCUSSION

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In contrast to the previously suggested origin of TWA in Brugada syndrome from the alternating success and failure of phase 2 reentry (12), our experiments suggested that phase 2 reentry was not the cause of macro-TWA but instead was the consequence of AP alternans. We observed that macro-TWA/random T wave changes (in 896 deep T waves) correlated directly with alternating epicardial APs (with longer epicardial APD during deep T waves, e.g., Figs. 2–4) and partially with phase 2 reentry (333 occurrences, e.g., Fig. 5). Therefore, the increased dynamic heterogeneities in the dome and duration of AP caused macro-TWA, phase 2 reentry, and ventricular arrhythmias.

In vitro ventricular model of Brugada syndrome. We used pilsicainide, pinacidil, and terfenadine to reproduce the major characteristics of TWA in Brugada syndrome (13, 16, 30), including S-T elevation, bradycardia-dependent TWA with alternating depth of T waves, deep phase 1 repolarization, large phase 2 dome and reentry, and frequent occurrence of ventricular arrhythmias. Pilsicainide blocks the membrane Na⁺ current, I_Na, with both resting and use-dependent effects and slows the recovery of I_Na after activation (time constants: 65–580 ms; see Ref. 14), similar to the effects of Na⁺ channel mutations (SCN5A) found in 15–30% patients with Brugada syndrome (6, 22, 29). Pinacidil augments the transient outward current, I_to, one of the major affected currents in Brugada syndrome. Terfenadine blocks the K⁺, Na⁺, and Ca²⁺ channels (18, 35), prolongs QT interval, promotes phase 2 dome, and induces polymorphic ventricular arrhythmias (2).

The use-dependent blockade of Na⁺ channels reduces peak I_Na density more during a longer APD (facilitated by longer activation CL), which shortens the subsequent APD, causing alternans in I_Na and APD. Alternans in I_Na and APD can be reduced by either rapid activation, which shortens APD and reduces the use-dependent blockade of Na⁺ channels, or by very slow activation, which provides a long diastolic interval that facilitates recovery of Na⁺ channels from the blockade during depolarization. Therefore, the use-dependent blockade of Na⁺ channels contributes to TWA within a range of a relatively slow rate of activation, as we observed in this study. This observation correlates well with clinical observations in patients with Brugada syndrome, in whom TWA occurred at normal (57–100 beats/min) and exercise-increased (>95 beats/min) heart rates, and could be eliminated by isoproterenol or by rapid atrial pacing (8, 9, 19–21, 24, 27, 28).

Alternans in I_Na can subsequently lead to alternans in phase 1 repolarization, in phase 2 dome, and in APD. Reducing I_Na (by pilsicainide) slows the rate of depolarization and facilitates a deep phase 1 repolarization, especially when coupled with the pinacidil-augmented I_to. The changes in depolarization and phase 1 repolarization modulate the slower-activating membrane ionic currents, thus affecting the phase 2 dome and phase 3 repolarization. Therefore, alternating I_Na can lead to alternans in the dome and duration of AP and produce TWA as a consequence. Terfenadine further enhanced the phase 2 dome of AP and promoted the occurrence of reentry and ventricular arrhythmias.

Our observations of APD alternans within the 2- to 3-mm depth from the epicardium (e.g., Fig. 3) correspond well with the known transmural gradient of I_to density, which is highest in the epicardium (11), thus supporting the role of I_to in APD alternans. The alternating epicardial APD caused corresponding alternans in the transmural gradient of APD and in the T wave (e.g., Fig. 3 and Table 4). Progressively deeper (more negative) phase 1 repolarization can cause an initial delay and amplitude augmentation of the AP dome (possibly by delaying the activation of the membrane Ca²⁺ current, I_Ca,L, with a low but suprathreshold phase 1 potential), then sudden abolition of the dome (phase 1 repolarization becoming subthreshold for I_Ca,L), and corresponding prolongation and sudden abbreviation of APD. The observed coexistence of adjacent epicardial regions having APs with domes, without domes, and with alternating domes (e.g., Fig. 4) could be because of regional variations in I_Na alternans and in sequential downstream alternans of I_to and I_Ca,L. Thus the higher epicardial density of I_to contributes to both transmural and epicardial dispersions of repolarization in this model of Brugada syndrome.

Differences in macro-TWA between long QT and Brugada syndromes. TWA has been reported previously in isolated ventricular models of long QT syndrome during rapid pacing (7, 25). Excessive midmyocardial prolongation of APD increased the transmural dispersion of repolarization and generated alternans in APD, in intracellular Ca²⁺, and in T waves when new activations were initiated before the full recovery from prior activations in left ventricles having long QT syndrome (25). Therefore, the major mechanism of TWA in long QT syndrome is APD alternans in the left ventricular midmyocardium during tachycardia. In contrast, TWA in this experimental model of Brugada syndrome is caused by AP alternans in the right ventricular epicardium (e.g., Fig. 4) that is bradycardia dependent and can be eliminated by increasing heart rate.

Limitations. The present study created an isolated ventricular tissue model of Brugada syndrome with pharmacological agents. Although these agents reproduced the major ECG characteristics of Brugada syndrome, differences between the drug actions and clinical channelopathies exist, and multiple mechanisms that lead to arrhythmias in clinical Brugada syndrome may be present. Although optical mapping enabled simultaneous recording from 256 sites, each channel of AP represented the combined activations of all surface cells within the 1.1 x 1.1 mm² area covered by a single photodiode. Both the aggregated cellular activations in each channel of AP and statistical representations of the endocardial, epicardial, and midmyocardial APs could cause averaging/filtering effects that reduce the depth of phase-1 notch, smooth the contour of AP, and reduce the dispersion of APDs. Compared with intact hearts, the isolated sections of right ventricular free wall are smaller and simpler, and thus could only host a subset of potential electrophysiological mechanisms, although this simplicity provided excellent experimental preparations for testing our hypothesis. In addition to the major regional differences in the dome and duration of AP, as demonstrated in the current study, ECG characteristics of Brugada syndrome can also be generated by conduction delay as reported due to altered I_Na and local fibrosis in the right ventricular outflow tract of a human heart (10). Therefore, the mechanism of TWA demonstrated in this model of Brugada syndrome is just one of the possible explanations of TWA in Brugada patients. Finally, we did not record activity in the left ventricle. Although the left ventricle is not thought to contribute to arrhythmias in Brugada syndrome, we cannot draw conclusions about what may be happening there.

	GRANTS

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This research was supported by Award 0455517Z from the American Heart Association Midwest Affiliation and by the Herman C. Krannert Fund, Indianapolis.

	FOOTNOTES

 

Address for reprint requests and other correspondence: J. Wu, Krannert Institute of Cardiology, Indiana Univ. School of Medicine, 1800 N. Capitol Ave., Indianapolis, IN 46202 (e-mail: jiaswu{at}iupui.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

	REFERENCES

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1. Acunzo RS, Konopka IV, Sánchez RA, Pizzarelli N, Guerra J, and Elizari MV. Atypical behavior of QTc and ST-T intervals in a patient with the Brugada syndrome. Rev Esp Cardiol 57: 268–270, 2004.[Medline]
2. Aiba T, Hidaka I, Shimizu W, Uemura K, Inagaki M, Sugimachi M, and Sunagawa K. Steep repolarization gradient is required for development of phase 2 reentry and subsequent ventricular tachyarrhythmias in a model of the Brugada syndrome: high-resolution optical mapping study (Abstract). Circulation 110, Suppl III: 318, 2004.
3. Anyukhovsky EP, Sosunov EA, and Rosen MR. Regional differences in electrophysiological properties of epicardium, midmyocardium, and endocardium. In vitro and in vivo correlations. Circulation 94: 1981–1988, 1996.[Abstract/Free Full Text]
4. Biermann M, Rubart M, Moreno A, Wu J, Josiah-Durant A, and Zipes DP. Differential effects of cytochalasin D and 2,3 butanedione monoxime on isometric twitch force and transmembrane action potential in isolated ventricular muscle. J Cardiovasc Electrophysiol 9: 1348–1357, 1998.[ISI][Medline]
5. Calaghan SC, White E, Bedut S, and Le Guennec JY. Cytochalasin D reduces Ca²⁺ sensitivity and maximum tension via interactions with myofilaments in skinned rat cardiac myocytes. J Physiol 529: 405–411, 2000.[Abstract/Free Full Text]
6. Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P, Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R, Wang Z, Antzelevitch C, O'Brien RE, Schulze-Bahr E, Keating MT, Towbin JA, and Wang Q. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392: 293–296, 1998.[CrossRef][Medline]
7. Chinushi M, Restivo M, Caref EB, and El-Sherif N. Electrophysiological basis of arrhythmogenicity of QT/T alternans in the long-QT syndrome. Tridimensional analysis of the kinetics of cardiac repolarization. Circ Res 83: 614–628, 1998.[Abstract/Free Full Text]
8. Chinushi M, Washizuka T, Okumura H, and Aizawa Y. Intravenous administration of class I antiarrhythmic drugs induced T wave alternans in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 12: 493–495, 2001.[Medline]
9. Chinushi Y, Chinushi M, Toida T, and Aizawa Y. Class I antiarrhythmic drug and coronary vasospasm-induced T wave alternans and ventricular tachyarrhythmia in a patient with Brugada syndrome and vasospastic angina. J Cardiovasc Electrophysiol 13: 191–194, 2002.[CrossRef][ISI][Medline]
10. Coronel R, Casini S, Koopmann TT, Wilms-Schopman FJG, Verkerk AO, de Groot JR, Bhuiyan Z, Bezzina CR, Veldkamp MW, Linnenbank AC, van der Wal AC, Tan HL, Brugada P, Wilde AAM, and de Bakker JMT. Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada Syndrome: a combined electrophysiological, genetic, histopathologic, and computational study. Circulation 112: 2769–2777, 2005.[Abstract/Free Full Text]
11. Di Diego JM, Sun ZQ, and Antzelevitch C. Ito and action potential notch are smaller in left vs. right canine ventricular epicardium. Am J Physiol Heart Circ Physiol 271: H548–H561, 1996.[Abstract/Free Full Text]
12. Fish JM and Antzelevitch C. Role of sodium and calcium channel block in unmasking the Brugada syndrome. Heart Rhythm 1: 210–217, 2004.[CrossRef][ISI][Medline]
13. Grant AO, Carboni MP, Nepliueva V, Starmer CF, Memmi M, Napolitano C, and Priori G. Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation. J Clin Invest 110: 1201–1209, 2002.[CrossRef][ISI][Medline]
14. Kodama I, Ogawa S, Inoue H, Kasanuki H, Kato T, Mitamura H, Hiraoka M, and Sugimoto T. The guideline committee for clinical use of antiarrhythmic drugs in Japan. Profiles of aprindine, cibenzoline, pilsicainide and pirmenol in the framework of the Sicilian Gambit. Jpn Circ J 63: 1–12, 1999.[CrossRef][Medline]
15. Krishnan SC and Antzelevitch C. Flecainide-induced arrhythmia in canine ventricular epicardium. Phase 2 reentry? Circulation 87: 562–572, 1993.[Abstract/Free Full Text]
16. Kyndt F, Probst V, Potet F, Demolombe S, Chevallier JC, Baro I, Moisan JP, Boisseau P, Schott JJ, Escande D, and Le Marec H. Novel SCN5A mutation leading either to isolated cardiac conduction defect or Brugada syndrome in a large French family. Circulation 104: 3081–3086, 2001.[Abstract/Free Full Text]
17. Merot J, Charpentier F, Poirier JM, Coutris G, and Weissenburger J. Effects of chronic treatment by amiodarone on transmural heterogeneity of canine ventricular repolarization in vivo: interactions with acute sotalol. Cardiovasc Res 44: 303–314, 1999.[Abstract/Free Full Text]
18. Ming Z and Nordin C. Terfenadine blocks time-dependent Ca²⁺, Na⁺, and K⁺ channels in guinea pig ventricular myocytes. J Cardiovasc Pharmacol 26: 761–769, 1995.[ISI][Medline]
19. Morita H, Morita ST, Nagase S, Banba K, Nishii N, Tani Y, Watanabe A, Nakamura K, Kusano KF, Emori T, Matsubara H, Hina K, Kita T, and Ohe T. Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J Am Coll Cardiol 42: 1624–1631, 2003.[Abstract/Free Full Text]
20. Morita H, Nagase S, Kusano K, and Ohe T. Spontaneous T wave alternans and premature ventricular contractions during febrile illness in a patient with Brugada syndrome. J Cardiovasc Electrophysiol 13: 816–818, 2002.[CrossRef][ISI][Medline]
21. Nishizaki M, Fujii H, Sakurada H, Kimura A, and Hiraoka M. Spontaneous T wave alternans in a patient with Brugada syndrome. Responses to intravenous administration of class I antiarrhythmic drug, glucose tolerance test, and atrial pacing. J Cardiovasc Electrophysiol 16: 217–220, 2005.[Medline]
22. Priori SG, Napolitano C, Gasparini M, Pappone C, Della Bella P, Brignole M, Giordano U, Giovannini T, Menozzi C, Bloise R, Crotti L, Terreni L, and Schwartz PJ. Clinical and genetic heterogeneity of right bundle branch block and ST-segment elevation syndrome. A prospective evaluation of 52 families. Circulation 102: 2509–2515, 2000.[Abstract/Free Full Text]
23. Schwartz PJ and Malliani A. Electrical alternans of the T-wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long Q-T syndrome. Am Heart J 89: 45–50, 1975.[CrossRef][ISI][Medline]
24. Shimizu W, Aiba T, Kurita T, and Kamakura S. Paradoxic abbreviation of repolarization in epicardium of the right ventricular outflow tract during augmentation of Brugada-type ST segment elevation. J Cardiovasc Electrophysiol 12: 1418–1421, 2001.[CrossRef][ISI][Medline]
25. Shimizu W and Antzelevitch C. Cellular and ionic basis for T-wave alternans under long-QT conditions. Circulation 99: 1499–1507, 1999.[Abstract/Free Full Text]
26. Surawicz B and Fisch C. Cardiac alternans: diverse mechanisms and clinical manifestations. J Am Coll Cardiol 20: 483–499, 1992.
27. Tada H, Nogami A, Shimizu W, Naito S, Nakatsugawa M, Oshima S, and Taniguchi K. ST segment and T wave alternans in a patient with Brugada syndrome. Pacing Clin Electrophysiol 23: 413–415, 2000.[CrossRef][Medline]
28. Takagi M, Doi A, Takeuchi K, and Yoshikawa J. Pilsicanide-induced marked T wave alternans and ventricular fibrillation in a patient with Brugada syndrome (Abstract). J Cardiovasc Electrophysiol 13: 837, 2002.[Medline]
29. Tan HL, Bezzina CR, Smits JPP, Verkerk AO, and Wilde AAM. Genetic control of sodium channel function. Cardiovasc Res 57: 961–973, 2003.[Abstract/Free Full Text]
30. Tan HL, Bink-Boelkens MT, Bezzina CR, Viswanathan PC, Beaufort-Krol GC, van Tintelen PJ, van den Berg MP, Wilde AA, and Balser JR. A sodium-channel mutation causes isolated cardiac conduction disease. Nature 409: 1043–1047, 2001.[CrossRef][Medline]
31. Ueda N, Zipes DP, and Wu J. Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT 3. Cardiovasc Res 63: 69–76, 2004.[Abstract/Free Full Text]
32. Ueda N, Zipes DP, and Wu J. Epicardial but not endocardial premature stimulation initiates ventricular tachyarrhythmia in canine in vitro model of Long QT syndrome. Heart Rhythm 1: 684–694, 2004.[CrossRef][Medline]
33. Ueda N, Zipes DP, and Wu J. Functional and transmural modulation of M cell behavior in canine ventricular wall. Am J Physiol Heart Circ Physiol 287: H2569–H2574, 2004.[Abstract/Free Full Text]
34. Walker ML and Rosenbaum DS. Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death. Cardiovasc Res 57: 599–614, 2003.[Abstract/Free Full Text]
35. Wang J, Penna KD, Wang H, Karczewski J, Connolly TM, Koblan KS, Bennett PB, and Salata JJ. Functional and pharmacological properties of canine ERG potassium channels. Am J Physiol Heart Circ Physiol 284: H256–H267, 2003.[Abstract/Free Full Text]
36. Wu J, Biermann M, Rubart M, and Zipes DP. Cytochalasin D as excitation-contraction uncoupler for optically mapping action potentials in wedges of ventricular myocardium. J Cardiovasc Electrophysiol 9: 1336–1347, 1998.[ISI][Medline]
37. Wu J and Zipes DP. Transmural reentry during global acute ischemia and reperfusion in canine ventricular muscle. Am J Physiol Heart Circ Physiol 280: H2717–H2725, 2001.[Abstract/Free Full Text]
38. Wu J and Zipes DP. Transmural reentry triggered by epicardial stimulation during acute ischemia in canine ventricular muscle. Am J Physiol Heart Circ Physiol 283: H2004–H2011, 2002.[Abstract/Free Full Text]
39. Yan GX and Antzelevitch C. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 100: 1660–1666, 1999.[Abstract/Free Full Text]
40. Zareba W, Moss AJ, Cessie SL, Chessie S, and Hall WJ. T wave alternans in idiopathic long QT syndrome. J Am Coll Cardiol 23: 1541–1546, 1994.[Abstract]

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