Transmural Heterogeneity of Ventricular Repolarization Under Baseline and Long QT Conditions in the Canine Heart In Vivo: Torsades de Pointes Develops with Halothane but not Pentobarbital Anesthesia

Weissenburger, Jacques; Nesterenko, Vladislav V.; Antzelevitch, Charles

doi:10.1111/j.1540-8167.2000.tb01798.x

Cited by 146 publications

(70 citation statements)

References 47 publications

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“…However, whereas gradients generated by the differences in APD were confirmed repeatedly in intact hearts (9,16,25,33,43,48), reports on rate-dependent changes of these gradients are limited. Weissenburger et al (43) described the transmural gradient as significantly increased with the slowing of the heart rate (43). Dispersion of APD between the left and right ventricular endocardium (48) or between the apex and base (16,33) showed only a tendency to decrease at higher rates.…”

Section: Relations To Previous Studiesmentioning

confidence: 99%

Ventricular gradient and nondipolar repolarization components increase at higher heart rate

Smetana

Batchvarov

Hnatkova

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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.-Differences in action potential duration reflect differences in ion channel properties. These properties also determine rate dependence of action potential duration, and transmural dispersion was confirmed experimentally to increase with cycle length. While several electrocardiographic indexes characterizing repolarization abnormalities have been proposed, studies of their heart rate dependence are missing. This study therefore investigated rate relationship of two repolarization descriptors, namely, the so-called total cosine of the QRS-T angle (TCRT), proposed to characterize global repolarization heterogeneity, and the so-called relative T wave residuum (TWR), linked to regional repolarization dispersion. During 24-h holter recordings in 60 healthy subjects (27 males), a 12-lead ECG was obtained every 30 s. RR intervals, QT intervals, and TCRT and TWR were calculated in each ECG and averaged over RR interval bins ranging from 550 to 1,150 ms in 10-ms steps. Women had uniformly greater TCRT and TWR values than men did over the entire range of investigated RR intervals. Whereas the TCRT in both sexes showed marked rate dependence with higher values at long RR intervals (550 vs. 1,150 ms: women, 0.46 Ϯ 0.31 vs. 0.76 Ϯ 0.18, P ϭ 9 ϫ 10 Ϫ7 ; men, 0.08 Ϯ 0.45 vs. 0.49 Ϯ 0.35, P ϭ 9 ϫ 10 Ϫ8 ), the rate dependence of TWR was more marked in women than in men, showing higher values at shorter RR intervals (550 ms vs. 1,150 ms: women: 0.29 Ϯ 0.14% vs. 0.08 Ϯ 0.06%, P ϭ 2 ϫ 10 Ϫ8 ; men: 0.14 Ϯ 0.12% vs. 0.04 Ϯ 0.02%, P ϭ 2 ϫ 10 Ϫ15 ). This suggests that both global and regional repolarization heterogeneity are increased at faster heart rates. Whereas in women at all heart rates the sequence of repolarization more closely replicates the sequence of depolarization, localized repolarization is more heterogeneous than in men especially at fast heart rates. repolarization heterogeneity; electrocardiogram; rate dependence; gender difference ACTION POTENTIAL DURATION (APD) differs not only between myocytes of different ventricular layers (35) but also between the cardiac apex and base (25), posterior and anterior endocardial surfaces (4), and right and left ventricle (8). This APD dispersion is potentially arrhytmogenic, especially when increased by ion channel mutations in congenital and druginduced long QT syndrome (3) or by abrupt changes in cycle length (17).Differences in APD reflect differences in ion channel properties (13,35). Because these properties also determine the rate dependence of APD (13,35,42), heart rate likely influences APD dispersion across the heart. However, experimental studies confirmed significant increase with cycle length prolongation for transmural dispersion (35) that was linked to the occurrence of torsades de pointes and QT interval prolongation at slow heart rates (3). Electrocardiographic investigations of heart rate dependence of other facets of repolarization heterogeneity are missing.Several electrocardiographic indexes have recently been proposed to characterize repolarization abnormalit...

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Section: Relations To Previous Studiesmentioning

confidence: 99%

Ventricular gradient and nondipolar repolarization components increase at higher heart rate

Smetana

Batchvarov

Hnatkova

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…28 We found a good association between the level of TDR max and the inducibility of pVT. The critical role of TDR as a substrate for functional reentry has been demonstrated in models of prolonged repolarization (congenital and acquired long-QT syndrome, [7][8][9]29 hypertrophy, 30 and heart failure). 31 In addition, epicardial and transmural dispersion of repolarization seems also to be a key mechanism of arrhythmias in the Brugada syndrome.…”

Section: Circulation December 14 2004mentioning

confidence: 99%

“…Previous studies involving the canine arterially perfused wedge preparation have demonstrated the arrhythmogenic role of increased TDR under long-QT conditions as well as in the Brugada syndrome. [7][8][9][10][11][12] In this study, we made use of the canine left ventricular (LV) wedge preparation to test the hypothesis that abbreviation of the QT interval is associated with an increase in TDR, which creates the substrate for reentry responsible for the development of life-threatening ventricular tachycardia/fibrillation (VT/VF). Because an I Kr activator is unavailable, we chose to use the ATP-sensitive potassium current (I K-ATP ) activator pinacidil to augment outward currents.…”

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confidence: 99%

Amplified Transmural Dispersion of Repolarization as the Basis for Arrhythmogenesis in a Canine Ventricular-Wedge Model of Short-QT Syndrome

2004

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Background-The short-QT syndrome is a new clinical entity characterized by corrected QT intervals Ͻ300 ms and a high incidence of ventricular tachycardia (VT) and fibrillation (VF). Gain-of-function mutations in the gene for outward potassium currents have been shown to underlie the congenital syndrome. The present study examined the cellular basis of VT/VF in an experimental model associated with short QT intervals created with a potassium channel activator. Methods and Results-Transmembrane action potentials from epicardial and M regions, 4 transmural unipolar electrograms, and a pseudo-ECG were simultaneously recorded in canine arterially perfused left ventricular wedge preparations. At a basic cycle length of 2000 ms, pinacidil (2 to 3 mol/L) abbreviated the QT interval from 303.7Ϯ5.4 to 247.3Ϯ6.9 ms (meanϮSEM, PϽ0.0001). The maximal transmural dispersion of repolarization (TDR max ) increased from 27.0Ϯ3.8 to 64.9Ϯ9.2 ms (PϽ0.01), and an S2 applied to the endocardium induced a polymorphic VT (pVT) in 9 of 12 wedge preparations (PϽ0.01). Addition of isoproterenol (100 nmol/L, nϭ5) led to greater abbreviation of the QT interval, a further increase in TDR max (from 55.4Ϯ13.7 to 69.7Ϯ8.3 ms), and more enduring pVT. TDR max was correlated significantly with the T peak -T end interval under all conditions. The effects of pinacidil were completely reversed by glybenclamide (10 mol/L, nϭ4) and partially reversed by E4031 (5 mol/L, nϭ5), which prevented induction of pVT in 3 of 5 preparations. Conclusions-Our

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“…By virtue of its actions to reduce transmural dispersion and inhibit EAD-induced triggered activity, the anesthetic is effective in suppressing D-sotalol-induced TdP. 20 Amiodarone is another agent that prolongs QT but does not typically induce TdP. In addition to its ␤-blocking properties, amiodarone is known to block the sodium, potassium, and calcium channels in the heart.…”

Section: Effect Of Cisapride In the Canine LV Wedge: Apd 90 Of M And mentioning

confidence: 99%

Cisapride-Induced Transmural Dispersion of Repolarization and Torsade de Pointes in the Canine Left Ventricular Wedge Preparation During Epicardial Stimulation

2003

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Background-Cisapride, a gastrointestinal prokinetic agent, was recently withdrawn from the market because of its propensity to induce torsade de pointes (TdP) arrhythmias. The present study examines the electrophysiological actions of cisapride in the isolated arterially perfused canine left ventricular wedge preparation. Methods and Results-Transmembrane action potentials from epicardial and M regions and a pseudo-ECG were simultaneously recorded. Cisapride (0.1 to 5 mol/L) was added to the coronary perfusate. Cisapride prolonged the QT interval and increased transmural dispersion of repolarization (TDR) at relatively low but not at high concentrations. TdP could be induced with programmed electrical stimulation only at a low concentration of drug (0.2 mol/L), when TDR was maximally prolonged. Moreover, TdP could only be induced during epicardial (but not endocardial) activation of the wedge, which was found to augment TDR. At higher concentrations of cisapride, QT was further prolonged, TDR was diminished, and TdP could no longer be induced. T peak -T end interval and T peak -T end area provided reasonable electrocardiographic indices of TDR. Conclusion-Our data (1) demonstrate a biphasic concentration/response relationship for the effect of cisapride to induce long-QT syndrome and TdP, (2) show the value of the left ventricular wedge preparation in identifying drugs that pose an arrhythmic risk, (3) support the hypothesis that risk for development of TdP is related to the increase in TDR rather than to prolongation of the QT interval, and (4) indicate that epicardial activation of the left ventricle, as occurs during biventricular pacing, can facilitate the development of TdP under long-QT conditions.

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Transmural Heterogeneity of Ventricular Repolarization Under Baseline and Long QT Conditions in the Canine Heart In Vivo: Torsades de Pointes Develops with Halothane but not Pentobarbital Anesthesia

Cited by 146 publications

References 47 publications

Ventricular gradient and nondipolar repolarization components increase at higher heart rate

Ventricular gradient and nondipolar repolarization components increase at higher heart rate

Amplified Transmural Dispersion of Repolarization as the Basis for Arrhythmogenesis in a Canine Ventricular-Wedge Model of Short-QT Syndrome

Cisapride-Induced Transmural Dispersion of Repolarization and Torsade de Pointes in the Canine Left Ventricular Wedge Preparation During Epicardial Stimulation

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