Effects of antiarrhythmic drugs on QT interval dispersion-Relationship to antiarrhythmic action and proarrhythmia

Effects of Antiarrhythmic Drugs on QT Interval Dispersion—Relationship to Antiarrhythmic Action and Proarrhythmia Anne M. Gillis

Class IA, IC, and III antiarrhythmic drugs prolong ventricular repolarization (VR) which is manifest as QT interval prolongation on the surface electrocardiogram. These drugs may prolong VR in a spatially heterogenous manner which results in increased dispersion of VR. This may be manifest as increased QT interval dispersion. Antiarrhythmic druginduced decreases in QT interval dispersion are associated with antiarrhythmic efficacy in patients with the long QT syndrome and in patients with sustained ventricular tachycardia. Antiarrhythmic drug-induced increases in QT interval dispersion are associated with ventricular proarrhythmia secondary to torsades de points ventricular tachycardia. A number of factors may modulate the effects of antiarrhythmic drugs on dispersion of VR, including the disease state, transient ischemia, electrolyte abnormalities, changes in autonomic tone, and hemodynamic stress. Copyright 娀 2000 by W.B. Saunders Company

C

lass IA, IC, and III antiarrhythmic drugs prolong ventricular repolarization, which is manifested as QT interval prolongation on the surface electrocardiogram (ECG).1,2 These drugs may exert their antiarrhythmic effects by creating more homogeneity of repolarization and suppressing reentrant activity. Increased dispersion of ventricular repolarization (VR) may create the electrophysiological environment favoring reentry.3-5 QT interval dispersion has been proposed as a clinical measure of heterogeneity of VR.6 Increased dispersion of the QT interval has been reported to be associated with ventricular arrhythmias6-9 and sudden cardiac death,10 as well as with antiarrhythmic drug-induced proarrhythmia torsade de pointes ventricular tachycardia (VT).11 There also are clinical data that antiarrhythmic drugs, which reduce or at least do not signifi-

cantly increase QT interval dispersion, are more likely to be efficacious.12,13 In addition, other cardiovascular drugs that are not traditionally considered to be antiarrhythmic drugs may confer antiarrhythmic effects by preventing ventricular remodeling, which is associated with increased dispersion of repolarization after myocardial infarction (MI) (eg, angiotensin converting enzyme inhibitors).14,15

QT Interval Dispersion QT interval dispersion has been measured as the difference in the maximal and minimal QT intervals measured on a 12-lead ECG (Fig 1).6-10,16,17 The methods and limitations of this measurement have been reviewed by Dr. Malik in this symposium. Some investigators have corrected the QT interval for heart rate generally employing Bazett’s formula.18 Other investigators have used normalization factors to adjust for missing ECG leads.6,12,19 We introduced the concept of measuring precordial QT interval dispersion as a marker of regional inhomogeneity of ventricular repolarization because the unipolar precordial QT intervals are more likely to represent regional VR abnormalities.11 In digital ECGs, 4 of the 6 bipolar limb leads are derived and thus contribute limited additional information to the measure-

From the Division of Cardiology, Foothills Hospital, and the Cardiovascular Research Group, University of Calgary, Calgary, Alberta, Canada. Supported by the Medical Research Council of Canada and Heart and Stroke Foundation of Alberta. Address reprint requests to Anne M. Gillis, MD, FRCPC, Rm 1634, Health Science Centre, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. Copyright 娀 2000 by W.B. Saunders Company 0033-0620/00/4205-0006$10.00/0

Progress in Cardiovascular Diseases, Vol. 42, No. 5 (March/April), 2000: pp 385-396

385

386

ANNE M. GILLIS

Fig 1. 12-lead ECGs obtained drug-free and during sotalol therapy. Note the QT prolongation, changes in T wave morphology and increased QT/QT-U dispersion in this patient who developed torsade de pointes VT during sotalol therapy.

ment of QT dispersion.20 There is considerable controversy about the validity of QT interval dispersion as a measure of heterogeneity of VR.21,22 It has been argued that the apparent QT dispersion is caused by differing spatial orientation of the ECG lead vectors and that to measure true dispersion of repolarization we need to be able to measure onset of VR. Thus, this review must be interpreted in light of this controversy.

QT Interval Dispersion and Antiarrhythmic Drug Efficacy Long QT Syndrome Increased QT interval dispersion has been reported in patients with congenital long QT syndrome (LQTS) and is associated with syncope and ventricular arrhythmias.6,12,23 Priori et al reported that ␤-adrenergic blocking drugs reduce QT interval dispersion in patients with congenital long QT syndrome who respond to such therapy (Fig 2).12 In contrast, patients with recurrent syncope or VT/VF during ␤-adrenergic blocking therapy manifested continued marked increased

dispersion of repolarization. ␤-adrenergic stimulation with either isoproterenol or epinephrine increases dispersion of VR measured as an increase in QT interval dispersion,24 an increase in dispersion of monophasic action potential durations,25 or increased disparity of body surface recovery times.26 ␤-adrenergic blockers and verapamil reduce the acute effects of epinephrine on dispersion of VR in these patients with LQTS.24,25 In experimental pharmacological models of the congenital LQTS, ␤-adrenergic stimulation increased heterogeneity of VR in the LQT1 model, which was inhibited by ␤-adrenergic blocking agents.27 The cellular mechanism of this response is believed to be an augmentation of Iks in epicardial and endocardial cells but not in M cells, which have low-density Iks.28 This results in increased transmural dispersion of repolarization. Mexilitine has been reported to shorten the QT interval in patients with the LQT3 genotype but not in patients with the LQT2 genotype.29 In experimental models of LQT2 and LQT3, mexilitine reduced dispersion of VR and the development of torsade de pointes VT (Fig 3).30,31 In a pharmacologic model of LQT1, mexilitine re-

QT DISPERSION AND ANTIARRHYTHMIC DRUGS

387

Fig 2. Effect of ␤-adrenergic receptor blocking therapy on QT interval dispersion in patients with congenital long QT syndrome based on response to therapy. QT dispersion is shown for 15 control subjects, 7 patients with LQTS who were not treated with ␤-blockers, 10 patients with LQTS who responded to ␤-blocker treatment and 11 patients with LQTS who did not respond to ␤-blocker treatment. *P F .05 v control and responders. (Data from Priori SG et al.12)

duced the effect of isoproterenol to induce torsade de pointes VT by reducing the magnitude of transmural dispersion of repolarization induced by isoproterenol.27 Mexilitine reduces QT dispersion in these models predominantly by shortening the action potential duration of M cells located in the midmyocardial layer and also by shortening the action potential duration of epicardial ventricular cells in the LQT3 model. Whether mexilitine is efficacious in the management of some clinical LQT genotypes remains to be tested. Nicorandil, a K⫹ channel opener, shortens the QT interval and reduces epinephrine-induced increased dispersion of VR in patients with LQT1 form of the congenital long QT syndrome.32 This was associated with a reduction in epinephrineinduced early afterdepolarizations measured using monophasic action potential catheters and a reduction in ventricular premature beats in 2 of 6 patients assessed. Whether this therapy will prevent VT/VF over the long-term in these patients is unknown at present.

VT in Coronary Artery Disease Class IA, IC, and III antiarrhythmic drugs prolong VR by blocking potassium repolarizing currents including the transient outward current (Ito, eg, quinidine) and the inward rectifying current (IKr, eg, quinidine, propafenone, sotalol).1,2 It is well recognized that heterogeneity of expression of Ito, Ikr, and other ionic currents is observed in epicar-

dial, endocardial, and midmyocardial cells.28,33 This heterogeneity of expression of repolarizing currents contributes to the development of dispersion of VR. Exaggerated heterogeneity of expression of repolarizing currents occurs in disease states including hypertrophy34,35 and after MI.36 It is thus likely that in some settings antiarrhythmic drugs may reduce dispersion of repolarization and exert antiarrhythmic effects whereas under other conditions these drugs may have exaggerated effects on VR including increased dispersion of repolarization and predispose to arrhythmia development. Precordial QT interval dispersion during antiarrhythmic therapy is an independent predictor of antiarrhythmic drug response assessed by electrophysiologic study in patients with spontaneous VT/VF after MI13 QT interval dispersion increased significantly during ineffective antiarrhythmic drug therapy compared with effective drug therapy (Fig 4). In support of the concept that antiarrhythmic drug effects on QT dispersion determines drug efficacy, QT interval dispersion was shorter during effective drug trials (27 ⫾ 14 ms) than during ineffective drug trials (47 ⫾ 24 ms, P ⬍ .05), in 7 responders who had experienced at least 1 ineffective drug trial before effective antiarrhythmic drug therapy was identified. We also examined the effect of antiarrhythmic drug class on QT interval dispersion in drug responders and nonresponders. QT interval dispersion during

388

Fig 3. Spontaneous nonsustained polymorphic VT with features similar to torsade de pointes VT, induced by ATX-II an agent that shows inactivation of the sodium channel and provides a pharmacologic model of LQT3. ATX-II prolongs the action potential duration and markedly increases transmural dispersion of repolarization because of exaggerated prolongation of the M cell compared with epicardial ventricular cells. Mexilitine suppresses VT and causes shortening of the M cell action potential duration. (Reprinted with permission from Shimizu W, Antzelevitch C: Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome. Effects of ␤-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 1997;96:2038-2047.)

quinidine therapy did not change from baseline in drug responders whereas QT interval dispersion increased significantly after initiation of quinidine in nonresponders (Fig 5). In a number of drug nonresponders QT dispersion did not change during quinidine therapy. Similar patterns were observed for class III drugs (mainly sotalol). QT interval dispersion tended to shorten during class III drug therapy in responders (24 ⫾ 16 ms) compared with baseline (40 ⫾ 26 ms, P ⫽ NS) whereas QT interval dispersion increased in drug nonresponders (60 ⫾ 29 ms) compared with baseline (40 ⫾ 24 ms, P ⬍ .05). In this study population with VT/VF in the setting of coronary artery

ANNE M. GILLIS

disease (CAD), QT interval dispersion less than or equal to 50 ms during antiarrhythmic drug therapy was an independent prediction of antiarrhythmic drug efficacy (P ⬍ .002) with a sensitivity of 91% and specificity of 52% for predicting drug efficacy, a positive predictive value of 32% and a negative predictive value of 96%. Dispersion of ventricular repolarization also can be measured using body surface potential mapping. In a separate series of patients with sustained VT, we have observed that quinidine increased disparity of VR as assessed by the degree of nondipolarity of the QRST isointegral distribution in patients in whom VT remained inducible compared with patients in whom VT could not be induced during quinidine therapy.37 Other investigators have evaluated the effects of some antiarrhythmic drugs on QT interval dispersion. Day et al reported that sotalol reduced QT interval dispersion in 39 patients after a MI compared with 28 patients treated with placebo.18 Cui et al reported that amiodarone but not sematilide or sotalol significantly reduced QT interval dispersion in patients with CAD and

Fig 4. Maximal precordial QT interval (QT max) and QT interval dispersion (QT disp) measured at baseline and during drug therapy in responders (R) and nonresponders (NR). Data are expressed as mean ⴞ1 SD. (Reprinted with permission from Gillis AM, Traboulsi M, Hii JT, et al: Antiarrhythmic drug effects on QT interval dispersion in patients undergoing electropharmacologic testing for ventricular tachycardia and fibrillation. Am J Cardiol 81:588-593, 1998.)

QT DISPERSION AND ANTIARRHYTHMIC DRUGS

389

Fig 5. QT interval dispersion (QT disp) at baseline and during quinidine therapy in responders and nonresponders. Drug efficacy was assessed by electrophysiology study. Each symbol represents QT interval dispersion for each patient at baseline or during drug therapy. Solid lines connect values measured at baseline and during drug therapy for each patient. Data are expressed as mean ⴞ1 SD. (Reprinted with permission from Gillis AM, Traboulsi M, Hii JT, et al: Antiarrhythmic drug effects on QT interval dispersion in patients undergoing electropharmacologic testing for ventricular tachycardia and fibrillation. Am J Cardiol 81:588-593, 1998.)

VT.38 These authors concluded that class III agents have differing effects on QT dispersion, which reflects differences in the mechanisms of their effects on VR and likely contributes to differences in efficacy and risk of proarrhythmia. Grimm et al evaluated the effect of amiodarone on QT interval dispersion and its relationship to VT/VF recurrence in 52 patients.39 Approximately one-half of patients had left ventricular dysfunction in the setting of CAD. Amiodarone did not significantly increase QT dispersion (58 ⫾ 24 ms v 61 ⫾ 26 ms before and after therapy initiation). During a mean follow-up of 31 ⫾ 25 months, arrhythmic events occurred in 11 of the 52 study patients. QT dispersion was similar in patients with (65 ⫾ 14 ms) and without (59 ⫾ 29 ms, P ⫽ NS) an arrhythmic event. Likewise, Meierhenrich et al observed no changes in QT dispersion in 47 patients with CAD after amiodarone initiation.40 Differences in patient populations, drug dosing regimens, duration of follow-up, or the limitations of the measurement might account for the apparent disparity in amiodarone effects in QT dispersion reported by these investigators compared with Cui et al.38

Hypertrophic Cardiomyopathy Increased QT interval dispersion has been reported in hypertrophic cardiomyopathy. Reports

are conflicting, however, on whether this parameter predicts patients at risk of life threatening ventricular arrhythmias.7,41 Some investigators have reported that amiodarone reduces QT dispersion in patients with hypertrophic cardiomyopathy but whether this is related to antiarrhythmic efficacy is uncertain.42,43

ACE Inhibitors in Cardiac Hypertrophy and Post MI Increased dispersion of VR has been observed in patients with hypertrophy,7,41,44 in patients with congestive heart failure,10 and in patients post MI.45 In patients with hypertrophy increased QT dispersion correlates with left ventricular mass.46 Experimental studies47 and clinical studies suggest the angiotensin converting enzyme (ACE) inhibitors reduce dispersion of VR and that this correlates with regression of hypertrophy.14,15,46,48 ACE inhibitors prevent ventricular remodeling post MI and this is also associated with a decrease in QT dispersion.14,15 At least some studies suggest a correlation with decreases in QT dispersion and reduced risk of ventricular arrhythmias.14,49 ACE inhibitors have been reported to reduce sudden cardiac death in patients post MI and the antiarrhythmic effect may well be at least in part to the prevention of the development increased dispersion of VR.50

390

ANNE M. GILLIS

QT Interval Dispersion and Ventricular Proarrhythmia Patients who develop ventricular proarrhythmia secondary to torsade de pointes VT manifest increased susceptibility to drugs that prolong VR.51-53 Antiarrhythmic drug-induced increased QT interval dispersion is a marker of risk of ventricular proarrhythmia caused by torsade de pointes VT.11 We have shown that class Ia antiarrhythmic drugs significantly increased QT interval dispersion compared with the drug-free state in patients who developed torsade de pointes VT during drug therapy.11 In contrast, patients who did not develop torsade de pointes VT during class Ia therapy did not manifest a significant increase in QT interval dispersion compared with the drug-free state (Fig 6). The patients who developed torsade de pointes VT on class I drug therapy, were subsequently treated with amiodarone. During amiodarone therapy, QT dispersion was similar to the baseline drug-free state. Amiodarone is reported to be associated with a verylow incidence of torsade de pointes VT.51 The

calcium antagonist and/or the ␤-adrenergic blocking effects of amiodarone may account for the greater homogeneity of amiodarone’s effects on VR compared with other class I/III drugs and the low incidence of torsade de pointes VT. Drouin et al recently evaluated the effects of amiodarone on action potential duration in ventricular myocytes isolated from explanted hearts of transplant recipients compared with control hearts and hearts explanted from patients with heart failure who were not on amiodarone.54 They observed that amiodarone therapy was associated with less bradycardia-induced prolongation of the action potential of the midmyocardial layer cells (M cells) resulting in reduced transmural dispersion of the action potential duration in the hearts of patients with heart failure who were treated with amiodarone compared with the hearts from patients with heart failure who were not treated with amiodarone or those from normal control hearts (Fig 7). Similar findings have been reported in experimental models.55,56 Thus, amiodarone appears to produce less heterogeneity of

Fig 6. Precordial QT, corrected QT (QTc), JT, and corrected JT (JTc) interval dispersions in 9 patients with (open bars) and 29 patients without (striped bars) class Ia drug-induced torsade de pointes in the antiarrhythmic drug free (DF) state, during class Ia drug therapy (Ia), and during chronic amiodarone therapy (AMIO). Data are mean ⴞ1 SD. *P F .05, NS, not statistically significant. (Reprinted with permission from Hii JTY, Wyse DG, Gillis AM, et al: Precordial QT interval dispersion as a marker of torsade de pointes: Disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 86: 1376-1382, 1992.11)

QT DISPERSION AND ANTIARRHYTHMIC DRUGS

391

Fig 7. Action potentials recorded under steady state conditions at pacing cycle lengths of 1 sec (a) and 10 sec (b) from epicardial (EPI), myocardial (M cell), and endocardial (ENDO) regions of transmural preparations isolated from the left ventricular of normal hearts (NH), heart failure (HF), and heart failure treated with amiodarone (AM) groups. (Reprinted with permission from Drouin E, Lande G, Charpentier F: Amiodarone reduces transmural heterogeneity of repolarization in the human heart. J Am Coll Cardiol 32:10631067, 1998.)

prolongation of the action potential duration, which is associated with decreased dispersion of ventricular repolarization compared with other antiarrhythmic drugs. This likely explains the low incidence of torsade de pointes VT occurring in association with amiodarone compared with class I or other class III antiarrhythmic drugs. In keeping with this, amiodarone has been reported to cause greater decreases in QT dispersion in patients after MI compared with other class III drugs sotalol or sematilide.38 Nevertheless, torsade de pointes VT may occur in some patients receiving amiodarone. In at least one case where torsade de pointes VT developed during amiodarone therapy in a patient with a

history of quinidine-induced torsade de pointes VT, a marked increased in QT interval dispersion (130 ms) compared with the baseline drug-free state (40 ms) was reported.57 More extensive data on the relationship between QT interval dispersion during amiodarone therapy and the risk of torsade de pointes VT is presently unknown. The development of torsade de pointes VT during sotalol therapy in 4 patients with chronic renal failure has been reported to be associated with a marked increase in QT dispersion (100160 ms) whereas the QT dispersion had shortened significantly after drug washout (Fig 8).58 The QT interval was also substantially prolonged in all 4 patients during sotalol therapy and

Fig 8. QT interval and QT interval dispersion in 4 patients with renal failure who developed torsade de pointes VT during sotalol therapy and after discontinuation of sotalol. (Data from Dancey D et al58)

392 whether increased QT dispersion independent of QT prolongation is an independent predictor of torsade de pointes VT is unknown. More recently, it has been reported that patients with atrial flutter or fibrillation who developed torsade de pointes VT during amoxalant infusion manifested marked QT prolongation and increased QT dispersion as well as marked morphological T wave changes.59 In this study of 100 patients, 6 developed torsade de pointes VT. During drug infusion, the occurrence of ventricular bigeminy, sequential bilateral bundle branch block, and a biphasic precordial T wave were predictors of development of torsade de pointes VT.

Differences in Class I Versus Class III Antiarrhythmic Drug Effects on QT Dispersion? Some clinical studies suggest that class III antiarrhythmic drugs decrease QT dispersion.18,38,60,61 Some drugs have greater effects on QT dispersion than others and this may reflect the selectivity of the drug’s effects.38,60-62 For instance it has been hypothesized that dofetilide which blocks both Ikr and Iks is less likely to cause increased dispersion of repolarization compared with sotalol. This may explain the proarrhythmia observed with d-sotalol

ANNE M. GILLIS

in the Survival With Oral d-Sotalol (SWORD) trial63 and the apparent lack of proarrhythmia noted with dofetilide in the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) trial.64 Class IA drugs tend to increase QT dispersion in patients with CAD13 and in patients with atrial fibrillation whereas class III drugs tend to decrease QT dispersion.13,60

Modulators of QT Dispersion QT interval dispersion is not a static measure. QT interval dispersion is believed to reflect temporal and spatial heterogeneity of repolarization. Many factors may influence ventricular repolarization including myocardial ischemia, ventricular hypertrophy, heart failure, ventricular preload, electrolyte abnormalities, and antiarrhythmic drugs. Thus, changes in cardiac physiologic conditions likely modulate QT dispersion. Acute ischemia during coronary angioplasty has been shown to accentuate the effects of propafenone on QT dispersion (Fig 9).65 This observation suggests that acute ischemia may exaggerate the effects of antiarrhythmic drug effects on dispersion of repolarization and predispose to ventricular proarrhythmia. This could explain the proarrhythmia observed with class I and class III drugs in the post MI population. ␤-blockers appear to reduce

Fig 9. QT interval dispersion at baseline and during acute coronary artery occlusion induced by balloon angioplasty in patients randomized to receive placebo or propafenone. (Data from Faber TS et al65)

393

QT DISPERSION AND ANTIARRHYTHMIC DRUGS

QT dispersion in the post MI population.66 This may explain the reduced probability of a proarrhythmic effect of class IC drugs if used in conjunction with a ␤-blocker observed in the Cardiac Arrhythmia Suppression Trial.67 Some antiarrhythmic drugs cause exaggerated prolongation of the ventricular action potential duration in disease states such as hypertrophy.68-71 This may be associated with increased dispersion of repolarization, which provides the substrate for proarrhythmia.

Preventing Proarrhythmia? Magnesium is frequently used as the initial therapy for the treatment of torsade de pointes VT. In a canine model of sotalol-induced torsade de pointes VT in the setting of complete heart block, magnesium eliminated torsade de pointes VT by shortening the QT interval and markedly reducing interventricular dispersion of the action potential duration.72 In patients with acute MI, magnesium infusions reduced ventricular arrhythmias and this was associated with decreased QT dispersion.73 The effects of magnesium on QT dispersion in patients with antiarrhythmic drug-induced proarrhythmia have not been studied in detail. Potassium infusions designed to increase the serum K⫹ by 0.6 mmol/L, however, have been shown to shorten QT dispersion in healthy volunteers receiving quinidine as well as in patients with heart failure.74 This effect is thought to be because of K⫹ activation of Ikr.

Summary Clinical data suggest that antiarrhythmic druginduced increases in QT dispersion is associated with antiarrhythmic inefficacy and ventricular proarrhythmia. Interventions aimed at preventing excessive QT prolongation and marked increases in QT dispersion should prevent drug-induced proarrhythmia. QT dispersion is a dynamic variable that is influenced by many factors. Thus, one measurement in time cannot be expected to be predictive of future events. That and the technical limitations of the measurement may limit broad clinical utility of this measurement.

References 1. Singh BN: Current antiarrhythmic drugs: An overview of mechanisms of action and potential clinical utility. J Cardiovasc Electrophysiol 10:283-301, 1999 2. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology: The Sicilian Gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circulation 84:1831-1851, 1991 3. Kuo CS, Atarashi H, Reddy CP, et al: Dispersion of ventricular repolarization and arrhythmia: Study of two consecutive ventricular premature complexes. Circulation 72:370-376, 1985 4. Surawicz B: Electrophysiologic substrate of torsade de pointes: Dispersion of repolarization or early afterdepolarizations? J Am Coll Cardiol 14:172-184, 1989 5. Antzelevitch C, Shimizu W, Yan GX, et al: Cellular basis for QT dispersion. J Electrocardiol 30:168-175, 1998 6. Day CP, McComb JM, Campbell RWF: QT dispersion: An indication of arrhythmia risk in patients with long QT intervals. Br Heart J 63:342-344, 1990 7. Buja G, Miorelli M, Turrini P, et al: Comparison of QT dispersion in hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death. Am J Cardiol 72:973-976, 1993 8. Yunus A, Gillis A, Duff H, et al: Increased precordial QTc dispersion predicts ventricular fibrillation during acute myocardial infarction. Am J Cardiol 78:706-708, 1996 9. Bogun F, Chan K, Harvey M, et al: QT dispersion in nonsustained ventricular tachycardia and coronary artery disease. Am J Cardiol 77:256-259, 1996 10. Barr CS, Naas A, Freeman M, et al: QT dispersion and sudden unexpected death in chronic heart failure. Lancet 343:327-329, 1994 11. Hii JTY, Wyse DG, Gillis AM, et al: Precordial QT interval dispersion as a marker of torsade de pointes: Disparate effects of class Ia antiarrhythmic drugs and amiodarone. Circulation 86:1376-1382, 1992 12. Priori SG, Napolitano C, Diehl L, et al: Dispersion of the QT interval. A marker of therapeutic efficacy in the idiopathic long QT syndrome. Circulation 89:16811689, 1994 13. Gillis AM, Traboulsi M, Hii JTY, et al: Antiarrhythmic drug effects on QT dispersion in patients undergoing electropharmacologic testing for ventricular tachycardia and fibrillation. Am J Cardiol 81:588-593, 1998 14. Dambrink JH, Sippens Groenewegen A, van Gilst WH, et al: Association of left ventricular remodeling and nonuniform electrical recovery expressed by nondipolar QRST integral map patterns in survivors of a first anterior myocardial infarction. Captopril and Thrombolysis Study Investigation. Circulation 92:300-312, 1995

394 15. Spargias KS, Lindsay SJ, Hall AS, et al: Ramipril reduces QT dispersion in patients with acute myocardial infarction and heart failure. Am J Cardiol 83:969971, 1999 16. Statters DJ, Malik M, Ward DE, et al: QT dispersion: Problems of methodology and clinical significance. J Cardiovasc Electrophysiol 5:672-685, 1994 17. Kautzner J, Malik M: QT interval dispersion and its clinical utility. Pacing Clin Electrophysiol 20:26252640, 1997 18. Zabel M: Is dispersion of ventricular repolarization rate dependent? Pacing Clin Electrophysiol 20:2405-2411, 1997 19. Day CP, McComb JM, Matthews J, et al: Reduction in QT dispersion by sotalol following myocardial infarction. Eur Heart J 12:423-427, 1991 20. de Bruyne MC, Hoes AW, Kors JA, et al: QTc dispersion predicts cardiac mortality in the elderly. The Rotterdam Study. Circulation 97:467-472, 1998 21. Coumel P, Maison-Blanche P, Badilini F: Dispersion of ventricular repolarization: Reality? illusion? significance? Circulation 97:2491-2493, 1998 22. Lux RL, Fuller MS, Macleod RS, et al: QT dispersion: Dispersion of ventricular repolarization or dispersion of the QT interval? J Electrocardiol 30:176-180, 1997 (suppl) 23. Stramba-Badiale M, Goulene K, Schwartz PJ: Effects of ␤-adrenergic blockade on dispersion of ventricular repolarization in newborn infants with prolonged QT interval. Am Heart J 134:406-410, 1997 24. Sun Z-H, Swan H, Viitasalo M, et al: Effects of epinephrine and phenylephrine on QT interval dispersion in congenital long QT syndrome. J Am Coll Cardiol 31:1400-1405, 1998 25. Shimizu W, Ohe T, Kurita T, et al: Effects of verapamil and propranolol on early afterdepolarizations and ventricular arrhythmias induced by epinephrine in congenital long QT syndrome. J Am Coll Cardiol 26:1299-1309, 1995 26. Shimizu W, Kamakura S, Kurita T, et al: Influence of epinephrine, propranolol and atrial pacing on spatial distribution of recovery time measured by body surface mapping in congenital long QT syndrome. J Cardiovasc Electrophysiol 8:1102-1114, 1997 27. Shimizu W, Antzelevitch C: Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome. Effects of ␤-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 98:2314-2322, 1998 28. Liu DW, Antzelevitch C: Characteristics of the delayed rectifier current (Ikr and Iks) in canine ventricular epicardial, mid-myocardial, and endocardial myocytes: A weaker Iks contributes to the longer action potential of the M cell. Circ Res 76:351-365, 1995 29. Schwartz PJ, Priori SG, Locati EH, et al: 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:

ANNE M. GILLIS

30.

31.

32.

33.

34.

35.

36. 37.

38.

39.

40.

41.

42.

43.

Implications for gene-specific therapy. Circulation 92: 3381-3386, 1995 Priori SG, Napolitano C, Cantu F, et al: Differential response to Na⫹ channel blockade, ␤-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects present in the long QT syndrome. Circ Res 78:1009-1015, 1996 Shimizu W, Antzelevitch C: Sodium channel block with mexilitine is effective in reducing dispersion of repolarization and preventing torsade de pointes in LQT2 and LQT3 models of the long-QT syndrome. Circulation 96:2038-2047, 1997 Shimizu W, Kurita T, Matsuo K, et al: Improvement of repolarization abnormalities by a K⫹ channel opener in LQT1 form of congenital long QT syndrome. Circulation 97:1581-1588, 1998 Liu DW, Gintant GA, Antzelevitch C: Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle. Circ Res 72:671-687, 1993 Gillis AM, Geonzon RA, Mathison HJ, et al: The effects of barium, dofetilide and 4-aminopyridine (4-AP) on ventricular repolarization in normal and hypertrophied rabbit heart. J Pharmacol Exp Ther 289:262-270, 1998 Beukelmann DJ, Nabauer M, Erdmann E: Alterations of K⫹ currents from patients with terminal heart failure. Circ Res 73:379-385, 1993 Boyden PA, Jeck CD: Ion channel function in disease. Cardiovasc Res 29:312-318, 1995 Mitchell LB, Hubley-Kozey CL, Smith ER, et al: Electrocardiographic body surface potential mapping in patients with ventricular tachycardia. Assessment of utility in the identification of effective pharmacologic therapy. Circulation 86:383-393, 1992 Cui G, Sen L, Sager P, et al: Effect of amiodarone, sematilide and sotalol on QT dispersion. Am J Cardiol 74:896-900, 1994 Grimm W, Steder U, Menz V, et al: Effect of amiodarone on QT dispersion in the 12-lead standard electrocardiogram and its significance for subsequent arrhythmic events. Clin Cardiol 20:107-110, 1997 Meierhenrich R, Helquera ME, Kidwell GA, et al: Influence of amiodarone on QT dispersion in patients with life-threatening ventricular arrhythmias and clinical outcome. Int J Cardiol 60:289-294, 1997 Yi G, Elliott P, McKenna WJ, et al: QT dispersion and risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy. Am J Cardiol 82:15141519, 1998 Dritsas A, Gilligan D, Nihoyannopoulos P, et al: Amiodarone reduces QT dispersion in patients with hypertrophic cardiomyopathy. Int J Cardiol 36:345-349, 1992 Miorelli M, Buja G, Melacini P, et al: QT-interval variability in hypertrophic cardiomyopathy patients with cardiac arrest. Int J Cardiol 45:121-127, 1994

QT DISPERSION AND ANTIARRHYTHMIC DRUGS 44. Mayet J, Shahi M, McGrath K, et al: Left ventricular hypertrophy and QT dispersion in hypertension. Hypertension 28:791-796, 1996 45. Mirvis DM: Spatial variation of QT intervals in normal persons and patients with acute myocardial infarction. J Am Coll Cardiol 5:625-631, 1985 46. Ichkhan K, Molnar J, Somberg J: Relation of left ventricular mass and QT dispersion in patients with systemic hypertension. Am J Cardiol 79:508-511, 1997 47. Gillis AM, Mathison HJ, Kulisz E, et al: Quinapril reduces dispersion of ventricular repolarization in a rabbit model of volume overload heart failure. Can J Cardiol 14:81F, 1998 (abstr) 48. Gonza´lez-Juanatey JR, Garcı´a-Acun˜a JM, Pose A, et al: Reduction of QT and QTc dispersion during longterm treatment of systemic hypertension with analapril. Am J Cardiol 81:170-174, 1998 49. Barr CS, Naas AA, Fenwick M, et al: Enalapril reduces QTc dispersion in mild congestive heart failure secondary to coronary artery disease. Am J Cardiol 79:328333, 1997 50. Domanski MJ, Exner DV, Borkowf CB, et al: Effect of angiotensin converting enzyme inhibition on sudden cardiac death in patients following acute myocardial infarction. A meta-analysis of randomized clinical trials. J Am Coll Cardiol 33:598-604, 1999 51. Hohnloser SH, Klingenheben T, Singh BN: Amiodarone-associated proarrhythmic effects. A review with special reference to torsade de pointes tachycardia. Ann Intern Med 121:529-535, 1994 52. Lehmann MH, Hardy S, Archibald D, et al: Sex difference in risk of torsade de pointes with d,1-sotalol. Circulation 94:2535-2541, 1996 53. Hohnloser SH, Singh BW: Proarrhythmia with Class III antiarrhythmic drugs: Definition, electrophysiologic mechanisms, incidence, predisposing factors, and clinical implications. J Cardiovasc Electrophysiol 6:920936, 1995 54. Drouin E, Charpentier F, Gauthier C, et al: Electrophysiological characteristics of cells spanning the left ventricular wall of human heat: Evidence for the presence of M cells. J Am Coll Cardiol 26:185-192, 1995 55. Zabel M, Hohnloser SH, Behrens S, et al: Differential effects of d-sotalol, quinidine, and amiodarone on dispersion of ventricular repolarization in the isolated rabbit heart. J Cardiovasc Electrophysiol 8:12391245, 1997 56. Sicouri S, Moro S, Litovsky S, et al: Chronic amiodarone reduces transmural dispersion of repolarization in the canine heart. J Cardiovasc Electrophysiol 8:1269-1279, 1997 57. Tran HT, Chow MSS, Kluger J: Amiodarone induced torsade de pointes with excessive QT dispersion following quinidine induced polymorphic ventricular tachycardia. Pacing Clin Electrophysiol 20:22752278, 1997 58. Dancey D, Wulffhart Z, McEwan P: Sotalol-induced torsade de pointes in patients with renal failure. Can J Cardiol 13:55-58, 1997

395 59. Houltz B, Darpo B, Edvardsson W, et al: Electrocardiographic and clinical predictors of torsade de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: A prospective study. Pacing Clin Electrophysiol 21:1044-1057, 1998 60. Hohnloser SH, van de Loo A, Baedeker F: Efficacy and proarrhythmic hazards of pharmacologic cardioversion of atrial fibrillation: Prospective comparison of sotalol versus quinidine. J Am Coll Cardiol 26:852858, 1995 61. Sarubbi B, Ducceshi V, Briglia N, et al: Compared effects of sotalol, flecainide and propafenone on ventricular repolarization in patients free of underlying structural heart disease. Int J Cardiol 66:157-164, 1998 62. Demolis J-L, Funck-Brentano C, Ropers J, et al: Influence of dofetilide on the QT-interval duration and dispersion at various heart rates during exercise in humans. Circulation 94:1592-1599, 1996 63. Waldo AL, Camm AJ, de Ruyter H, et al: Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol. Lancet 348:7-12, 1996 64. Moller M: DIAMOND antiarrhythmic trials. Danish Investigations of Arrhythmia and Mortality on Dofetilide. Lancet 348:1597-1598, 1996 65. Faber TS, Zehender M, Krahnefeld O, et al: Propafenone during acute myocardial ischemia in patients: A double-blind randomized, placebo-controlled study. J Am Coll Cardiol 29:561-567, 1997 66. Puljevic D, Smalcelj A, Darakovic Z, et al: The influence of atenolol and propafenone on QT interval dispersion in patients 3 months after myocardial infarction. Int J Clin Pharmacol Ther 35:381-384, 1997 67. Kennedy JL: Beta-blocker prevention of proarrhythmia and proischemia: Clues from CAST, CAMIAT and EMIAT. Am J Cardiol 80:1208-1211, 1997 68. Verduyn SC, Vos MA, Van de Zande J, et al: Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired torsade de pointes arrhythmias. A comparison between almokalant and d-sotalol using the dog as its own control. J Am Coll Cardiol 30:1575-1584, 1997 69. Volders PGA, Sipido KR, Vos MA, et al: Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation 98:11361147, 1998 70. Gillis AM, Mathison HJ, Kulisz G, et al: Influence of ventricular dilation and potassium channel blockers on dispersion of ventricular repolarizations in hypertrophied rabbit hearts. Can J Cardiol 13:78C, 1997 (abstr) 71. Geonzon RA, Gunka V, Gillis AM, et al: Enhanced dofetilide-induced prolongation of cardiac action potential in pressure overload cardiac hypertrophy. Can J Cardiol 13:101C, 1997 (abstr)

396 72. Verduyn SC, Vos MA, Van der Zande J, et al: Role of interventricular dispersion of repolarization in acquired torsade de pointes arrhythmias: Reversal by magnesium. Cardiovasc Res 34:453-463, 1997 73. Parikka H, Toivonen L, Naukkarinen V, et al: Decreases by magnesium of QT dispersion and ventricu-

ANNE M. GILLIS lar arrhythmias inpatients with acute myocardial infarction. Eur Heart J 20:111-120, 1999 74. Yang T, Roden DM: Extracellular potassium modulation of drug block of IKr: implications for torsade de pointes and reverse use-dependence. Circulation 93: 407-411, 1996