Familial And Acquired Long QT Syndrome And The Cardiac Rapid Delayed Rectifier Potassium Current

Clinical and Experimental Pharmacology and Physiology - Tập 27 Số 10 - Trang 753-766 - 2000
Harry J. Witchel1, Jules C. Hancox2
1Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, United Kingdom.
2Department of Physiology and Cardiovascular Research Laboratories, School of Medical Sciences, University of Bristol, Bristol, United Kingdom

Tóm tắt

SUMMARY1. Long QT syndrome (LQTS) is a cardiac disorder characterized by syncope, seizures and sudden death; it can be congenital, idiopathic, or iatrogenic.2. Long QT syndrome is so‐named because of the connection observed between the distinctive polymorphic ventricular tachycardia torsade de pointes and prolongation of the QT interval of the electrocardiogram, reflecting abnormally slowed ventricular action potential (AP) repolarization. Acquired LQTS has many similar clinical features to congenital LQTS, but typically affects older individuals and is often associated with specific pharmacological agents.3. A growing number of drugs associated with QT prolongation and its concomitant risks of arrhythmia and sudden death have been shown to block the ‘rapid’ cardiac delayed rectifier potassium current (IKr) or cloned channels encoded by the human ether‐a‐go‐go‐related gene (HERG; the gene believed to encode native IKr). Because IKr plays an important role in ventricular AP repolarization, its inhibition would be expected to result in prolongation of both the AP and QT interval of the electrocardiogram.4. The drugs that produce acquired LQTS are structurally heterogeneous, including anti‐arrhythmics, such as quinidine, non‐sedating antihistamines, such as terfenadine, and psychiatric drugs, such as haloperidol. In addition to heterogeneity in their structure, the electrophysiological characteristics of HERG/IKr inhibition differ between agents.5. Here, clinical observations are associated with cellular data to correlate acquired LQTS with the IKr/HERG potassium (K+) channel. One strategy for developing improved compounds in those drug classes that are currently associated with LQTS could be to design drug structures that preserve clinical efficacy but are modified to avoid pharmacological interactions with IKr. Until such time, awareness of the QT‐prolongation risk of particular agents is important for the clinician.

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Tài liệu tham khảo

10.1161/01.CIR.84.4.1516

10.1093/eurheartj/14.suppl_H.3

Sanguinetti MC, 1990, Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents., J. Gen. Physiol., 96, 195, 10.1085/jgp.96.1.195

Sanguinetti MC, 1997, Role of delayed rectifier potassium channels in cardiac repolarization and arrhythmias., News Physiol. Sci., 12, 152

10.1161/01.CIR.71.1.17

10.1161/01.CIR.84.3.1136

10.1016/0002-9149(76)90420-3

10.1111/j.1540-8159.1991.tb04076.x

10.1161/01.CIR.68.4.846

10.1161/01.CIR.79.3.674

10.1111/j.1540-8167.1990.tb01059.x

10.1161/01.RES.64.5.977

10.1023/A:1009963228964

10.1172/JCI5073

10.1038/ng0196-17

10.1093/hmg/4.9.1603

10.1038/384078a0

10.1038/384080a0

10.1016/S0092-8674(00)80728-X

10.1073/pnas.91.8.3438

10.1016/0092-8674(95)90358-5

10.1016/0092-8674(95)90340-2

10.1101/SQB.1990.055.01.004

10.1161/01.RES.81.5.719

10.1016/S0092-8674(00)81635-9

10.1016/s0008-6363(99)00224-2

10.1126/science.7604285

10.1038/379833a0

10.1111/j.1469-7793.1997.045bl.x

10.1016/S0006-3495(98)77782-3

10.1007/s004240050713

10.1161/01.CIR.99.4.518

10.1161/01.CIR.92.12.3381

10.1161/01.CIR.94.5.1018

Vaughan‐WilliamsEM.Classification of antiarrhythmic actions. In: Vaughan‐Williams EM (ed.).Antiarrhythmic Drugs.Springer‐Verlag Berlin. 1989; 45–67.

10.1056/NEJM199801013380107

10.1161/01.RES.72.1.75

10.1097/00005344-199410000-00007

10.1161/01.RES.78.1.26

10.1111/j.1540-8167.1999.tb00676.x

10.1111/j.1540-8159.1997.tb05496.x

10.1016/S0008-6363(97)00216-2

Bril A, 1995, Electrophysiological effect of BRL‐32872, a novel antiarrhythmic agent with potassium and calcium channel blocking properties, in guinea pig cardiac isolated preparations., J. Pharmacol. Exp. Ther., 273, 1264

10.1161/01.RES.78.3.499

Snyders DJ, 1996, High affinity open channel block by dofetilide of HERG expressed in a human cell line., Mol. Pharmacol., 49, 949

10.1161/01.CIR.94.10.2572

10.1161/01.RES.82.3.386

10.1016/0002-9149(93)90020-D

10.1093/cvr/26.11.1145

10.1016/S0002-8703(99)70484-9

10.1016/S0140-6736(96)02149-6

10.1016/S0002-9149(98)00006-X

10.1002/j.1875-9114.1997.tb03765.x

Verduyn SC, 1997, Role of interventricular dispersion of repolarization in acquired torsade‐de‐pointes arrhythmias: Reversal by magnesium., Cardiovasc. Res., 34, 453, 10.1016/S0008-6363(97)00067-9

10.1097/00005344-199612000-00013

10.1007/s003950050073

10.1006/jmcc.1996.0275

10.1016/S0014-5793(97)01030-2

10.1111/j.1469-7793.1998.129bo.x

10.1016/S0002-9149(98)00152-0

10.1038/sj.bjp.0701575

10.1161/01.RES.69.2.519

KatritsisD&CammAJ.Amiodarone in long term prophylaxis.Drugs1991;41(Suppl. 2): 54–66.

Bosch RF, 1999, Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes., J. Pharmacol. Exp. Ther., 289, 156

10.1007/PL00005344

10.1023/A:1009975915702

10.1016/S0008-6363(98)00021-2

Bril A, 1996, Combined potassium and calcium channel blocking activities as a basis for antiarrhythmic efficacy with low proarrhythmic risk: Experimental profile of BRL‐32872., J. Pharmacol. Exp. Ther., 276, 637

Brodsky MA, 1996, Regional attitudes of generalists, specialists, and subspecialists about management of atrial fibrillation., Arch. Intern. Med., 156, 2553, 10.1001/archinte.1996.00440210063007

Lewis T., 1922, The value of quinidine in cases of auricular fibrillation and methods of studying the clinical reaction., Am. J. Med. Sci., 163, 781

10.1056/NEJM199409223311207

10.1016/0002-8703(86)90010-4

10.1097/00005344-199902000-00002

Colatsky TJ, 1990, Channel specificity in antiarrhythmic drug action: Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias., Circulation, 72, 1092

10.1016/0002-9149(85)91015-X

10.1007/PL00005167

10.1097/00005344-198705000-00014

10.2165/00003495-199550020-00005

10.1161/01.RES.76.2.223

10.1111/j.1540-8167.1992.tb00992.x

Chouabe C, 1998, HERG and KvLQT1/IsK, the cardiac K+ channels involved in long QT syndromes, are targets for calcium channel blockers., Mol. Pharmacol., 54, 695

10.1161/01.RES.84.9.989

10.1111/j.1540-8159.1990.tb02000.x

10.1016/0002-8703(86)90660-5

10.1161/01.RES.75.1.144

10.1038/sj.bjp.0702321

10.1007/s002280050241

10.1016/S0002-9149(97)00569-9

10.1038/sj.bjp.0702502

10.1136/hrt.74.1.53

10.1038/sj.bjp.0702173

10.1185/03007998809114244

10.1111/j.1476-5381.1988.tb11533.x

10.1001/jama.1990.03450210088038

10.1093/oxfordjournals.eurheartj.a060277

10.1001/jama.1993.03500120070028

Crumb WJ, 1995, Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: Possible mechanism for terfenadine associated cardiotoxicity., Mol. Pharmacol., 47, 181

10.1161/01.CIR.94.4.817

10.1016/0014-5793(96)00355-9

Ko CM, 1997, Suppression of mammalian K+ channel family by ebastine., J. Pharmacol. Exp. Ther., 281, 233

10.1124/mol.54.1.113

10.1177/096032719101000110

10.1038/sj.bjp.0700989

Rampe D, 1998, The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG., J. Pharmacol. Exp. Ther., 286, 788

10.1016/0014-2999(85)90716-2

10.1007/BF00174748

10.1038/sj.bjp.0702800

Dumaine R, 1998, Blockade of HERG, and Kv1.5 by ketoconazole., J. Pharmacol. Exp. Ther., 286, 727

10.1016/S0735-1097(96)00377-4

10.1016/S1461-5347(99)00172-8

10.1074/jbc.274.15.10113

10.1074/jbc.272.2.705

10.1073/pnas.93.5.2208

10.1161/01.CIR.95.3.565

10.1016/S0008-6363(99)00195-9

10.1002/(SICI)1098-1004(1999)13:4<301::AID-HUMU7>3.0.CO;2-V

10.1006/jmcc.1996.0151

10.1161/01.CIR.93.10.1791

AkimotoK FurutaniM ImamuraSet al.Novel missense mutation (G601S) of HERG in a Japanese long QT syndrome family.Hum. Mutat.1998; Suppl. 1: S184–6.

10.1007/s004390050690

10.1002/(SICI)1096-8628(19961002)65:1<27::AID-AJMG4>3.0.CO;2-V

10.1074/jbc.273.42.27231

10.1161/01.CIR.99.11.1464

10.1016/S0735-1097(86)80272-8

10.1161/01.CIR.94.7.1592

10.1016/0014-2999(88)90535-3

10.1093/cvr/27.12.2186

10.1161/01.RES.73.5.857

10.1161/01.CIR.88.3.1072

10.1097/00005344-199502000-00021

10.1016/S0002-9149(96)00560-7

10.1161/01.CIR.91.6.1799

10.1046/j.1365-2125.1997.t01-1-00603.x

Dukes ID, 1990, Tedisamil blocks the transient and delayed rectifier K+ currents in mammalian cardiac and glial cells., J. Pharmacol. Exp. Ther., 254, 560

10.1097/00005344-199312000-00006

10.1161/01.CIR.86.5.1376

Yang T, 1997, Inhibition of cardiac potassium currents by the vesnarinone analog OPC‐18790: Comparison with quinidine and dofetilide., J. Pharmacol. Exp. Ther., 280, 1170

10.1056/NEJM199002223220806

Duan D, 1993, Potassium channel blocking properties of propafenone in rabbit atrial myocytes., J. Pharmacol. Exp. Ther., 264, 1113

Dangman KH, 1980, In vivo and in vitro antiarrhythmic and arrhythmogenic effects of N‐acetyl procainamide., J. Pharmacol. Exp. Ther., 217, 851

10.1016/S0022-0736(81)80013-1

10.1136/hrt.44.3.330

10.1146/annurev.pa.36.040196.001313

10.1097/00004714-199304000-00007

10.1016/S0140-6736(72)91958-7

10.1161/01.RES.74.4.687

10.1016/0002-8703(80)90153-2

10.1111/j.1600-0447.1991.tb01421.x

Drolet B, 1999, Thioridazine lengthens repolarization of cardiac ventricular myocytes by blocking the delayed rectifier potassium current., J. Pharmacol. Exp. Ther., 288, 1261

BarnettAA.Safety concerns over antipsychotic drug sertindole.Lancet1996;348: 256.

10.1016/0002-9343(90)90305-W

10.1161/01.CIR.91.12.3010

10.1378/chest.112.3.646

Karbwang J, 1993, A comparison of the pharmacokinetic and pharmacodynamic properties of quinine and quinidine in healthy Thai males., Br. J. Clin. Pharmacol., 35, 265

Bustos MD, 1994, The pharmacokinetics and electrocardiographic effects of chloroquine in healthy subjects., Trop. Med. Parasitol., 45, 83

10.1016/0140-6736(93)92412-M

10.1056/NEJM199607253350416

10.1038/sj.bjp.0702774

BenhorinJ&MedinaA.Images in clinical medicine. Congenital long‐QT syndrome.N. Engl. J. Med.1997;336: 1568.

10.1161/01.RES.62.3.563

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Clinical and Experimental Pharmacology and Physiology

Tập 27 Số 10

753-766

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