Congenital LQT Syndromes: From Gene to Torsade de Pointes

  • Published : 2002.02.21


Congenital Long QT syndrome (LQTs) is a relatively rare pathologic disorder but results frequently in sudden cardiac death. Of the six LQTs that have been clinically described, five have been worked out for their genetic and biophysical profile. Most are generated by mutations which cause a loss of function in two delayed $K^+$ currents, $i_{Ks}\;and\;i_{Kr}.$ One syndrome is generated by mutations in the $Na^+$ channel which causes essentially a gain of function in the channel. Clinically the syndromes are characterized by slowed repolarization of the cardiac ventricular action potential and the occurrence of typical arrhythmias with undulating peaks in the electrocardiogram, called Torsade de Pointes. Arrhythmias are initiated by early or delayed afterdepolarizations and continue as reentry. Triggers for cardiac events are exercise (swimming; LQT1), emotion (arousal; LQT2) and rest/sleep (LQT3). ${\beta}-blockers$ have a high efficacy in the treatment of LQT1 and LQT2. In LQT3 their use is questionable. The study of congenital LQTsyndromes is a remarkable example of how basic and clinical science converge and take profit of each other's contribution.


  1. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann, MH, Timothy KW, Keating MT, Goldstein SA. MiRPl forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97: 175-187, 1999
  2. Arrighi I, Bloch-Faure M, Grahammer F, Bleich M, Warth R, Mengual R, Drici MD, Barhanin J, Meneton P. Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome. Pmc Natl Acad Sci USA 98: 8792-8797, 2001
  3. Benhorin J, Taub R, Goldmit M, Kerem B, Kass RS, Windman I, Medina A. Effects of flecainide in patients with new SCN5A mutation: mutation-specific therapy for long-QT syndrome? Circulation 101: 1698-1706, 2000
  4. Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. JAm Coli Cardiol 20: 1391-1396, 1992
  5. Dessertenne F. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur Vaiss 59: 263-272, 1966
  6. Ficker E, Dennis AT, Obejero-Paz CA, Castaldo P, Taglialatela M, Brown AM. Retention in the endoplasmic reticulum as a mechanism of dominant-negative current suppression in human long QT syndrome. J Mol Cell Cardiol 32: 2327-2337, 2000a
  7. Fujiki A, Masuda A, Inoue H. Effects of unilateral stellate ganglion block on the spectral characteristics of heart rate variability. Jpn Circ J 63: 854-858, 1999
  8. Kagan A, Yu Z, Fishman GI, McDonald TV. The dominant negative LQT2 mutation A561V reduces wild-type HERG expression. J BioI Chem 275: 11241-11248, 2000
  9. Kass RS, Davies MP. The roles ofion channels in an inherited heart disease: molecular genetics of the long QT syndrome. Cardiovasc Res 32: 443-454, 1996.
  10. Nakajima T, Kurabayashi M, Ohyama Y, Kaneko Y, Furukawa T, Hoh T, Taniguchi Y, Tanaka T, Nakamura Y, Hiraoka M, Nagai R. Characterization of S818L mutation in HERG C-terminus in LQT2. Modification of activation-deactivation gating properties. FEBS Lett 481: 197-203, 2000
  11. Schwartz PJ, Priori SG, Locati EH, Napolitano C, Cantu F, Towbin JA, Keating MT, Hammoude H, Brown AM, Chen LS. Long QT syndrome patients with mutations of the SCN5A and HERC genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. Cirwlation 92: 3381-3386, 1995
  12. Seebohm G, Scherer CR, Busch AE, Lerche C. Identification of specific pore residues mediating KCNQ1 inactivation. A novel mechanism for long QT syndrome. J BioI Chem 276: 13600-13605, 2001
  13. Viswanathan PC, Bezzina CR, George AL, Jr, Roden DM, Wilde AA, Balser JR. Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes. Cirwlation 104:1200-1205, 2001
  14. Wu Y, Roden DM, Anderson ME. Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current, Circ Res 84: 906-912, 1999b
  15. Ono K, Kaku T, Makita N, Kitabatake A, Arita M. Selective block of late currents in the L,KPQ Na+ channel mutant by pilsicainide and lidocaine with distinct mechanisms. Mol Pharmacal 57: 392-400, 2000
  16. Chouabe C, Neyroud N, Guicheney P, Lazdunski M, Romey G, Barhanin J. Properties of KvLQT1 $K^+$ channel mutations in Romano-Ward and J ervell and Lange-Nielsen inherited cardiac arrhythmias. Embo J 16: 5472-5479, 1997
  17. Lees-Miller JP, Duan Y, Teng GQ, Thorstad K, Duff HJ. Novel gain-of-function mechanism in $K^+$ channel-related long-QT syndrome: altered gating and selectivity in the HERG1 N629D mutant. Circ Res 86: 507-513, 2000
  18. Wehrens XH, Abriel H, Cabo C, Benhorin J, Kass RS. Arrhythmogenic mechanism of an LQT-3 mutation of the human heart Na+ channel a-subunit: A computational analysis. Circulation 102: 584-590, 2000
  19. Shimizu W, Antzelevitch C. Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome. J Electrocardiol 32: 177-184, 1999
  20. Nuyens D, Stengl M, Dugarmaa S, Rossenbacker T, Compernolle V, Rudy Y, Smits JF, Flameng W, Clancy CE, Moons L, Vos MA, Dewerchin M, Benndorf K, Collen D, Carmeliet E, Carmeliet P. Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med 7: 1021-1027, 2001
  21. Vetter DE, Mann JR, Wangemann P, Liu J, McLaughlin KJ, Lesage F, Marcus DC, Lazdunski M, Heinemann SF, Barhanin J. Inner ear defects induced by null mutation of the isk gene. Neuron 17: 1251-1264, 1996
  22. Shimizu W, Antzelevitch C. Differential effects of tJ-adrenergic agonists and antagonists in LQT1, LQT2 and LQT3 models of the long QT syndrome. J Am Call Cardiol 35: 778-786, 2000
  23. Stramba-Badiale M, Priori SG, Napolitano C, Locati EH, Vinolas X, Haverkamp W, Schulze-Bahr E, Goulene K, Schwartz PJ. Gene-specific differences in the circadian variation of ventricular repolarization in the long QT syndrome: a key to sudden death during sleep? Ital Heart J 1: 323-328, 2000
  24. Viskin S. Cardiac pacing in the long QT syndrome: review of available data and practical recommendations. J Cardiovasc Electrophysiol 11: 593-600, 2000
  25. Balser JR. The cardiac sodium channel: gating function and molecular pharmacology. J Mol Cell Cardiol 33: 599-613, 2001
  26. Burashnikov A, Antzelevitch C. Block of II{, does not induce early afterdepolarization activity but promotes beta-adrenergic agonistinduced delayed afterdepolarization activity. J Cardiovasc Electmphysiol 11: 458-465, 2000
  27. Noda T, Takaki H, Kurita T, Taguchi H, Suyama K, Aihara N, Kamakura S, Nakamura K, Ohe T, Towbin JA, Priori SG. Differential response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital Long QT syndrome. PACE 24: 589, 2001
  28. Priori SG, Napolitano C, Cantu F, Brown AM, Schwartz PJ. Differential response to Na+ channel blockade, tJ-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
  29. Bianchi L, Priori SG, Napolitano C, Surewicz KA, Dennis AT, Memmi M, Schwartz PJ, Brown AM. Mechanisms of h, suppression in LQTl mutants. Am J Physiol 279: H3003-3011, 2000
  30. Huang L, Bitner-Glindzicz M, Tranebjaerg L, Tinker A. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. Cardiovasc Res 51: 670-680, 2001
  31. Nakajima T, Furukawa T, Tanaka T, Katayama Y, Nagai R, Nakamura Y, Hiraoka M. Novel mechanism of HERG current suppression in LQT2: shift in voltage dependence of HERG inactivation. Circ Res 83: 415-422, 1998
  32. Roden DM, George AL, Bennett PB. Recent advances in understanding the molecular mechanisms of the long QT syndrome. J Cardiovasc Electrophysiol 6: 1023-1031, 1995
  33. Viswanathan PC, Rudy Y. Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovasc Res 42: 530-542, 1999
  34. Wu Y, MacMillan LB, McNeill RB, Colbran RJ, Anderson ME. CaM kinase augments cardiac L-type $Ca^{2+}$ current: a cellular mechanism for long Q-T arrhythmias, Am J Physiol 276: H2168-2178, 1999a
  35. Ali RH, Zareba W, Moss AJ, Schwartz, PJ, Benhorin, J, Vincent GM, Locati EH, Priori S, Napolitano C, Towbin JA, Hall WJ, Robinson JL, Andrews ML, Zhang L, Timothy K, Medina A. Clinical and genetic variables associated with acute arousal and nonarousal-related cardiac events among subjects with long QT syndrome. Am J Cardiol 85: 457-461, 2000
  36. Nagatomo T, January CT, Makielski JC. Preferential block of late sodium current in the LQT3 KPQ mutant by the class Ie antiarrhythmic flecainide. Mol Pharmacol 57: 101-107, 2000
  37. Zhou Z, Gong Q, Epstein ML, January CT, HERG channel dysfunction in human long QT syndrome, Intracellular transport and functional defects, J BioI Chem 273: 21061-21066, 1998
  38. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink P, Wilde AA, Toivonen L, Zareba W, Robinson JL, Timothy KW, Corfield V, Wattanasirichaigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel P, Bloise R. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for lifethreatening arrhythmias. Cirwlation 103: 89-95, 2001
  39. Coraboeuf E, Deroubaix E, Coulombe A. Effect of tetrodotoxin on action potentials of the conducting system in the dog heart. Am J Physiol 236: H561-567, 1979
  40. Kambouris NG, Nuss HB, Johns DC, Marban E, Tomaselli GF, Balser JR. A revised view of cardiac sodium channel 'blockade' in the long-QT syndrome. J Clin Invest 105: 1133-1140, 2000
  41. Sesti F, Goldstein SA. Single-channel characteristics of wild-type IK' channels and channels formed with two minK mutants that cause long QT syndrome. J Cen Physiol 112: 651-663, 1998
  42. Ben-David J, Zipes DP. Differential response to right and left ansae subclaviae stimulation of early afterdepolarizations and ventricular tachycardia induced by cesium in dogs. Circulation 78: 1241-1250, 1988
  43. Veldkamp MW, Viswanathan PC, Bezzina C, Baartscheer A, Wilde AA, Balser JR. Two distinct congenital arrhythmias evoked by a multidysfunctional Na+ channel. Circ Res 86: E91-97, 2000
  44. Wehrens XHT, Rossenbacker T, Jongbloed RJ, Gewillig M, Heidbiihel H, Doevendans FA, Vas MA, Wellens HJJ, Kass RS, Heterozygous SCNSA mutation in the domain I-II linker causes long QT syndrome with 2 : 1 atrioventricular block In preparation.
  45. Ficker E, Thomas D, Viswanathan PC, Dennis AT, Priori SG, Napolitano C, Memmi M, Wible BA, Kaufman ES, Iyengar S, Schwartz PJ, Rudy Y, Brown AM. Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome. Am J Physiol 279: H1748-1756, 2000b
  46. Abriel H, Cabo C, Wehrens XH, Rivolta I, Motoike HK, Memmi M, Napolitano C, Priori SG, Kass RS. Novel arrhythmogenic mechanism revealed by a long-QT syndrome mutation in the cardiac Na+ channel. Circ Res 88: 740-745, 2001
  47. An RH, Wang XL, Kerem B, Benhorin, J, Medina A, Goldmit M, Kass RS. Novel LQT-3 mutation affects Na+ channel activity through interactions between a-and pl-subunits. Circ Res 83: 141-146, 1998
  48. El-SherifN, Chinushi M, CarefEB, Restivo M. Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long-QT syndrome: detailed analysis of ventricular tridimensional activation patterns. Cirwlation 96: 4392-4399, 1997
  49. Shimizu W, Antzelevitch C. Cellular basis for the ECG features ofthe LQT1 form ofthe long-QT syndrome. Effects of tJ-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Cirwlation 98: 2314-2322, 1998
  50. Casimiro MC, Knollmann BC, Ebert SN, Vary JC Jr, Greene AE, Franz MR, Grinberg A, Huang SP, Pfeifer K. Targeted disruption of the Kcnql gene produces a mouse model of Jervell and Lange-Nielsen Syndrome. Proc Natl Acad Sci USA 98: 2526-2531, 2001
  51. Chandra R, Starmer CF, Grant AO. Multiple effects of KPQ deletion mutation on gating of human cardiac Na+ channels expressed in mammalian cells. Am J Physiol 274: H1643-1654, 1998
  52. Moss AJ, Zareba W, Hall WJ, Schwartz PJ, Crampton RS, Benhorin J, Vincent GM, Locati EH, Priori SG, Napolitano C, Medina A, Zhang L, Robinson JL, Timothy K, Towbin JA, Andrews ML. Effectiveness and limitations of tJ-blocker therapy in congenital long-QT syndrome. Circulation 101: 616-623, 2000