(Circulation. 1999;99:518-528.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Parts I and II1
From the Molecular Cardiology and Electrophysiology Laboratory (S.G.P.), Fondazione S. Maugeri, IRCCS, Pavia, Italy; Institut de Pharmacologie Moleculaire et Cellulaire (J.B.), Laboratoire de Genetique de la Neurotrasmission, CNRS, Valbonne, France; University Hospital of Utrecht, Heart Lung Institute (R.N.W.H.), Netherlands; Medizinische Klinik und Poliklinik (W.H.), Innere Medizin C-Universitat Munster, Germany; Physiologic Laboratory (H.J.J.), University of Utrecht, Netherlands; Department of Physiology (A.G.K.), University of Bern, Switzerland; Department of Cardiological Sciences (W.J.M.), St. George's Hospital Medical School, London, UK; Division of Medicine and Pharmacology (D.M.R.), Vanderbilt University Medical Center, Nashville, Tenn; Department of Biomedical Engineering (Y.R.), Case Western Reserve University, Cleveland, Ohio; UR 153 INSERM (K.S.), Pavillon Rambuteau, Groupe Hopitalier Pitie-Salpetriere, Paris, France; Dipartimento di Cardiologia (P.J.S.), Policlinico S. Matteo, IRCCS, Pavia, Italy; Ped Molecular Cardiology (J.A.T.), Baylor College of Medicine, Texas Children's Hospital, Houston, Tex; and Department of Clinical and Experimental Cardiology (A.M.W.), Academic Medical Centre, Amsterdam, Netherlands.
Correspondence to Silvia G. Priori, MD, PhD, Molecular Cardiology and Electrophysiology Laboratory, Fondazione "S. Maugeri" IRCCS, Via Ferrata, 8, 27100 Pavia, Italy. E-mail spriori{at}fsm.it
Abstract—Genetic approaches have succeeded in defining the molecular basis of an increasing array of heart diseases, such as hypertrophic cardiomyopathy and the long-QT syndromes, associated with serious arrhythmias. Importantly, the way in which this new knowledge can be applied to managing patients and to the development of syndrome-specific antiarrhythmic strategies is evolving rapidly because of these recent advances. In addition, the extent to which new knowledge represents a purely research tool versus the extent to which it can be applied clinically is also evolving. The present article represents a consensus report of a meeting of the European Working Group on Arrhythmias. The current state of the art of the molecular and genetic basis of inherited arrhythmias is first reviewed, followed by practical advice on the role of genetic testing in these and other syndromes and the way in which new findings have influenced current understanding of the molecular and biophysical basis of arrhythmogenesis.
Key Words: death, sudden • genetics • arrhythmia • molecular biology • electrophysiology
This article has been cited by other articles:
 |
|
 |
|
  Heart Rhythm UK Familial Sudden Death Syndromes St Clinical indications for genetic testing in familial sudden cardiac death syndromes: an HRUK position statement Heart, April 1, 2008; 94(4): 502 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Stephenson and C. I. Berul Electrophysiological Interventions for Inherited Arrhythmia Syndromes Circulation, August 28, 2007; 116(9): 1062 - 1080. [Full Text] [PDF]
|
|
|
|
 |
|
 C.-u. Choe, E. Schulze-Bahr, A. Neu, J. Xu, Z. I. Zhu, K. Sauter, R. Bahring, S. Priori, P. Guicheney, G. Monnig, et al. C-terminal HERG (LQT2) mutations disrupt IKr channel regulation through 14-3-3{epsilon} Hum. Mol. Genet., October 1, 2006; 15(19): 2888 - 2902. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Developed in Collaboration With the European Heart, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: A Report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J. Am. Coll. Cardiol., September 5, 2006; 48(5): e247 - e346. [Full Text] [PDF]
|
|
|
|
 |
|
 Writing Committee Members, D. P. Zipes, A. J. Camm, M. Borggrefe, A. E. Buxton, B. Chaitman, M. Fromer, G. Gregoratos, G. Klein, A. J. Moss, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society Europace, September 1, 2006; 8(9): 746 - 837. [Full Text] [PDF]
|
|
|
|
|
|
J.P. van Tintelen, M. M. Entius, Z. A. Bhuiyan, R. Jongbloed, A. C.P. Wiesfeld, A. A.M. Wilde, J. van der Smagt, L. G. Boven, M. M.A.M. Mannens, I. M. van Langen, et al. Plakophilin-2 Mutations Are the Major Determinant of Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Circulation, April 4, 2006; 113(13): 1650 - 1658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Priori and C. Napolitano Role of Genetic Analyses in Cardiology: Part I: Mendelian Diseases: Cardiac Channelopathies Circulation, February 28, 2006; 113(8): 1130 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Crotti, A. L. Lundquist, R. Insolia, M. Pedrazzini, C. Ferrandi, G. M. De Ferrari, A. Vicentini, P. Yang, D. M. Roden, A. L. George Jr, et al. KCNH2-K897T Is a Genetic Modifier of Latent Congenital Long-QT Syndrome Circulation, August 30, 2005; 112(9): 1251 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. D.C. Paulussen, A. Raes, R. J. Jongbloed, R. A.H.J. Gilissen, A. A.M. Wilde, D. J. Snyders, H. J.M. Smeets, and J. Aerssens HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency Cardiovasc Res, August 15, 2005; 67(3): 467 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Rossenbacker, K. Mubagwa, R. J. Jongbloed, J. Vereecke, K. Devriendt, M. Gewillig, E. Carmeliet, D. Collen, H. Heidbuchel, and P. Carmeliet Novel Mutation in the Per-Arnt-Sim Domain of KCNH2 Causes a Malignant Form of Long-QT Syndrome Circulation, March 1, 2005; 111(8): 961 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Weiss, G. Seemann, F. B. Sachse, and O. Dössel Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall Europace, January 1, 2005; 7(s2): S105 - S117. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Oginosawa, T. Nagatomo, H. Abe, N. Makita, J. C. Makielski, and Y. Nakashima Intrinsic mechanism of the enhanced rate-dependent QT shortening in the R1623Q mutant of the LQT3 syndrome Cardiovasc Res, January 1, 2005; 65(1): 138 - 147. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Zimetbaum and M. E. Josephson Is There a Role for Maintaining Sinus Rhythm in Patients with Atrial Fibrillation? Ann Intern Med, November 2, 2004; 141(9): 720 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Thompson and J. R. Balser Perioperative cardiac arrhythmias Br. J. Anaesth., July 1, 2004; 93(1): 86 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Schwartz Stillbirths, Sudden Infant Deaths, and Long-QT Syndrome: Puzzle or Mosaic, the Pieces of the Jigsaw Are Being Fitted Together Circulation, June 22, 2004; 109(24): 2930 - 2932. [Full Text] [PDF]
|
|
|
|
|
|
B. J. Maron, B. R. Chaitman, M. J. Ackerman, A. Bayes de Luna, D. Corrado, J. E. Crosson, B. J. Deal, D. J. Driscoll, N.A. M. Estes III, C. G. S. Araujo, et al. Recommendations for Physical Activity and Recreational Sports Participation for Young Patients With Genetic Cardiovascular Diseases Circulation, June 8, 2004; 109(22): 2807 - 2816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, Z. Luo, and P. F. White A Model for Evaluating Droperidol's Effect on the Median QTc Interval Anesth. Analg., May 1, 2004; 98(5): 1330 - 1335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gaita, C. Giustetto, F. Bianchi, R. Schimpf, M. Haissaguerre, L. Calo, R. Brugada, C. Antzelevitch, M. Borggrefe, and C. Wolpert Short QT syndrome: pharmacological treatment J. Am. Coll. Cardiol., April 21, 2004; 43(8): 1494 - 1499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. KLEBER and Y. RUDY Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias Physiol Rev, April 1, 2004; 84(2): 431 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Shafer, A. S. Habib, and T. J. Gan Safety of Patients Reason for FDA Black Box Warning on Droperidol * Response Anesth. Analg., February 1, 2004; 98(2): 551 - 552. [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Beery, M. Dyment, K. Shooner, T. K. Knilans, and D. W. Benson A Candidate Locus Approach Identifies a Long QT Syndrome Gene Mutation Biol Res Nurs, October 1, 2003; 5(2): 97 - 104. [Abstract] [PDF]
|
|
|
|
|
|
K. J Paavonen, H. Chapman, P. J Laitinen, H. Fodstad, K. Piippo, H. Swan, L. Toivonen, M. Viitasalo, K. Kontula, and M. Pasternack Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG) Cardiovasc Res, September 1, 2003; 59(3): 603 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Ma, C. Lin, S. Teng, Y. Chai, R. Bahring, V. Vardanyan, L. Li, O. Pongs, and R. Hui Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family Cardiovasc Res, September 1, 2003; 59(3): 612 - 619. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gaita, C. Giustetto, F. Bianchi, C. Wolpert, R. Schimpf, R. Riccardi, S. Grossi, E. Richiardi, and M. Borggrefe Short QT Syndrome: A Familial Cause of Sudden Death Circulation, August 26, 2003; 108(8): 965 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Lange, F. Er, N. Gassanov, and U. C. Hoppe Andersen mutations of KCNJ2 suppress the native inward rectifier current IK1 in a dominant-negative fashion Cardiovasc Res, August 1, 2003; 59(2): 321 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Bezzina, A. O. Verkerk, A. Busjahn, A. Jeron, J. Erdmann, T. T. Koopmann, Z. A. Bhuiyan, R. Wilders, M. M.A.M. Mannens, H. L. Tan, et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization Cardiovasc Res, July 1, 2003; 59(1): 27 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. I. Berul Electrophysiological phenotyping in genetically engineered mice Physiol Genomics, May 13, 2003; 13(3): 207 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Priori, P. J. Schwartz, C. Napolitano, R. Bloise, E. Ronchetti, M. Grillo, A. Vicentini, C. Spazzolini, J. Nastoli, G. Bottelli, et al. Risk Stratification in the Long-QT Syndrome N. Engl. J. Med., May 8, 2003; 348(19): 1866 - 1874. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yong, X. Tian, and Q. Wang LQT4 Gene: The "Missing" Ankyrin Mol. Interv., May 1, 2003; 3(3): 131 - 136. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I.M van Langen, E Birnie, N.J Leschot, G.J Bonsel, and A.A.M Wilde Genetic knowledge and counselling skills of Dutch cardiologists: sufficient for the genomics era? Eur. Heart J., March 2, 2003; 24(6): 560 - 566. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I M Van Langen, E Birnie, M Alders, R J Jongbloed, H Le Marec, and A A M Wilde The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome J. Med. Genet., February 1, 2003; 40(2): 141 - 145. [Full Text] [PDF]
|
|
|
|
|
|
X. H.T. Wehrens, M. A. Vos, P. A. Doevendans, and H. J.J. Wellens Novel Insights in the Congenital Long QT Syndrome Ann Intern Med, December 17, 2002; 137(12): 981 - 992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Paulussen, A. Raes, G. Matthijs, D. J. Snyders, N. Cohen, and J. Aerssens A Novel Mutation (T65P) in the PAS Domain of the Human Potassium Channel HERG Results in the Long QT Syndrome by Trafficking Deficiency J. Biol. Chem., December 6, 2002; 277(50): 48610 - 48616. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Chinushi, H. Kasai, M. Tagawa, T. Washizuka, Y. Hosaka, Y. Chinushi, and Y. Aizawa Triggers of ventricular tachyarrhythmias and therapeutic effects of nicorandil in canine models of LQT2 and LQT3 syndromes J. Am. Coll. Cardiol., August 7, 2002; 40(3): 555 - 562. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Priori, C. Napolitano, M. Memmi, B. Colombi, F. Drago, M. Gasparini, L. DeSimone, F. Coltorti, R. Bloise, R. Keegan, et al. Clinical and Molecular Characterization of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia Circulation, July 2, 2002; 106(1): 69 - 74. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Lynch Jr., J. J. Salata, A. A. Wallace, G. L. Stump, D. B. Gilberto, H. Jahansouz, N. J. Liverton, H. G. Selnick, and D. A. Claremon Antiarrhythmic Efficacy of Combined IKs and beta -Adrenergic Receptor Blockade J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 283 - 289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Shimizu, Y. Tanabe, T. Aiba, M. Inagaki, T. Kurita, K. Suyama, N. Nagaya, A. Taguchi, N. Aihara, K. Sunagawa, et al. Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the lqt1 and lqt2 forms of congenital long qt syndrome J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1984 - 1991. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Noda, H. Takaki, T. Kurita, K. Suyama, N. Nagaya, A. Taguchi, N. Aihara, S. Kamakura, K. Sunagawa, K. Nakamura, et al. Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome Eur. Heart J., June 2, 2002; 23(12): 975 - 983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nagatomo, C. T. January, B. Ye, H. Abe, Y. Nakashima, and J. C. Makielski Rate-dependent QT shortening mechanism for the LQT3 {Delta}KPQ mutant Cardiovasc Res, June 1, 2002; 54(3): 624 - 629. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. S. Rubenstein and R. I. Lopez-Soler The Genetics of Sudden Death JAMA, October 3, 2001; 286(13): 1636 - 1636. [Full Text] [PDF]
|
|
|
|
|
|
J. Kang, X.-L. Chen, L. Wang, and D. Rampe Interactions of the Antimalarial Drug Mefloquine with the Human Cardiac Potassium Channels KvLQT1/minK and HERG J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 290 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. VALLON, F. GRAHAMMER, K. RICHTER, M. BLEICH, F. LANG, J. BARHANIN, H. VOLKL, and R. WARTH Role of KCNE1-Dependent K+ Fluxes in Mouse Proximal Tubule J. Am. Soc. Nephrol., October 1, 2001; 12(10): 2003 - 2011. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.G. Priori, E. Aliot, C. Blomstrom-Lundqvist, L. Bossaert, G. Breithardt, P. Brugada, A.J. Camm, R. Cappato, S.M. Cobbe, C. Di Mario, et al. Task Force on Sudden Cardiac Death of the European Society of Cardiology Eur. Heart J., August 2, 2001; 22(16): 1374 - 1450. [PDF]
|
|
|
|
 |
|
 I. Arrighi, M. Bloch-Faure, F. Grahammer, M. Bleich, R. Warth, R. Mengual, M.-D. Drici, J. Barhanin, and P. Meneton Altered potassium balance and aldosterone secretion in a mouse model of human congenital long QT syndrome PNAS, June 28, 2001; (2001) 141233398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. Spooner, C. Albert, E. J. Benjamin, R. Boineau, R. C. Elston, A. L. George Jr, X. Jouven, L. H. Kuller, J. W. MacCluer, E. Marban, et al. Sudden Cardiac Death, Genes, and Arrhythmogenesis : Consideration of New Population and Mechanistic Approaches From a National Heart, Lung, and Blood Institute Workshop, Part I Circulation, May 15, 2001; 103(19): 2361 - 2364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J Myerburg and P. M Spooner Opportunities for sudden death prevention: Directions for new clinical and basic research Cardiovasc Res, May 1, 2001; 50(2): 177 - 185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G Priori, C. Napolitano, and M. Grillo Concealed arrhythmogenic syndromes: the hidden substrate of idiopathic ventricular fibrillation? Cardiovasc Res, May 1, 2001; 50(2): 218 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.M van Opstal, S.C Verduyn, H.D.M Leunissen, S.H.M de Groot, H.J.J Wellens, and M.A Vos Electrophysiological parameters indicative of sudden cardiac death in the dog with chronic complete AV-block Cardiovasc Res, May 1, 2001; 50(2): 354 - 361. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Corrado, C. Basso, and G. Thiene Sudden cardiac death in young people with apparently normal heart Cardiovasc Res, May 1, 2001; 50(2): 399 - 408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Towbin, Z. Wang, and H. Li Genotype and Severity of Long QT Syndrome Drug Metab. Dispos., April 1, 2001; 29(4): 574 - 579. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Tanabe, M. Inagaki, T. Kurita, N. Nagaya, A. Taguchi, K. Suyama, N. Aihara, S. Kamakura, K. Sunagawa, K. Nakamura, et al. Sympathetic stimulation produces a greater increase in both transmural and spatial dispersion of repolarization in LQT1 than LQT2 forms of congenital long QT syndrome J. Am. Coll. Cardiol., March 1, 2001; 37(3): 911 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Schwartz, S. G. Priori, C. Spazzolini, A. J. Moss, G. M. Vincent, C. Napolitano, I. Denjoy, P. Guicheney, G. Breithardt, M. T. Keating, et al. Genotype-Phenotype Correlation in the Long-QT Syndrome : Gene-Specific Triggers for Life-Threatening Arrhythmias Circulation, January 2, 2001; 103(1): 89 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Priori, C. Napolitano, M. Gasparini, C. Pappone, P. Della Bella, M. Brignole, U. Giordano, T. Giovannini, C. Menozzi, R. Bloise, et al. Clinical and Genetic Heterogeneity of Right Bundle Branch Block and ST-Segment Elevation Syndrome : A Prospective Evaluation of 52 Families Circulation, November 14, 2000; 102(20): 2509 - 2515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. A. Kuryshev, A. M. Brown, L. Wang, C. R. Benedict, and D. Rampe Interactions of the 5-Hydroxytryptamine 3 Antagonist Class of Antiemetic Drugs with Human Cardiac Ion Channels J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 614 - 620. [Abstract] [Full Text]
|
|
|
|
|
|
J. E. Burnes, B. Taccardi, and Y. Rudy A Noninvasive Imaging Modality for Cardiac Arrhythmias Circulation, October 24, 2000; 102(17): 2152 - 2158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|