Drug-induced arrhythmia: pharmacogenomic prescribing?

Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from www.qtdrugs.org up to January 2012, case reports and articles from www.pubmed.com up to January 2012, and the British National Formulary edition at www.bnf.org.

[1]  C. January,et al.  The International Serious Adverse Events Consortium (iSAEC) phenotype standardization project for drug-induced torsades de pointes. , 2013, European heart journal.

[2]  M. Rieder,et al.  Novel Rare Variants in Congenital Cardiac Arrhythmia Genes are Frequent in Drug-induced Torsades de Pointes , 2012, The Pharmacogenomics Journal.

[3]  Dan M Roden,et al.  Common variation in the NOS1AP gene is associated with drug-induced QT prolongation and ventricular arrhythmia. , 2012, Journal of the American College of Cardiology.

[4]  G. Ginsburg,et al.  Clinical application of cardiovascular pharmacogenetics. , 2012, Journal of the American College of Cardiology.

[5]  E. Clayton,et al.  Operational Implementation of Prospective Genotyping for Personalized Medicine: The Design of the Vanderbilt PREDICT Project , 2012, Clinical pharmacology and therapeutics.

[6]  Ruben Coronel,et al.  Repolarization gradients in the intact heart: transmural or apico-basal? , 2012, Progress in biophysics and molecular biology.

[7]  I. Cohen,et al.  Suppression of Phosphoinositide 3-Kinase Signaling and Alteration of Multiple Ion Currents in Drug-Induced Long QT Syndrome , 2012, Science Translational Medicine.

[8]  Marylyn D. Ritchie,et al.  A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes , 2012, Circulation. Cardiovascular genetics.

[9]  D. Roden,et al.  Refining repolarization reserve. , 2011, Heart rhythm.

[10]  D. Roden,et al.  The Phenotype Standardization Project: Improving Pharmacogenetic Studies of Serious Adverse Drug Reactions , 2011, Clinical pharmacology and therapeutics.

[11]  Michael R. Johnson,et al.  HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. , 2011, The New England journal of medicine.

[12]  Chen-Yang Shen,et al.  Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. , 2011, The New England journal of medicine.

[13]  R. Bellazzi,et al.  Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome. , 2010, Journal of the American College of Cardiology.

[14]  P. Elliott,et al.  Principles and Practice of Clinical Cardiovascular Genetics , 2010 .

[15]  P. Syrris.  Principles and Practice of Clinical Cardiovascular Genetics , 2010 .

[16]  Yusuke Nakamura,et al.  Abstract 1971: Genome-wide Association Study Identifies Novel Genomic Regions Associated With Drug-induced Long Qt Syndrome , 2009 .

[17]  P. Schwartz,et al.  NOS1AP Is a Genetic Modifier of the Long-QT Syndrome , 2009, Circulation.

[18]  M. Horie,et al.  Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome , 2009, Circulation. Arrhythmia and electrophysiology.

[19]  M. Daly,et al.  HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin , 2009, Nature Genetics.

[20]  Thomas Lumley,et al.  Common variants at ten loci influence QT interval duration in the QTGEN Study , 2009, Nature Genetics.

[21]  Christian Gieger,et al.  Common variants at ten loci modulate the QT interval duration in the QTSCD Study , 2009, Nature Genetics.

[22]  T. Rea,et al.  Genetic Variations in Nitric Oxide Synthase 1 Adaptor Protein Are Associated With Sudden Cardiac Death in US White Community-Based Populations , 2009, Circulation.

[23]  D. Roden.  Repolarization reserve: a moving target. , 2008, Circulation.

[24]  P. McKeigue,et al.  Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. , 2008, British journal of clinical pharmacology.

[25]  E. Marbán,et al.  CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart , 2008, Proceedings of the National Academy of Sciences.

[26]  S. Mallal,et al.  HLA-B*5701 screening for hypersensitivity to abacavir. , 2008, The New England journal of medicine.

[27]  Johnf . Thompson,et al.  Association of torsades de pointes with novel and known single nucleotide polymorphisms in long QT syndrome genes. , 2006, American heart journal.

[28]  Charles Antzelevitch,et al.  Cellular Basis for the Repolarization Waves of the ECG , 2006, Annals of the New York Academy of Sciences.

[29]  Christian Gieger,et al.  A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization , 2006, Nature Genetics.

[30]  Matthew W State,et al.  A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y. , 2006, The Journal of clinical investigation.

[31]  D. Roden.  Long QT syndrome: reduced repolarization reserve and the genetic link , 2006, Journal of internal medicine.

[32]  B. Stricker,et al.  Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. , 2005, European heart journal.

[33]  P. C. Viswanathan,et al.  Genetics of acquired long QT syndrome. , 2005, The Journal of clinical investigation.

[34]  D. Roden,et al.  Genetic susceptibility to acquired long QT syndrome: pharmacologic challenge in first-degree relatives. , 2005, Heart rhythm.

[35]  O. D. de Leon-Casasola,et al.  Oral erythromycin and the risk of sudden death from cardiac causes , 2004, The New England journal of medicine.

[36]  Johan van der Lei,et al.  Antipsychotics and the risk of sudden cardiac death. , 2004, Archives of internal medicine.

[37]  G. Breithardt,et al.  Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients , 2004, Journal of Molecular Medicine.

[38]  F. Cappuccio,et al.  Variant of SCN5A Sodium Channel Implicated in Risk of Cardiac Arrhythmia , 2002, Science.

[39]  R. Berecz,et al.  QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients , 2002, Journal of psychopharmacology.

[40]  S. Ayis,et al.  Thioridazine and sudden unexplained death in psychiatric in-patients. , 2002, The British journal of psychiatry : the journal of mental science.

[41]  P. C. Viswanathan,et al.  Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes , 2002, Circulation.

[42]  B. Darpö,et al.  Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes , 2001 .

[43]  S. Doddamani,et al.  Risk of torsades de pointes with non-cardiac drugs , 2001, BMJ : British Medical Journal.

[44]  D M Roden,et al.  A common polymorphism associated with antibiotic-induced cardiac arrhythmia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[45]  A. Camm,et al.  The potential for QT prolongation and pro-arrhythmia by non-anti-arrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology. , 2000, Cardiovascular research.

[46]  C Antzelevitch,et al.  The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. , 2000, European heart journal.

[47]  S. Priori,et al.  Evidence for a Cardiac Ion Channel Mutation Underlying Drug‐Induced QT Prolongation and Life‐Threatening Arrhythmias , 2000, Journal of cardiovascular electrophysiology.

[48]  F. Ponti,et al.  QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience , 2000, European Journal of Clinical Pharmacology.

[49]  S. Ayis,et al.  QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients , 2000, The Lancet.

[50]  A. Camm,et al.  Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. , 1999, The New England journal of medicine.

[51]  A J Camm,et al.  Arrhythmogenic mechanisms of non‐sedating antihistamines , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[52]  S. Priori,et al.  Low penetrance in the long-QT syndrome: clinical impact. , 1999, Circulation.

[53]  L. K. Smith,et al.  Torsade De Pointes Resulting from the Addition of Droperidol to an Existing Cytochrome P450 Drug Interaction , 1998, The Annals of pharmacotherapy.

[54]  D. Roden.  Taking the “Idio” out of “Idiosyncratic”: Predicting Torsades de Pointes , 1998, Pacing and clinical electrophysiology : PACE.

[55]  P. Coumel,et al.  KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. , 1997, Circulation.

[56]  H. Wellens,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. , 1997, Journal of the American College of Cardiology.

[57]  R. Platt,et al.  Terfenadine-associated ventricular arrhythmias and QTc interval prolongation. A retrospective cohort comparison with other antihistamines among members of a health maintenance organization. , 1995, Annals of epidemiology.

[58]  C Antzelevitch,et al.  Clinical relevance of cardiac arrhythmias generated by afterdepolarizations. Role of M cells in the generation of U waves, triggered activity and torsade de pointes. , 1994, Journal of the American College of Cardiology.

[59]  P. Broadhurst,et al.  Cardiac arrest in a young woman with the long QT syndrome and concomitant astemizole ingestion. , 1993, British heart journal.

[60]  Y Chen,et al.  Mechanism of the cardiotoxic actions of terfenadine. , 1993, JAMA.

[61]  D. Wortham,et al.  Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. , 1993, JAMA.

[62]  P. Lévy,et al.  Torsades de Pointes after treatment with terfenadine and ketoconazole. , 1992, European heart journal.

[63]  C. L. Ferguson,et al.  Torsades de pointes occurring in association with terfenadine use. , 1990, JAMA.

[64]  L. Soyka,et al.  Clinical safety profile of sotalol in patients with arrhythmias. , 1990, The American journal of cardiology.

[65]  V. Harindra,et al.  Cardiotoxic effect with convulsions in terfenadine overdose. , 1989, BMJ.

[66]  E. Aliot,et al.  The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. , 1988, Progress in cardiovascular diseases.

[67]  P. Brugada,et al.  Arrhythmogenesis of antiarrhythmic drugs. , 1988, The American journal of cardiology.

[68]  E. Varnauskas,et al.  Clinical course, serum concentrations and elimination rate in a case of massive sotalol intoxication. , 1987, European heart journal.

[69]  B F Hoffman,et al.  Action Potential Prolongation and Induction of Abnormal Automaticity by Low Quinidine Concentrations in Canine Purkinje Fibers Relationship to Potassium and Cycle Length , 1985, Circulation research.