Genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying drug-induced arrhythmia and sudden unexplained deaths |
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| Affiliation: | 1. Cardiology Department, APHM, La Timone Hospital, Marseille, France;2. Département de génétique médicale, APHM, Hôpital d''enfants de la Timone, Marseille, France;3. Aix Marseille University, INSERM, Marseille Medical Genetics, Faculté de Médecine, France;4. APHP, Functional Unit of Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Hôpitaux Universitaires de la Pitié-Salpêtrière-Charles Foix, Paris, France;5. Sorbonne Universités, UPMC Univ. Paris 06, INSERM, UMR_S 1166 and ICAN Institute for Cardiometabolism and Nutrition, Paris, France;6. Service de Cardiologie, Centre Hospitalier Régional Universitaire Pontchaillou, Rennes, France;7. Service de Cardiologie, CHU Dijon Bourgogne - Hôpital François Mitterrand, 2 bd Maréchal de Lattre de Tassigny, Dijon, France;8. Service de Cardiologie, CHU de Nancy, Hôpitaux de Brabois, rue du Morvan, Vandoeuvre-lès-Nancy, France;9. Service de Cardiologie, CHU de Poitiers, Poitiers, France;10. APHP, Service Cardiologie, CHU Paris Nord- Val de Seine - Hôpital Xavier Bichat-Claude Bernard, Paris, France;11. APHP, Service de Cardiologie, CHU Ambroise Paré, Boulogne Billancourt, France;12. Centre de génétique et FHU TRANSLAD, Hôpital d''Enfants et Université de Bourgogne, Dijon, France;13. APHP, Centre de référence pour les maladies cardiaques héréditaires, Hôpital Pitié-Salpêtrière, Paris, France;14. Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France;1. Department of Surgery and Cancer, Imperial College London, UK;2. Clinical Genetics and Genomics Laboratory, Royal Brompton Hospital, London, UK;3. Royal Brompton and Harefield Foundation Trust, UK;4. Guy Scadding Building, Marfan Trust, London, UK;5. Sonalee Laboratory, Imperial College, London, UK;6. Aortovascular Unit, Barts Heart Centre, UK |
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| Abstract: | Drug-induced arrhythmia is an adverse drug reaction that can be potentially fatal since it is mostly related to drug-induced QT prolongation, a known risk factor for Torsade de Pointes and sudden cardiac death (SCD). Several risk factors have been described in association to these drug-induced events, such as preexistent cardiac disease and genetic variation. Our objective was to study the genetic susceptibility in pharmacodynamic and pharmacokinetic pathways underlying suspected drug-induced arrhythmias and sudden unexplained deaths in 32 patients. The genetic component in the pharmacodynamic pathway was studied by analysing 96 genes associated with higher risk of SCD through massive parallel sequencing. Pharmacokinetic-mediated genetic susceptibility was investigated by studying the genes encoding cytochrome P450 enzymes using medium-throughput genotyping. Pharmacodynamic analysis showed three probably pathogenic variants and 45 variants of uncertain significance in 28 patients, several of them previously described in relation to mild or late onset cardiomyopathies. These results suggest that genetic variants in cardiomyopathy genes, in addition to those related with channelopathies, could be relevant to drug-induced cardiotoxicity and contribute to the arrhythmogenic phenotype. Pharmacokinetic analysis showed three patients that could have an altered metabolism of the drugs they received involving CYP2C19 and/or CYP2D6, probably contributing to the arrhythmogenic phenotype. The study of genetic variants in both pharmacodynamic and pharmacokinetic pathways may be a useful strategy to understand the multifactorial mechanism of drug-induced events in both clinical practice and forensic field. However, it is necessary to comprehensively study and evaluate the contribution of the genetic susceptibility to drug-induced cardiotoxicity. |
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| Keywords: | SUD Drug-induced arrhythmia Genetic susceptibility Pharmacodynamics Pharmacokinetics |
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