title: Sudden Arrhythmic Death During Exercise: A Post-Mortem Genetic Analysis.
abstract: BACKGROUND
  Sudden cardiac death is a natural and unexpected death that occurs within 1 h of the first symptom. Most sudden cardiac deaths occur during exercise, mostly as a result of myocardial infarction. After autopsy, some cases, especially in the young, are diagnosed as cardiomyopathies or remain without a conclusive cause of death. In both situations, genetic alterations may explain the arrhythmia.
  
  
  OBJECTIVE
  Our aim was to identify a genetic predisposition to sudden cardiac death in a cohort of post-mortem cases of individuals who died during exercise, with a structurally normal heart, and were classified as arrhythmogenic death.
  
  
  METHODS
  We analyzed a cohort of 52 post-mortem samples from individuals <50 years old who had a negative autopsy. Next-generation sequencing technology was used to screen genes associated with sudden cardiac death.
  
  
  RESULTS
  Our cohort showed a male prevalence (12:1). Half of the deaths occurred in individuals 41-50 years of age. Running was the most common exercise activity during the fatal event, accounting for 46.15% of cases. Genetic analysis identified 83 rare variants in 37 samples (71.15% of all samples). Of all rare variants, 36.14% were classified as deleterious, being present in 53.84% of all cases.
  
  
  CONCLUSIONS
  A comprehensive analysis of sudden cardiac death-related genes in individuals who died suddenly while exercising enabled the identification of potentially causative variants. However, many genetic variants remain of indeterminate significance, thus further work is needed before clinical translation. Nonetheless, comprehensive genetic analysis of individuals who died during exercise enables the detection of potentially causative variants and helps to identify at-risk relatives.
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.|Medical Science Department, School of Medicine, University of Girona, Girona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
authors.forename: Oscar
authors.identifier: http://orcid.org/0000-0001-5298-5276
authors.initials: O
authors.lastname: Campuzano
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.
authors.forename: Olallo
authors.initials: O
authors.lastname: Sanchez-Molero
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Fernandez
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Mademont-Soler
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Coll
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Perez-Serra
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Mates
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.
authors.forename: Bernat
authors.initials: B
authors.lastname: Del Olmo
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Pico
authors.affiliation: Medical Science Department, School of Medicine, University of Girona, Girona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Nogue-Navarro
authors.affiliation: Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Georgia
authors.initials: G
authors.lastname: Sarquella-Brugada
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Cesar
authors.affiliation: Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Carro
authors.affiliation: Histopathology Unit, Instituto Nacional Toxicología y Ciencias Forenses (INTCF), Barcelona, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Borondo
authors.affiliation: Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Brugada
authors.affiliation: Forensic Pathology Service, Institut de Medicina Legal i Ciències Forenses de Catalunya (IMLCFC), Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Castellà
authors.affiliation: Forensic Pathology Service, Institut de Medicina Legal i Ciències Forenses de Catalunya (IMLCFC), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Medallo
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica Girona (IDIBGI), University of Girona, C/Dr Castany s/n, Parc Hospitalari Martí i Julià (M-2), Salt, 17190, Girona, Spain. ramon@brugada.org.|Medical Science Department, School of Medicine, University of Girona, Girona, Spain. ramon@brugada.org.|Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain. ramon@brugada.org.|Cardiology Service, Hospital Josep Trueta, Girona, Spain. ramon@brugada.org.
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: D000328:Adult; D001145:Arrhythmias, Cardiac; D001344:Autopsy; D009202:Cardiomyopathies / Q000401:mortality / Q000473:pathology*; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000473:pathology*; D005260:Female; D053803:Forensic Genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D014644:Genetic Variation; D006331:Heart Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction
keywords: Brugada Syndrome; Catecholaminergic Polymorphic Ventricular Tachycardia; Human Gene Mutation Database; Rare Variant; Sudden Cardiac Death