title: Detailed characterization of familial idiopathic ventricular fibrillation linked to the DPP6 locus.
abstract: BACKGROUND
  Familial idiopathic ventricular fibrillation (IVF) is a severe disease entity and is notoriously difficult to manage because there are no clinical risk indicators for premature cardiac arrest. Previously, we identified a link between familial IVF and a risk haplotype on chromosome 7q36 (involving the arrhythmia gene DPP6).
  
  
  OBJECTIVE
  The purpose of this study was to expand our knowledge of familial IVF and to discuss its (extended) clinical characteristics.
  
  
  METHODS
  We studied 601 family members and probands: 286 DPP6 risk-haplotype positive (haplotype-positive) and 315 DPP6 risk-haplotype negative (haplotype-negative) individuals. Clinical parameters, a combination of all-cause mortality and (aborted) cardiac arrest and differences between haplotype-positives and haplotype-negatives, were evaluated.
  
  
  RESULTS
  There were no differences in electrocardiographic indices between haplotype-positives and haplotype-negatives, or between haplotype-positives with or without events. Cardiac magnetic resonance documented slightly larger ventricular volumes in haplotype-positives compared to controls (P <.05), but these were not clinically useful. Mortality and/or cardiac arrest occurred in 85 haplotype-positives (30%) and 18 haplotype-negatives (6%). Twenty-four haplotype-positives (8% male) were resuscitated from ventricular fibrillation (VF). Documented VF was always elicited by monomorphic short-coupled extrasystoles from the right ventricular apex/lower free wall. Median survival in risk-haplotype haplotype-positives was 70 vs. 93 years for haplotype-negatives (P < .01), with a worse phenotype in males (median survival 63 vs. 83 years in females, P < .01). Implantable cardioverter-defibrillators were implanted in 99 patients (76 [77%] for primary prevention). Two arrhythmic events occurred in the primary prevention group during follow-up (5 ± 3 years).
  
  
  CONCLUSIONS
  Despite our extensive analysis, the complexity in identifying asymptomatic IVF family members at risk for future arrhythmias based on clinical parameters is once more demonstrated.
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Ten Sande
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: p.g.postema@amc.uva.nl.
authors.forename: Pieter G
authors.initials: PG
authors.lastname: Postema
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: S Matthijs
authors.initials: SM
authors.lastname: Boekholdt
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jeroen F
authors.initials: JF
authors.lastname: van der Heijden
authors.affiliation: Department of Cardiology, Erasmus Medical Center, Rotterdam, Rotterdam, The Netherlands.
authors.forename: Natasja M S
authors.initials: NM
authors.lastname: de Groot
authors.affiliation: Department of Cardiology, Maastricht University Medical Center, The Netherlands, Maastricht, The Netherlands.
authors.forename: Paul G A
authors.initials: PG
authors.lastname: Volders
authors.affiliation: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Katja
authors.initials: K
authors.lastname: Zeppenfeld
authors.affiliation: Department of Cardiology, St. Antonius Hospital Nieuwegein, Nieuwegein, The Netherlands.
authors.forename: Lucas V A
authors.initials: LV
authors.lastname: Boersma
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Eline A
authors.initials: EA
authors.lastname: Nannenberg
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Imke
authors.initials: I
authors.lastname: Christiaans
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Kingdom of Saudi Arabia. Electronic address: a.a.wilde@amc.uva.nl.
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
mesh_terms: D058406:Cardiac Resynchronization Therapy; D004247:DNA / Q000235:genetics*; D016757:Death, Sudden, Cardiac / Q000453:epidemiology* / Q000517:prevention & control; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics* / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D006239:Haplotypes; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006801:Humans; D015994:Incidence; D019028:Magnetic Resonance Imaging, Cine / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009426:Netherlands / Q000453:epidemiology; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D011322:Primary Prevention / Q000379:methods; D012307:Risk Factors; D015996:Survival Rate / Q000639:trends; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology
chemical_list: D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D004247:DNA; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
keywords: DPP6; Idiopathic ventricular fibrillation; Sudden cardiac death