title: Long-Term Arrhythmic and Nonarrhythmic Outcomes of Lamin A/C Mutation Carriers.
abstract: Mutations in LMNA are variably expressed and may cause cardiomyopathy, atrioventricular block (AVB), or atrial arrhythmias (AAs) and ventricular arrhythmias (VA). Detailed natural history studies of LMNA-associated arrhythmic and nonarrhythmic outcomes are limited, and the prognostic significance of the index cardiac phenotype remains uncertain.
  
  
  
  This study sought to describe the arrhythmic and nonarrhythmic outcomes of LMNA mutation carriers and to assess the prognostic significance of the index cardiac phenotype.
  
  
  
  The incidence of AVB, AA, sustained VA, left ventricular systolic dysfunction (LVD) (= left ventricular ejection fraction ≤50%), and end-stage heart failure (HF) was retrospectively determined in 122 consecutive LMNA mutation carriers followed at 5 referral centers for a median of 7 years from first clinical contact. Predictors of VA and end-stage HF or death were determined.
  
  
  
  The prevalence of clinical manifestations increased broadly from index evaluation to median follow-up: AVB, 46% to 57%; AA, 39% to 63%; VA, 16% to 34%; and LVD, 44% to 57%. Implantable cardioverter-defibrillators were placed in 59% of patients for new LVD or AVB. End-stage HF developed in 19% of patients, and 13% died. In patients without LVD at presentation, 24% developed new LVD, and 7% developed end-stage HF. Male sex (p = 0.01), nonmissense mutations (p = 0.03), and LVD at index evaluation (p = 0.004) were associated with development of VA, whereas LVD was associated with end-stage HF or death (p < 0.001). Mode of presentation (with isolated or combination of clinical features) did not predict sustained VA or end-stage HF or death.
  
  
  
  LMNA-related heart disease was associated with a high incidence of phenotypic progression and adverse arrhythmic and nonarrhythmic events over long-term follow-up. The index cardiac phenotype did not predict adverse events. Genetic diagnosis and subsequent follow-up, including anticipatory planning for therapies to prevent sudden death and manage HF, is warranted.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Cardiology, Inselspital, Bern University Hospital, Bern, Switzerland.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Baldinger
authors.affiliation: Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux De Paris (AP-HP), Department of Cardiology, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Gandjbakhch
authors.affiliation: Toulouse University Hospital, Rangueil, Toulouse, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Maury
authors.affiliation: Hôpital Cardiologique du Haut-Lévêque (CHU), Bordeaux-Pessac, France; L'Institut de Rythmologie et Modélisation Cardiaque (LIRYC), Bordeaux, France; Institut Hospitalo-Universitaire (IHU), Bordeaux, France; Centre Hospitalier Universitaire de Nancy, Nancy, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Sellal
authors.affiliation: Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Alexander F A
authors.initials: AF
authors.lastname: Androulakis
authors.affiliation: Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux De Paris (AP-HP), Department of Cardiology, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Waintraub
authors.affiliation: Hôpital Pitié-Salpêtrière, Assistance Publique Hôpitaux De Paris (AP-HP), Department of Cardiology, Paris, France; Centre de Référence Maladies Cardiaques Héréditaires, Institute for Cardiometabolism and Nutrition (ICAN), Paris, France; Université de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne-Billancourt, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
authors.affiliation: Toulouse University Hospital, Rangueil, Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rollin
authors.affiliation: Cardiomyogenetics, Department of Biochemistry and INSERM U582, University Hospital Pitié-Salpêtrière, AP-HP, Paris, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Richard
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: William G
authors.initials: WG
authors.lastname: Stevenson
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Ciorsti J
authors.initials: CJ
authors.lastname: Macintyre
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Carolyn Y
authors.initials: CY
authors.lastname: Ho
authors.affiliation: Department of Genetic Medicine, The Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Tina
authors.initials: T
authors.lastname: Thompson
authors.affiliation: Department of Cardiology, Division of Medicine, The Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jitendra K
authors.initials: JK
authors.lastname: Vohra
authors.affiliation: Department of Cardiology, Division of Medicine, The Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kalman
authors.affiliation: Department of Cardiology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: Katja
authors.initials: K
authors.lastname: Zeppenfeld
authors.affiliation: Hôpital Cardiologique du Haut-Lévêque (CHU), Bordeaux-Pessac, France; L'Institut de Rythmologie et Modélisation Cardiaque (LIRYC), Bordeaux, France; Institut Hospitalo-Universitaire (IHU), Bordeaux, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Sacher
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Usha B
authors.initials: UB
authors.lastname: Tedrow
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address: nlakdawala@partners.org.
authors.forename: Neal K
authors.initials: NK
authors.lastname: Lakdawala
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D005602:France / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D016277:Ventricular Function, Left / Q000502:physiology*; D014739:Victoria / Q000453:epidemiology; D055815:Young Adult
chemical_list: D034904:Lamin Type A
keywords: atrial fibrillation; cardiomyopathy; complete atrioventricular block; genetics; heart failure; ventricular tachycardia