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CLINICAL RESEARCH: CARDIOMYOPATHY

Long-Term Outcome and Risk Stratification in Dilated Cardiolaminopathies

Michele Pasotti, MD^_*, Catherine Klersy, MD, Andrea Pilotto, BS^_*, Nicola Marziliano, PhD^_*, Claudio Rapezzi, MD, Alessandra Serio, MD^_*, Savina Mannarino, MD^_*, Fabiana Gambarin, MD^_*, Valentina Favalli, BME^_*, Maurizia Grasso, PhD^_*, Manuela Agozzino, MD^_*, Carlo Campana, MD, Antonello Gavazzi, MD^||, Oreste Febo, MD^¶, Massimiliano Marini, MD^#, Maurizio Landolina, MD, Andrea Mortara, MD^_**, Giovanni Piccolo, MD, Mario Viganò, MD, Luigi Tavazzi, MD and Eloisa Arbustini, MD^_*,_*

^_* Centre for Inherited Cardiovascular Diseases, Molecular Diagnostic Laboratory, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Department of Biometry and Clinical Epidemiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Department of Cardiac Surgery, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
^|| Cardiology Department, Ospedali Riuniti di Bergamo, Italy
^¶ Cardiology Department, IRCCS Fondazione Salvatore Maugeri, Montescano, Italy
^# Cardiology Department, Ospedale Santa Chiara di Trento, Trento, Italy
^_** Cardiology Department, Policlinico di Monza, Monza, Italy
Institute of Cardiology, University of Bologna and S. Orsola-Malpighi Hospital, Bologna, Italy
Neurology Department, IRCCS Fondazione Mondino, Pavia, Italy

Manuscript received February 6, 2008; revised manuscript received May 23, 2008, accepted June 23, 2008.

^_* Reprint requests and correspondence: Dr. Eloisa Arbustini, Centre for Inherited Cardiovascular Diseases, IRCCS Fondazione Policlinico San Matteo, Viale Forlanini 16, Pavia 27100, Italy (Email: e.arbustini{at}smatteo.pv.it).

Objectives: The aim of this study was to analyze the long-term follow-up of dilated cardiolaminopathies.

Background: Lamin A/C (LMNA) gene mutations cause a variety of phenotypes. In the cardiology setting, patients diagnosed with idiopathic dilated cardiomyopathy (DCM) plus atrioventricular block (AVB) constitute the majority of reported cases.

Methods: Longitudinal retrospective observational studies were conducted with 27 consecutive families in which LMNA gene defects were identified in the probands, all sharing the DCM phenotype.

Results: Of the 164 family members, 94 had LMNA gene mutations. Sixty of 94 (64%) were phenotypically affected whereas 34 were only genotypically affected, including 5 with pre-clinical signs. Of the 60 patients, 40 had DCM with AVB, 12 had DCM with ventricular tachycardia/fibrillation, 6 had DCM with AVB and Emery-Dreifuss muscular dystrophy type 2 (EDMD2), and 2 had AVB plus EDMD2. During a median of 57 months (interquartile range 36 to 107 months), we observed 49 events in 43 DCM patients (6 had a later event, excluded from the analysis). The events were related to heart failure (15 heart transplants, 1 death from end-stage heart failure) and ventricular arrhythmias (15 sudden cardiac deaths and 12 appropriate implantable cardioverter-defibrillator interventions). By multivariable analysis, New York Heart Association functional class III to IV and highly dynamic competitive sports for 10 years were independent predictors of total events. By a bivariable Cox model, splice site mutations and competitive sport predicted sudden cardiac death.

Conclusions: Dilated cardiomyopathies caused by LMNA gene defects are highly penetrant, adult onset, malignant diseases characterized by a high rate of heart failure and life-threatening arrhythmias, predicted by New York Heart Association functional class, competitive sport activity, and type of mutation.

Key Words: LMNA gene mutation • idiopathic dilated cardiomyopathy • atrioventricular block

Abbreviations and Acronyms   AVB = atrioventricular block   DCM = dilated cardiomyopathy   EDMD2 = Emery-Dreifuss muscular dystrophy type 2   HF = heart failure   ICD = implantable cardioverter-defibrillator   ins-del/stop = insertions/deletions and stop mutations   LMNA = lamin A/C   LV = left ventricular   SCD = sudden cardiac death

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