Primary Prevention of Sudden Death in Patients with Lamin A/C Gene Mutations
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《新英格兰医药杂志》
To the Editor: Lamin A/C gene mutations are associated with various disorders,1,2 including cardiac abnormalities characterized by atrial fibrillation, conduction-system disturbances, sudden death, and heart failure.3,4 In retrospective analyses, we have previously investigated the high incidence of sudden death among carriers of such mutations.4,5 Although there is consensus regarding the efficacy of implantable cardioverter–defibrillators (ICDs) in the secondary prevention of sudden death in persons with cardiovascular disease and also in primary prevention in patients with a reduced ejection fraction (<35 percent), it is not yet known whether ICD therapy is efficacious as primary prevention in carriers of a lamin A/C mutation.
We prospectively studied patients with genetically proven lamin A/C gene mutations; between March 1999 and January 2004, all patients referred to a participating center for permanent cardiac pacing were systematically offered the implantation of an ICD. A history of ventricular tachyarrhythmia, spontaneous or inducible by programmed ventricular stimulation, was not a selection criterion, and patients were enrolled solely on the basis of the presence of lamin A/C mutations associated with cardiac conduction defects. Indications for pacemaker implantation were progressive conduction block and sinus block. All the ICDs used in the study had storage capabilities, and events were scored as inappropriate or appropriate by two investigators. The study protocol was reviewed and approved by the ethics committee of each participating center, and all patients provided written informed consent.
The study included 19 patients whose clinical characteristics are listed in Table 1. During a mean follow-up period of 33.9±21.0 months, eight of the patients (42 percent) received appropriate ICD therapy. Six patients received ICD shocks for ventricular fibrillation (cycle length, <240 msec), two patients received ICD shocks for ventricular tachycardia (cycle length, >240 msec), and one patient received antitachycardia pacing for ventricular tachycardia. One patient received an inappropriate shock. The mean (±SD) left ventricular ejection fraction (LVEF) in the overall study population was 58±12 percent. No factor — including LVEF, spontaneous or inducible ventricular tachycardia or ventricular fibrillation, or drug therapy — was found to be related to the occurrence of ventricular arrhythmias. The LVEF was not depressed in patients receiving appropriate ICD therapy, indicating a high risk of sudden death before the development of cardiac failure.
Table 1. Baseline Clinical Characteristics of the 19 Patients.
In conclusion, ICD implantation in patients with a lamin A/C mutation who are in need of a pacemaker is effective in treating possibly lethal tachyarrhythmias. The implantation of an ICD, rather than a pacemaker, should be considered for these patients.
Christophe Meune, M.D.
Paris V University Hospital Cochin
75014 Paris, France
Jop H. Van Berlo, M.D.
University Hospital Maastricht
6229 HX Maastricht, the Netherlands
Frédéric Anselme, M.D.
Charles Nicolle Hospital
76000 Rouen, France
Gisèle Bonne, M.D., Ph.D.
INSERM Unité 582
75013 Paris, France
Yigal M. Pinto, M.D., Ph.D.
Interuniversity Cardiology Institute
3501 DG Utrecht, the Netherlands
Denis Duboc, M.D., Ph.D.
Paris V University Hospital Cochin
75014 Paris, France
denis.duboc@cch.ap-hop-paris.fr
References
Ben Yaou R, Muchir A, Arimura T, et al. Genetics of laminopathies. Novartis Found Symp 2005;264:81-90.
Bonne G, Di Barletta MR, Varnous S, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 1999;21:285-288.
Taylor MR, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003;41:771-780.
van Berlo JH, de Voogt WG, van der Kooi AJ, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med 2005;83:79-83.
Bécane HM, Bonne G, Varnous S, et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000;23:1661-1666.
We prospectively studied patients with genetically proven lamin A/C gene mutations; between March 1999 and January 2004, all patients referred to a participating center for permanent cardiac pacing were systematically offered the implantation of an ICD. A history of ventricular tachyarrhythmia, spontaneous or inducible by programmed ventricular stimulation, was not a selection criterion, and patients were enrolled solely on the basis of the presence of lamin A/C mutations associated with cardiac conduction defects. Indications for pacemaker implantation were progressive conduction block and sinus block. All the ICDs used in the study had storage capabilities, and events were scored as inappropriate or appropriate by two investigators. The study protocol was reviewed and approved by the ethics committee of each participating center, and all patients provided written informed consent.
The study included 19 patients whose clinical characteristics are listed in Table 1. During a mean follow-up period of 33.9±21.0 months, eight of the patients (42 percent) received appropriate ICD therapy. Six patients received ICD shocks for ventricular fibrillation (cycle length, <240 msec), two patients received ICD shocks for ventricular tachycardia (cycle length, >240 msec), and one patient received antitachycardia pacing for ventricular tachycardia. One patient received an inappropriate shock. The mean (±SD) left ventricular ejection fraction (LVEF) in the overall study population was 58±12 percent. No factor — including LVEF, spontaneous or inducible ventricular tachycardia or ventricular fibrillation, or drug therapy — was found to be related to the occurrence of ventricular arrhythmias. The LVEF was not depressed in patients receiving appropriate ICD therapy, indicating a high risk of sudden death before the development of cardiac failure.
Table 1. Baseline Clinical Characteristics of the 19 Patients.
In conclusion, ICD implantation in patients with a lamin A/C mutation who are in need of a pacemaker is effective in treating possibly lethal tachyarrhythmias. The implantation of an ICD, rather than a pacemaker, should be considered for these patients.
Christophe Meune, M.D.
Paris V University Hospital Cochin
75014 Paris, France
Jop H. Van Berlo, M.D.
University Hospital Maastricht
6229 HX Maastricht, the Netherlands
Frédéric Anselme, M.D.
Charles Nicolle Hospital
76000 Rouen, France
Gisèle Bonne, M.D., Ph.D.
INSERM Unité 582
75013 Paris, France
Yigal M. Pinto, M.D., Ph.D.
Interuniversity Cardiology Institute
3501 DG Utrecht, the Netherlands
Denis Duboc, M.D., Ph.D.
Paris V University Hospital Cochin
75014 Paris, France
denis.duboc@cch.ap-hop-paris.fr
References
Ben Yaou R, Muchir A, Arimura T, et al. Genetics of laminopathies. Novartis Found Symp 2005;264:81-90.
Bonne G, Di Barletta MR, Varnous S, et al. Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet 1999;21:285-288.
Taylor MR, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations. J Am Coll Cardiol 2003;41:771-780.
van Berlo JH, de Voogt WG, van der Kooi AJ, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med 2005;83:79-83.
Bécane HM, Bonne G, Varnous S, et al. High incidence of sudden death with conduction system and myocardial disease due to lamins A and C gene mutation. Pacing Clin Electrophysiol 2000;23:1661-1666.