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Dilated cardiomyopathy (DCM) is often caused by mutations in the gene for Lamin A/C (LMNA), which encodes proteins of the nuclear envelope. Mutation carriers may also present with atrial fibrillation, atrioventricular conduction disturbances, or ventricular tachycardia (VT). Less frequently patients are affected by muscular dystrophy.
The aim of the study by van Rijsingen and colleagues was to determine clinical and genetic risk factors for malignant ventricular arrhythmias (MVA) in LMNA mutation carriers. The study cohort consisted of 269 European individuals carrying pathogenic LMNA mutations.The patients were recruited from 109 different families at 8 tertiary referral centres, and the size of the families ranged from 1 to 24 persons. Clinical data at first evaluation and at follow-up were reported. The endpoint for survival analysis was the first episode of MVA defined as appropriate ICD discharge, cardiac arrest, or sudden cardiac death. The median follow-up period was 43 months (interquartile range: 17-101 months). In addition, independent risk factors for MVA were investigated by univariate and multivariate statistical analysis.
At baseline, LMNA mutation carriers had a high arrhythmic burden and frequently impairment of the left ventricular systolic function. Atrial fibrillation, conduction disease, and non-sustained ventricular tachycardia were present in 36%, 47%, and 37% of patients, respectively. Thirty-seven per cent had left ventricular dysfunction with a LVEF<45%. During the follow-up period beginning at first examination, a total of 48 (18%) the mutation carriers experienced a first episode of MVA: 11 received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment while 12 persons died suddenly. In total, 45 persons (17%) had died during follow-up at a mean age of 50 ± 11 years with heart failure (n=21, 47%) or sudden cardiac death (n=14, 31%) being the most prevalent causes of death.
Univariate statistical analysis identified non-sustained VT, LVEF<45%, male gender, left ventricular dilation as risk factors for MVA. When corrected for age at initial evaluation in multivariate analysis, non-sustained VT (Hazard ratio [HR]: 4.4; CI 1.7-11), LVEF<45% (HR: 4.4; CI 1.9-10.4), male gender (HR: 2.6; CI 1.2-7.0) were shown to be independent risk factors for the composite MVA endpoint. Proband status, atrial arrhythmias, conduction disease, and afamily history of SCD, unexplained syncope, mutation type, or NYHA functional class >3 were not associated with a higher risk of MVA. However, survival analysis according to sex, type of mutation, and age at first MVA, demonstrated that male sex (HR 3.9; CI 1.9-7.9) and non-missense mutationsin the LMNA gene (HR 2.5; CI 1.4-4.5) were also risk factors for lifetime occurrence of MVA.
Groups of patients with 1, 2, 3, or 4 risk factors (non-sustained VT, LVEF<45%, male gender, and carrier of non-missense mutation) were compared. Persons with 0 to 1 risk factorshad no episodes of MVA during a median follow-up periodof 43 months (IQR: 16 to 92 months). In LMNA mutation carriers with 2 or 3 risk factors, 17% and 40%, respectively, developed MVA. The age of onset was 34 years in persons with 2 risk factors and 26 years in persons with 3 risk factors. Nine of 13 (71%) LMNA mutation carriers with 4 risk factors had MVA with an age of onset of 20 years. Importantly, none of the persons without left ventricular dysfunction (LVEF<45%) and episodes of non-sustained VT met the composite MVA endpoint in the follow-up period. Furthermore, no MVA occurred in persons with the combination of male sex and non-missense mutations risk factors.
The authors concluded that prophylactic ICD implantation should be considered in LMNA mutation carriers having 2 or more of the following risk factors: LVEF<45%, non-sustained VT, non-missense mutation, and male gender. Consequently, mutation carriers with a normal left ventricular function and no ventricular arrhythmias do not require an ICD but should be followed and risk stratified on a regular basis.
Pathogenic mutations in the LMNA gene are frequently identified in DCM patients with additional features of atrial arrhythmias and conduction disease, and the condition may be associated with skeletal muscular dystrophy.1-3Furthermore, the phenotype associated with LMNA mutations may clinically and histologically mimic the phenotype of arrhythmogenic cardiomyopathy.4 Carriers of pathogenic LMNA mutations are likely to develop heart failure, and the presence of left ventricular dysfunction in these patients is associated with a high risk of sudden cardiac death.5,6 The present study suggests that risk stratification in LMNA mutation carriers for should be based on the presence of left ventricular dysfunction, ventricular tachyarrhythmias, male gender, and type of mutation. The study indicates that prophylactic implantation of ICD should considered in LMNA-patients with LVEF<45% and episodes of non-sustained VT.
Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med 1999;341:1715-24.