In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 136, No. suppl_1 ( 2017-11-14)
Abstract:
Introduction: Mutations in LMNA, which encodes lamin A and C, typically cause age-dependent cardiac phenotypes, including dilated cardiomyopathy, cardiac conduction disturbance (CCD), atrial fibrillation, and malignant ventricular arrhythmias (MVAs). Although the type of LMNA mutations have been reported to be associated with susceptibility to MVAs, the gene-based risk stratification for cardiac complications remains unexplored. Hypothesis: We hypothesized that truncation mutations might be associated with poor prognosis in LMNA mutation carriers, due to CCD, MVAs, and heart failure. Methods: The multicenter cohort included 77 LMNA mutation carriers (49 male, mean age: 45+/-17 yrs old) in 45 families from 7 institutions in Japan. All cause mortality and cardiac disorders were retrospectively analyzed. Results: Genetic analysis showed truncation mutations in 58 patients from 31 families and missense mutations in 19 patients from 14 families, in which 71 (92%) were phenotypically affected, and showed CCD (81%), lower left ventricular ejection fraction (LVEF 〈 50%; 45%), atrial arrhythmias (AAs: 58%), and MVAs (26%). During the follow-up period (median 47 months), 9 (12%) patients died due to end-stage heart failure (n=7) or suddenly (n=2), but not differ between the the type of mutations. On the other hand, the onset of cardiac disorders indicated that subjects with truncation mutations had an earlier occurrence of CCD (41+/-12 vs. 51+/-10 yrs old; p=0.004) and LVEF 〈 50% (47+/-12 vs. 56+/-7 yrs old; p=0.07) compared to those with missense mutations. In addition, the truncation mutation was found to be at risk for the early onset of CCD (Odds ratio [OR]=3.55, 95%CI:1.1-12.3, p=0.04) and the occurrence of AAs (OR=5.18 [1.4-20.4] , p=0.01), LVEF 〈 50% (OR=3.92 [1.0-16.6], p=0.04), and MVAs (OR=12.8 [1.9-259] , p=0.006), as estimated using multivable analyses. However, no significant difference was observed in each cardiac phenotype between probands vs. relatives and male vs. female. Conclusions: The truncation mutations were associated with earlier manifestation of cardiac phenotypes in LMNA -related cardiomyopathy, suggesting that genetic analysis might be useful for diagnosis and risk stratification in LMNA mutation carriers.
Type of Medium:
Online Resource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.136.suppl_1.21144
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2017
detail.hit.zdb_id:
1466401-X
detail.hit.zdb_id:
80099-5
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