Abstract
Background: Mutations in DES gene, encoding the intermediate filament desmin, have been related to arrhythmogenic cardiomyopathy (AC). Our aim is to describe the clinical phenotype, natural history and outcomes in a multicentric international cohort of desmin-related AC patients. Methods: Probands and relatives (85 individuals from 11 families (45% men; mean age 35 [IQR] 23.5-53.5 years old)) carrying a DES mutation from 8 European centers were included. Clinical, electrocardiographical and advanced cardiac imaging data were retrospectively collected and analysed. DES mutations were transfected into cell lines and analyzed by confocal microscopy. Results: Disease penetrance in individuals ≥30 years was 80.8% and 71.4% in individuals <30 years; A left dominant or biventricular form of AC was the main clinical phenotype (69 cases, 81 %). More than half of the patients presented low voltage on the ECG, the mean LVEF was 48.9±16% and the mean RVEF was 53.8±10%. A high prevalence of patients with magnetic resonance imaging (n=30) presented fibrosis (65,2%), with a particular circunferencial (“ring-like”) pattern in 46.4% (Figure A). After a median follow-up of 6 years, 24.7% died (mean age 62[33-76]) (Figure B) and 8.2% suffered appropriate shocks (age 47[31-69.5]) or SD (age 33 [24.5-49]). Finally, there were 6 heart transplants (age 54 [33-68]). A LVEF<50% and male sex were associated with major cardiovascular events. In three DES mutations (E401D, L115E and R415Q) desmin aggreggates were observed (Figure C) Conclusions AC due to DES mutations have a high clinical penetrance as a left dominant or biventricular form of the disease, with an early onset and a high burden of cardiovascular events. A LV “ring-like” LGE pattern was particularly common. Male sex or mildly depressed LVEF were predictors for SD. DES mutation may be pathogenic by causing desmin aggregates. A) Annular pattern of fibrosis B) Carriers free-of-events survival curve. C) Desmin aggregates
Published Version
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