Phenotype and Clinical Outcomes in Desmin-Related Arrhythmogenic Cardiomyopathy.

Background: Desmin (DES) pathogenic variants cause a small proportion of arrhythmogenic cardiomyopathy (ACM). Outcomes data on DES-related ACM are scarce.
Objectives: This study sought to provide information on the clinical phenotype and outcomes of patients with ACM caused by pathogenic variants of the DES gene in a multicenter cohort.
Methods: We collected phenotypic and outcomes data from 16 families with DES-related ACM from 10 European centers. We assessed in vitro DES aggregates. Major cardiac events were compared to historical controls with lamin A/C truncating variant (LMNA-tv) and filament C truncating variant (FLNC-tv) ACM.
Results: Of 82 patients (54% males, median age: 36 years), 11 experienced sudden cardiac death (SCD) (n = 7) or heart failure death (HFd)/heart transplantation (HTx) (n = 4) before clinical evaluation. Among 68 survivors, 59 (86%) presented signs of cardiomyopathy, with left ventricular (LV) dominant (50%) or biventricular (34%) disease. Mean LV ejection fraction was 51% ± 13%; 36 of 53 had late gadolinium enhancement (ring-like pattern in 49%). During a median of 6.73 years (Q1-Q3: 3.55-9.52 years), the composite endpoint (sustained ventricular tachycardia, aborted SCD, implantable cardioverter-defibrillator therapy, SCD, HFd, and HTx) was achieved in 15 additional patients with HFd/HTx (n = 5) and SCD/aborted SCD/implantable cardioverter-defibrillator therapy/sustained ventricular tachycardia (n = 10). Male sex (P = 0.004), nonsustained ventricular tachycardia (P = 0.017) and LV ejection fraction ≤50% (P = 0.012) were associated with the composite endpoint. Males with DES variants had similar outcomes to historical FLNC-tv and LMNA-tv controls. However, females showed better outcomes than those with LMNA-tv. In vitro experiments showed the characteristic finding of DES aggregates in 7 of 12 variants.
Conclusions: DES ACM is associated with poor outcomes which can be predicted with potentially successful treatments, underscoring the importance of familial evaluation and genetic studies to identify at risk individuals.
Competing Interests: Funding Support and Author Disclosures Dr Bermudez-Jimenez has received grants from Instituto de Salud Carlos III (ISCIII) through the project JR21/00031 (cofounded by European Regional Development Fund). Dr Zorio has received grants from the Instituto de Salud Carlos III through the projects PI18/01582 and PI21/01282 (co-funded by European Regional Development Fund “A way to make Europe”). Dr Brodehl has received grants from the Medical Faculty of the Ruhr-University Bochum (FoRUM, F1074-2023) and the ‘Deutsche Herzstiftung e.V. (Frankfurt a.M., Germany); and is a shareholder with Tenaya Therapeutics. Dr Lopes has received grants from a Medical Research Council (MRC) Clinical Academic Research Partnership (CARP) award (MR/T005181/1). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)