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Meta-Analysis
. 2025 Apr;18(2):e004878.
doi: 10.1161/CIRCGEN.124.004878. Epub 2025 Feb 19.

Natural History, Phenotype Spectrum, and Clinical Outcomes of Desmin (DES)-Associated Cardiomyopathy

Babken Asatryan  1 , Marina Rieder  2 , Brittney Murray  1 , Steven A Muller  1   3   4 , Crystal Tichnell  1 , Alessio Gasperetti  1 , Richard T Carrick  1 , Emily Joseph  5 , Doris G Leung  6 , Anneline S J M Te Riele  3   4   7 , Stefan L Zimmerman  8 , Hugh Calkins  1 , Cynthia A James #  1 , Andreas S Barth #  1
Affiliations
Meta-Analysis

Natural History, Phenotype Spectrum, and Clinical Outcomes of Desmin (DES)-Associated Cardiomyopathy

Babken Asatryan et al. Circ Genom Precis Med. 2025 Apr.

Abstract

Background: Pathogenic/likely pathogenic (LP) desmin (DES) variants cause heterogeneous cardiomyopathy and skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACEs), including cardiac conduction disease, sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, left ventricular assist device/cardiac transplant, HF-related death) in patients with pathogenic/LP DES variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization. We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with pathogenic/LP DES variants through a systematic review and individual patient data meta-analysis using published reports.

Methods: We searched Medline (PubMed) and Embase for studies that evaluated cardiac phenotypes in patients with pathogenic/LP DES variants. Cardiomyopathy diagnosis or occurrence of MACE was considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from cardiac conduction disease, sustained VA, HF events, and composite MACE was assessed.

Results: Of the 4212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% men, 52.2% probands, median age: 31 years [22.0-42.8] at first evaluation, median follow-up: 3 years [0-11.0]). Overall, 124 (53.9%) patients were diagnosed with cardiomyopathy, predominantly dilated cardiomyopathy (14.8%), followed by restrictive cardiomyopathy (13.5%), whereas other forms were less common: arrhythmogenic cardiomyopathy (7.0%), hypertrophic cardiomyopathy (6.1%), arrhythmogenic right ventricular cardiomyopathy (5.2%), and other forms (7.4%). Overall, 132 (57.4%) patients developed MACE, with 96 (41.7%) having cardiac conduction disease, 36 (15.7%) sustained VA, and 43 (18.7%) HF events. Familial penetrance of cardiac disease was 63.6% among relatives with pathogenic/LP DES variants. Male sex was associated with an increased risk of sustained VA (hazard ratio, 2.28; P=0.02) and HF events (hazard ratio, 2.45; P=0.008).

Conclusions: DES cardiomyopathy exhibits heterogeneous phenotypes and a distinct natural history, characterized by high familial penetrance and a substantial MACE burden. Male patients face a higher risk of sustained VA events.

Keywords: cardiac arrhythmia; cardiomyopathies; death; genomics; penetrance; precision medicine; sudden cardiac arrest.

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Conflict of interest statement

Dr Asatryan received support from Abbott, Biosense-Webster and Boston Scientific for attending meetings and travel unrelated to this work. Dr Calkins receives research support from Boston Scientific for unrelated work. Drs Tichnell and James receive salary support from this grant. Dr James receives research support from Lexeo, Inc, for unrelated work. C. Tichnell receives salary support from this grant. Dr te Riele is a consultant for Tenaya Therapeutics, Rocket Pharmaceutical, and BioMarin for unrelated work. Dr James received research funding from Lexeo Therapeutics, StrideBio, Inc, Tenaya Therapeutics, and ARVADA Therapeutics for unrelated work. Dr James received consulting fees from Pfizer, Inc and Lexeo Therapeutics. The other authors report no conflicts.

Update of

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Supplementary concepts