
==== Front
medRxiv
MEDRXIV
medRxiv
Cold Spring Harbor Laboratory

10.1101/2024.08.24.24311904
preprint
1
Article
Natural History, Phenotype Spectrum and Clinical Outcomes of Desmin ( DES )-Associated Cardiomyopathy
Asatryan Babken http://orcid.org/0000-0002-0050-5717

Rieder Marina
Murray Brittney http://orcid.org/0000-0001-7870-8584

Muller Steven A. http://orcid.org/0000-0002-2674-8709

Tichnell Crystal
Gasperetti Alessio http://orcid.org/0000-0003-3432-070X

Carrick Richard T.
Joseph Emily
Leung Doris G.
te Riele Anneline S.J.M. http://orcid.org/0000-0002-4694-4790

Zimmerman Stefan L. http://orcid.org/0000-0002-9422-6742

Calkins Hugh http://orcid.org/0000-0002-9262-9433

James Cynthia A. http://orcid.org/0000-0001-8040-4600

Barth Andreas S. http://orcid.org/0000-0001-5275-8049

26 8 2024
2024.08.24.24311904https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://medrxiv.org/lookup/doi/10.1101/2024.08.24.24311904
nihpp-2024.08.24.24311904.pdf
ABSTRACT

Background

Pathogenic/likely pathogenic (P/LP) desmin ( DES ) variants cause heterogeneous cardiomyopathy and/or skeletal myopathy phenotypes. Limited data suggest a high incidence of major adverse cardiac events (MACE), including cardiac conduction disease (CCD), sustained ventricular arrhythmias (VA), and heart failure (HF) events (HF hospitalization, LVAD/cardiac transplant, HF-related death), in patients with P/LP DES variants. However, pleiotropic presentation and small cohort sizes have limited clinical phenotype and outcome characterization.

Objectives

We aimed to describe the natural history, phenotype spectrum, familial penetrance and outcomes in patients with P/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 P/LP DES variants. Cardiomyopathy diagnosis or occurrence of MACE were considered evidence of cardiac involvement/penetrance. Lifetime event-free survival from CCD, sustained VA, HF events, and composite MACE was assessed.

Results

Out of 4,212 screened publications, 71 met the inclusion criteria. A total of 230 patients were included (52.6% male, 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 CCD, 36 [15.7%] sustained VA, and 43 [18.7%] HF events. Familial penetrance of cardiac disease was 63.6% among relatives with P/LP DES variants. Male sex was associated with increased risk of sustained VA (HR 2.28, p=0.02) and HF events (HR 2.45, p=0.008).

Conclusions

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