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

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.

Keywords: cardiac arrhythmia; cardiomyopathy; genetics; genomics; penetrance; precision medicine; prognosis; risk stratification; sudden cardiac death.

Figure 1.. Structural organization of the human desmin (DES) gene and localization of variants included in this study.

Pathogenic variants are found across the entire DES gene, with majority of patients carrying variants localized in the α-helical-rod 2B and in the tail domains. Variants are classified into three groups depending on the ensuing phenotype: cardiac involvement (red), skeletal myopathy (blue), both cardiac involvement and skeletal myopathy (purple), and neither (black). Associated cardiomyopathy phenotypes are provided with additional markers (see figure legend). † Considered carrier status in heterozygous state, but pathogenic or likely pathogenic in homozygous state. ‡ Considered carrier status unless identified in compound heterozygous state. 1A and 1B, coil 1A and coil 1B; 2A and 2B, coil 2A and coil 2B; L1, L12 and L2, non-alpha-helical linker regions.

Figure 2.. Survival free from major adverse cardiac events (MACE).

Survival free from composite MACE (A), cardiac conduction disease (CCD) requiring cardiac implantable electronic device (CIED) implantation (B), sustained ventricular arrhythmia (VA) events, (C), and heart failure (HF) events (HF hospitalization, left ventricular assist device (LVAD)/cardiac transplantation, HF-related death) (D) are presented with 95% CIs (shaded area) in the overall population.

Figure 3.. Survival free from major adverse cardiac events (MACE) stratified by sex.

Survival free from composite MACE (A), cardiac conduction disease (CCD) requiring cardiac implantable electronic device implantation (B), sustained ventricular arrhythmia (VA) events, (C), and heart failure (HF) events (HF hospitalization, left ventricular assist device (LVAD)/cardiac transplantation, HF-related death) (D) are presented with 95% CIs (shaded area) in males vs females.

Figure 4.. Proportion of patients with individual and composite major adverse cardiac events (MACE) stratified by the underlying cardiomyopathy phenotype.

Note, for patients with transition of phenotype, the more advanced phenotype stage was chosen for this analysis. ACM = arrhythmogenic cardiomyopathy; ARVC = arrhythmogenic right ventricular cardiomyopathy; CMP = cardiomyopathy; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; RCM = restrictive cardiomyopathy.