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[Preprint]. 2025 Jun 23:2025.06.16.25329734.
doi: 10.1101/2025.06.16.25329734.

Diagnostic Criteria and Disease Staging for Desmoplakin Cardiomyopathy

Eric Smith  1 , Alessio Gasperetti  2 , Richard T Carrick  2 , Alexandros Protonotarios  3 , Petros Syrris  3 , Barbara Bauce  4 , Kalliopi Pilichou  4 , Brittney Murray  2 , Crystal Tichnell  2 , Cristina Basso  4 , Paul Anders Sletten Olsen  5 , Chiara Cappelletto  6 , Victoria N Parikh  7 , Liang Chen  8 , Stacey Peters  9 , Antonella Mancinelli  10 , Anna Maria Iorio  10 , Roberta Scotto  11 , Julia Cadrin-Tourigny  12 , Nisha A Gilotra  2 , Manuela Iseppi  13 , Giovanni Peretto  14 , Marco Schiavone  15 , Mark Abela  16 , Daniela Vargas  17 , Cinzia Crescenzi  18 , Leonardo Calò  18 , James Ware  19   20 , Lia Crotti  21 , Michele Ciabatti  22 , Michela Casella  23 , Alexandra Apostu  24 , Ruxandra Jurcut  24 , Claudia Raineri  25 , Filippo Angelini  25 , Carlos Fernández-Sellers  26 , Esther Zorio  26   27   28   29 , Sing-Chien Yap  30 , Moniek G Cox  31 , Arman Salavati  32 , Anneline Te Riele  32 , Arthur Wilde  33 , Ahmad S Amin  33 , Peter van Tintelen  32 , Ardan M Saguner  34   35 , Firat Duru  34   35 , Dominic Abrams  36 , Marina Cerrone  37 , Maddalena Graziosi  38 , Elena Biagini  38 , Juan Ramon Gimeno  39 , Estelle Gandjbakhch  40 , Neal Lakdawala  41 , Maurizio Pieroni  42 , Marco Merlo  6 , Gianfranco Sinagra  6 , Kristina Haugaa  5 , Elena Arbelo  17   43   44 , Perry M Elliott  3 , Matthew Taylor  45 , Luisa Mestroni  45 , Hugh Calkins  2 , Cynthia A James  2 , Adam S Helms  1
Affiliations

Diagnostic Criteria and Disease Staging for Desmoplakin Cardiomyopathy

Eric Smith et al. medRxiv. .

Abstract

Background: Desmoplakin (DSP) cardiomyopathy, caused by variants in the gene DSP, is a unique subtype of cardiomyopathy distinct from typical dilated or arrhythmogenic right ventricular cardiomyopathies. Specific diagnostic and disease staging criteria have yet to be developed for DSP cardiomyopathy.

Objective: Utilizing a large cohort of DSP cardiomyopathy patients and their genotype-positive family members, this study aims to develop diagnostic and disease staging criteria for DSP cardiomyopathy.

Methods: Patients from the DSP-ERADOS Network with complete rhythm monitoring, electrocardiogram and cardiac magnetic resonance imaging were enrolled. Diagnostic criteria were assessed in initially-presenting patients (probands) and their genotype-positive family members. Early disease criteria (with preserved left ventricular ejection fraction, LVEF) were integrated into standard LVEF-based classifications. Diagnostic and staging criteria were assessed by time-event analyses (major ventricular arrhythmia and heart failure events).

Results: A total of 605 patients with complete diagnostic testing were included (mean age 40 yr, 60% female, 40% probands). The most prevalent disease features in probands were premature ventricular contractions (PVCs) >500/24hr (66%), nonsustained ventricular tachycardia (NSVT, 29%), LV late gadolinium enhancement (LGE, 53%), and reduced LVEF (44%). The presence of any one of these features was 97% sensitive for diagnosis (along with a DSP pathogenic variant) and were therefore considered as diagnostic criteria. Using these criteria, 77% of genotype-positive family members were considered clinically affected. Isolated right ventricular (RV) involvement occurred in only 0.7%. The absence of diagnostic criteria identified a low-risk group (composite event rate 0.8%/year, p<0.001). Integration of these criteria into LVEF-based classification improved identification of composite arrhythmia/heart failure events (early: diagnostic criteria with LVEF ≥50%, HR 2.7, p=0.04; intermediate: LVEF 41-49%, HR 3.7, p=0.009; advanced: LVEF ≤40% HR 10.3, p<0.001). LGE was mostly subepicardial (87%). Circumferential (ring-like) LGE was more frequent in intermediate or advanced vs early disease (66% vs 48%, p<0.001).

Conclusion: This study identifies genotype-specific diagnostic and disease staging criteria for DSP cardiomyopathy that improve identification of risk for both heart failure and sustained ventricular arrhythmias. This work highlights how gene-specific criteria may be used to refine diagnosis and staging for cardiomyopathy subtypes - a critical step as gene-targeted treatments move toward clinical trials.

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Figures

Figure 1 (Central Figure).
Figure 1 (Central Figure).
Proposed disease stages for DSP cardiomyopathy.
Figure 2.
Figure 2.. Diagnostic Feature Overlap in DSP Cardiomyopathy.
A. LV LGE, frequent PVCs or NSVT, and LVEF <50% are prevalent features of DSP cardiomyopathy with substantial but incomplete overlap shown by scaled Venn diagram. B. Left ventricular involvement (indicated by LV LGE and/or LVEF <50%) is most common in DSP cardiomyopathy while a small proportion exhibit biventricular involvement and rare patients may exhibit isolated RV involvement, shown by scaled Venn diagram.
Figure 3.
Figure 3.. Adverse events by disease stage over 5 years of follow up.
A. Composite adverse events (major arrhythmia and major heart failure) are shown up to 5 years of follow-up after baseline comprehensive diagnostic testing. B. Adverse event proportions are shown by ventricular arrhythmia or heart failure subtype for each disease stage. Corresponding Cox regression statistics are shown in Table 4.
Figure 4.
Figure 4.. Late gadolinium distribution by disease stage and myocardial segment.
A 36-segment model was used to capture presence/absence of late gadolinium enhancement (LGE) by region, ventricular level, and muscle layer (top row). The proportion of patients with LGE in each segment for each disease stage is shown by heat map (2nd – 4th rows). The relative proportion of patients with number of LGE segments by bin is shown for each disease stage (top right).
See this image and copyright information in PMC

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