Clinical features and outcomes in carriers of pathogenic desmoplakin variants
Authors: Gasperetti Alessio , Carrick Richard T , Protonotarios Alexandros , Murray Brittney , Laredo Mikael , van der Schaaf Iris , Lekanne Ronald H , Syrris Petros , Cannie Douglas , Tichnell Crystal , Cappelletto Chiara , Gigli Marta , Medo Kristen , Saguner Ardan M , Duru Firat , Gilotra Nisha A , Zimmerman Stefan , Hylind Robyn , Abrams Dominic J , Lakdawala Neal K , Cadrin-Tourigny Julia , Targetti Mattia , Olivotto Iacopo , Graziosi Maddalena , Cox Moniek , Biagini Elena , Charron Philippe , Casella Michela , Tondo Claudio , Yazdani Momina , Ware James S , Prasad Sanjay K , Calò Leonardo , Smith Eric D , Helms Adam S , Hespe Sophie , Ingles Jodie , Tandri Harikrishna , Ader Flavie , Peretto Giovanni , Peters Stacey , Horton Ari , Yao Jess , Dittmann Sven , Schulze-Bahr Eric , Qureshi Maria , Young Katelyn , Carruth Eric D , Haggerty Chris , Parikh Victoria N , Taylor Matthew , Mestroni Luisa , Wilde Arthur , Sinagra Gianfranco , Merlo Marco , Gandjbakhch Estelle , van Tintelen J Peter , te Riele Anneline S J M , Elliott Perry M , Calkins Hugh , James Cynthia A 
Published: September 2024

Abstract

Background and Aims
Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown.

Methods
All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine–Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes.

Results
Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4–7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P &lt; .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P &lt; .001, and HR 5.064, P &lt; .001, respectively).

Conclusions
Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events.