Abstract 4142400: Clinical implication and potential role of immunosuppression for myocarditis episodes in patients with desmoplakin cardiomyopathy: hope from the DSP-ERADOS Network?
Authors: Gasperetti Alessio , Peretto Giovanni , Muller Steven , Laredo mikael , Carrick Richard , Asatryan Babken , Protonotarios Alexandros , Murray Brittney , Scheel Paul , Pilichou Kalliopi , Syrris Petros , Jason Max , Medo Kristen , Rossi Valentina , Saguner Ardan , Hylind Robyn , Abrams Dominic , Cadrin-Tourigny Julia , olivotto iacopo , Biagini Elena , Cox Moniek , CHARRON Philippe , Ware James , Cal Leonardo , smith eric , Ingles Jodie , Ader Flavie , Peters Stacey , russo jeremy , Zentner Dominica , Bahr Eric , Carruth Eric , Haggerty Chris , Parikh Victoria , Taylor Matthew , Mestroni Luisa , Sinagra Gianfranco , Wilde Arthur , Gandjbakhch Estelle , Te Riele Anneline , Van Tintelen Peter , Elliott Perry , Adamo Luigi , James Cynthia , Merlo Marco , Lakdawala Neal , Bauce Barbara , Helms Adam , Calkins Hugh , Gilotra Nisha 
Published: November 2024

Introduction:
Variants in the desmoplakin (DSP) gene are associated with a form of arrhythmogenic cardiomyopathy (ACM) characterized by high risk of ventricular arrhythmias (VAs), heart failure (HF), and recurrent myocarditis. The clinical implications and management of myocarditis episodes in DSP-ACM have been scarcely investigated and are a major unmet clinical challenge.

Research Question:
what is the clinical impact of myocarditis episodes in DSP-ACM? Is there any role for immunosuppression?

Methods:
Patients (pts) with DSP-ACM in the worldwide DSP-ERADOS Network (26 institutions across 9 countries in 3 continents) were enrolled. Pts were classified as myocarditis-positive (Myo+) if they had a diagnosis of myocarditis at any time as per ESC criteria and otherwise as negative (Myo-). A multi-state model was used to compare the time-dependent risk of the outcome of interest (combined occurrence of VAs or HF hospitalization) at follow up. Hazard ratios (HR) were reported for quantifying the impact of single or repeated myocarditis on combined outcome occurrences, as well as the impact of immunosuppression.

Results:
A total of 801 pts (38.8±17.3 yo, 63.9% female; LVEF 49.7±14.7%; RVEF 50.1±13.2%) were enrolled. Over 3.5 [1.2–6.7] years, 153 (19.1%) patients (Myo+) experienced 260 myocarditis episodes (1.7 episode/pt; n=54 pts with 2+ episodes), 79 of which were treated with immunosuppression. A total of 193 (24.1%; 6.7%/year) pts experienced the combined end-point (n=120/648 (18.5%) Myo-; n=73/153 (47.7%) Myo+; log rank p <0.001). Occurrence of myocarditis was associated with increased risk in the composite outcome, with repeated myocarditis having a non-significant trend towards a higher risk than single events (Panel A). However, when adjusting for treatment with immunosuppressants in the Myo+ cohort, there were no differences in endpoint compared to pts in the Myo- cohort (Panel B) (Relative HR to Myo- pt: for treated Myo+ episodes: 0.76 [0.33–1.72], p=0.503; for untreated Myo+ episodes: 2.89 [2.11–3.95], p <0.001).

Application:
Myocarditis episodes in pts with DSP-ACM are associated with increased risk in VA/HF hospitalizations. This analysis suggests a potential benefit of immunosuppression therapy for myocarditis episodes in DSP cardiomyopathy and warrants further study.

Next Steps/Future:
A randomized controlled trial is needed to test the role of immunotherapy in this patient population.