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Multicenter Study
. 2025 May 2;111(10):480-486.
doi: 10.1136/heartjnl-2024-324525.

Coexistence of cardiac sarcoidosis and arrhythmogenic cardiomyopathy-associated genetic variants: a multicentre case-control study

Valentina Alice Rossi  1   2 , Matteo Palazzini  3 , Enrico Ammirati  3   4 , Alessio Gasperetti  5   6 , Martin Grubler  7   8   9 , Corinna Brunckhorst  10 , Robert Manka  10   11 , Andreas Giannopoulos  12 , Felix C Tanner  10 , Argelia Medeiros-Domingo  13 , Piero Gentile  3   4 , Manuela Bramerio  14 , Dörthe Schmidt  10 , Claudio Tondo  6   15 , Andreas J Flammer  10   2 , Frank Ruschitzka  10   2 , Firat Duru  10   2 , Ardan Muammer Saguner  1   2
Affiliations
Multicenter Study

Coexistence of cardiac sarcoidosis and arrhythmogenic cardiomyopathy-associated genetic variants: a multicentre case-control study

Valentina Alice Rossi et al. Heart. .

Abstract

Background: Cardiac sarcoidosis (CS) is a chronic inflammatory disease characterised by non-caseating granulomas, while arrhythmogenic cardiomyopathy (ACM) is a genetic condition mainly affecting desmosomal proteins. The coexistence of CS and genetic variants associated with ACM is not well understood, creating challenges in diagnosis and management. This study aimed to describe the clinical, imaging and genetic features of patients with both conditions.

Methods: This was a multicentre retrospective case-control study involving three groups of patients: those with biopsy-proven CS and pathogenic or likely pathogenic genetic variants linked to ACM (n=5); patients with genetic variants but no CS (n=5); and patients with CS without genetic variants (n=5). Clinical data, including symptoms, electrocardiographic findings and imaging results from echocardiography, cardiac magnetic resonance and positron-emission tomography, were analysed.

Results: Patients with CS and genetic variants were more likely to exhibit atrioventricular block (100%), PR prolongation (204 ms vs 160 ms) and paroxysmal atrial fibrillation (80%) compared with those with genetic variants alone (0% for both). Imaging findings showed a higher prevalence of septal involvement in patients with both conditions (80%) than in those with genetic variants alone (20%). No significant differences were observed between patients with CS and genetic variants and those with CS without genetic variants. The genetic variants identified included variants in PKP2 (40%), DSG2 (20%), DSP (20%) and TTN (20%).

Conclusions: The coexistence of CS and ACM-associated genetic variants is associated with distinct clinical features, including PR prolongation, AVB1°, septal involvement and paroxysmal atrial fibrillation. These findings emphasise the need to evaluate for CS in individuals with ACM and associated genetic variants who present with conduction abnormalities or septal involvement, guiding tailored diagnostic and therapeutic strategies.

Keywords: Arrhythmogenic Right Ventricular Dysplasia; Cardiomyopathies; Cardiomyopathy, Dilated; Myocarditis.

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Conflict of interest statement

Competing interests: AMS has received speaker/consulting fees from Bayer Healthcare, Biotronik, Medtronic, Pfizer, Stride Bio Inc. and Zoll. AJF declares fees from Abbott, Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pierre Fabre, Pfizer, Roche, Vifor and Zoll, as well as grant support by Novartis, AstraZeneca and Berlin Heart unrelated to this article. AG is supported by research funding grants from the Promedica Foundation and Max and Sophielene Iten-Kohaut Foundation. VAR is supported by research funding grants from the Rutishauser Foundation. EA received a grant from the Italian Ministry of Health (GR-2019-12368506; principal investigator of the investigator-driven MYTHS (Myocarditis Therapy with Steroids) trial) and a grant from Italian Ministry of Health and NextGenerationEU (PNRR-MAD-2022-12376225), serves as consultant for Lexeo and served as consultant for Kiniksa, AstraZeneca and Cytokinetics. All other authors declare no conflict of interest related to this manuscript.

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