Myocarditis is an inflammatory disease of the myocardium with infectious or noninfectious causes and variable presentation depending on the extent of cardiac involvement. , In some patients, the disease recurs, leading to multiple inflammatory episodes (i.e., recurrent myocarditis). Previous studies suggest that myocarditis may represent an active “hot phase” of an underlying genetic cardiomyopathy. In particular, pathogenic variants in the desmoplakin gene ( DSP ) have been implicated in recurrent myocardial inflammation, arrhythmic sudden cardiac death (SCD), and heart failure.
The 2025 European Society of Cardiology (ESC) guidelines for the management of myocarditis and pericarditis and the 2024 American College of Cardiology (ACC) Expert Consensus Decision Pathway on Strategies and Criteria for the Diagnosis and Management of Myocarditis recommend genetic testing in recurrent myocarditis, but these statements rely primarily on expert opinion and case reports. We aimed to determine the prevalence of pathogenic or likely pathogenic (P/LP) variants in patients with recurrent myocarditis.
From January 2021 to August 2025, 87 patients (mean age 25 ± 5 years; range 12–45 years; 71% male) were admitted with myocarditis (clinically suspected or biopsy-proven). Eleven patients (12.6%; mean age 21 ± 10 years; 73% male) had recurrent myocarditis (≥2 episodes) and underwent genetic testing using a next-generation sequencing panel of 202 cardiomyopathy-associated genes ( Figure 1 ).
Clinical, genetic, and imaging characteristics of patients with recurrent myocarditis: A) Clinical characteristics of the study cohort; B) Main features of patients with recurrent myocarditis and DSP variants. Abbreviations: CMR = cardiac magnetic resonance, HT, heart transplantation, ICD = implantable cardioverter defibrillator, P/LP = pathologic/likely pathologic, SCD = sudden cardiac death.
Three patients (27%) carried a P/LP DSP variant (Patient 3: c.8471_8483del, p.Gly2824Alafs*55; Patient 7: c.1112A> G , p.His371Arg; Patient 11: c.5428C> T , p.Gln1810Ter). The remaining 8 patients carried no P/LP variant or only variants of uncertain significance. All the 3 DSP -positive patients had family history of SCD and myocarditis: Patient 3 had multiple relatives with myocarditis; Patient 7 had a first-degree relative who died suddenly; and Patient 11 had a first-degree relative with myocarditis. Among DSP -negative patients only one had a family history of myocarditis and one of heart transplantation.
Clinical presentation was uniform across the cohort, with chest pain, elevated troponin and ECG changes. Cardiac magnetic resonance (CMR) confirmed the diagnosis and was used for follow-up evaluations. A ring-like late gadolinium enhancement pattern was observed in 5 patients, including all 3 with DSP variants. Due to the small numbers, no genotype-phenotype comparison was performed. In our series, DSP -positive status prompted implantable-cardioverter defibrillator (ICD) implantation according with the 2023 ESC guidelines on the management of cardiomyopathy, while no genotype-negative patient underwent ICD implantation.
In this cohort, approximately 27% of patients with recurrent myocarditis carried a pathogenic or likely pathogenic DSP variant, all of them with family history for SCD and myocarditis and ring-like LGE pattern at CMR, underscoring the potential role of genetic testing in this setting. Our findings support the concept that recurrent myocarditis may unmask an underlying DSP -related cardiomyopathy, which is characterized by a high risk of SCD and heart failure related outcome. Pathogenic DSP variants are a well-established cause of cardiomyopathy, with clinical indicators including left ventricular systolic dysfunction, fibrosis, and ventricular arrhythmias. Episodes of clinically apparent myocardial injury are common among DSP carriers, and myocardial injury and fibrosis often precede overt LV systolic dysfunction. Consistent with this, our DSP -positive patients exhibited recurrent inflammatory injury with CMR evidence of fibrosis, while systolic dysfunction was not uniformly present. Life-threatening ventricular arrhythmias may occur even in the absence of significant LV dysfunction, and the incidence of arrhythmic events appears relatively constant across left ventricular ejection fraction. These observations reinforce the need for early recognition of DSP carriers. In our series, ICD implantation was performed in all DSP -positive patients based on genetic status and clinical features (including the extent of fibrosis).
Taken together, these data highlight the complex interplay between myocardial inflammation, genetic predisposition, and arrhythmic risk in DSP cardiomyopathy. Recurrent myocarditis may represent both a clinical manifestation of the disease and a trigger for accelerated injury and fibrosis. Clinicians should therefore maintain a high index of suspicion for underlying DSP variants in young patients presenting with recurrent myocarditis, especially in the presence of a positive family history or a ring-like LGE pattern on CMR. Genetic testing in this context not only facilitates diagnosis but also directly informs management, including prophylactic ICD implantation for arrhythmic prevention and family screening.
Larger multicentre studies are required to validate these findings.
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