Natural history of recurrent myocarditis in the AMPHIBIA registry
M Proust, M Pineton de Chambrun, E Gandjbakhch, F Ader, J Proukhnitzky, P Charron, M Laredo, M Zeitouni, F Cohen-Aubart, G Gorochov, E Vicaut, M Schmidt, J Silvain, G Montalescot, M KerneisAbstract
Background
Recurrent acute myocarditis (AM) is increasingly recognized in the context of genetic predisposition, particularly in carriers of pathogenic variants in desmosomal and other cardiomyopathy-associated genes, yet genetics alone does not capture the full spectrum of its phenotypic and clinical heterogeneity (1, 2). This study sought to phenotype patients with multiple AM, describe the natural history of the disease and identify factors associated with these phenotypes.
Methods
This is an observational ambispective cohort study based on the AMPHIBIA registry, including patients hospitalized for proven AM between 2008 and 2024 at our Hospital. Clinical, biological, immunological, and imaging data were collected, with genetic panel testing and exome sequencing analyzed when available. Patients were classified into the group “recurrence of AM” if they presented at least one other episode of AM after a first episode. A multivariable logistic regression was used to identify variables associated with AM recurrence.
Results
A total of 591 patients with AM were included, of whom 78 (13%) experienced recurrent AM following the first episode, with up to five episodes. After the first episode, the probability of recurrence was 13%, increasing to 32% after the second episode. Severe episodes tended to recur at a similar level of severity, while uncomplicated cases relapsed in a milder form. Factors associated with recurrence included anti-RNA polymerase III positivity (3), young age, familial history of non-ischemic cardiomyopathy, sudden cardiac death or AM, and immunological disorder. In patients with recurrent AM undergoing exome sequencing, four distinct phenotypes emerged: idiopathic; linked to pathogenic variants in cardiomyopathy-associated genes; associated with immunologic disorders; and a combined phenotype with both immunologic disease and cardiomyopathy gene variants, underscoring the interplay between genetic predisposition and immune-mediated mechanisms.
Conclusion
These findings highlight the phenotypic heterogeneity of recurrent AM, identify risk factors at the intersection of infectious, immune, and genetic factors, and demonstrate that early recognition of high-risk profiles can guide individualized management and improve risk stratification.Graphical abstract