Myocarditis has garnered significant attention in recent years due to its association with SARS-CoV-2 infection and, in rare instances, mRNA-based COVID-19 vaccination. While the association between SARS-CoV-2 and myocarditis has been clinically observed, the precise cellular and molecular mechanisms have remained unclear. 
A groundbreaking study published in Nature Cardiovascular Research by Maatz et al. sheds new light on these mechanisms, offering a detailed comparison of myocarditis subtypes and their distinct inflammatory pathways.

This collaborative effort, led by Prof. Carsten Tschöpe (Clinical and translational research, Charité, Berlin) and Prof. Norbert Hübner ( Basic science, MDC, Berlin), leverages single-nucleus RNA sequencing (snRNA-seq) to analyze left ventricular endomyocardial biopsies from patients with myocarditis. The study focuses on three distinct groups: Non-COVID-19 myocarditis (unrelated to COVID-19), Post-COVID-19 myocarditis (following SARS-CoV-2 infection), and Post-Vaccination myocarditis (after mRNA-based COVID-19 vaccination). 

The authors employ single-nucleus RNA sequencing (snRNA-seq) on left ventricular endomyocardial biopsies from affected patients. This high-resolution approach allows for a detailed comparison of the inflammatory and structural changes in Non-COVID-19, Post-COVID-19, and Post-Vaccination myocarditis.
By examining these groups, the authors uncover distinct immune activation pathways elucidating the mechanistic diversity of myocarditis subtypes. 

Post-COVID-19 myocarditis is marked by an expansion of cytotoxic CD8+ T cells and natural killer (NK) cells, alongside an upregulation of interferon-γ (IFNG) signaling. This pattern reflects a strong antiviral immune response, consistent with the body’s attempt to combat SARS-CoV-2. In contrast, post-vaccination myocarditis exhibits a predominance of CD4+ T cells and is distinguished by increased expression of IL16 and IL18. These findings suggest inflammasome activation and a more immunoregulatory cytokine environment, potentially linked to the immune response triggered by mRNA vaccines. Interestingly, while classic Non-COVID-19 myocarditis is also characterized by a lymphocytic infiltrate, it lacks these distinct cytokine and T cell signatures, highlighting unique inflammatory pathways triggered by SARS-CoV-2 infection and vaccination.

Despite these differences, all three myocarditis subtypes share common inflammatory features which contribute to persistent inflammatory signaling. A key shared characteristic is the activation of myeloid-derived immune responses, including macrophage infiltration and endothelial cell activation. Additionally, endothelial dysfunction emerges as a central feature, with vascular barrier disruption most pronounced in post-COVID-19 myocarditis, while angiogenesis-associated pathways, driven by increased VEGFA expression, are evident across all groups. Furthermore, fibroblast remodeling and altered TGF-β signaling suggest potential long-term implications for cardiac structure and function.

These shared features underscore the complexity of myocarditis and the need for targeted therapeutic strategies that address both the unique and common aspects of the disease.
By identifying these distinct immune and molecular signatures, this study enhances our mechanistic understanding of myocarditis and provides a foundation for future biomarker development and targeted therapeutic strategies. 
The study also emphasizes the need to differentiate between myocarditis subtypes, and the importance of personalized medicine. By unraveling the complex interplay of immune and molecular pathways, it paves the way for more effective, patient-specific treatments tailored to the specific underlying pathophysiology.
For instance, therapies targeting cytotoxic T cells or interferon-γ signaling may be effective in post-COVID-19 myocarditis, while interventions modulating inflammasome activation or IL16/IL18 pathways could benefit patients with post-vaccination myocarditis. 

As research into inflammatory cardiomyopathies progresses, these findings pave the way for more precise, personalized interventions aimed at mitigating cardiac inflammation while preserving heart function.