Not all myocarditis is the same

Heart muscle inflammation differs depending on the trigger - be it COVID-19, the mRNA vaccination against COVID-19 or other causes. These findings pave the way for more tailored therapies, report Berlin and Munich researchers together with international colleagues in "Nature Cardiovascular Research".

The immune signatures in heart muscle inflammation (myocarditis) differ depending on the cause. They vary depending on whether they were triggered by infections with SARS-CoV-2 and mRNA vaccines compared to myocarditis unrelated to COVID-19, according to a collaboration led by Dr. Henrike Maatz, a scientist in the "Genetics and Genomics of Cardiovascular Diseases" research group led by Professor Norbert Hübner at the Max Delbrück Center in Berlin. The study has been published in "Nature Cardiovascular Research".

"We found significant differences in immune activation," says Maatz, co-first author of the study. "This knowledge could help to develop new and more precise therapies that are tailored to specific types of inflammation."

The pandemic offered a unique opportunity

Myocarditis is caused by various infections, autoimmune diseases, genetic and environmental factors and, in rare cases, vaccinations. COVID-19 is primarily a respiratory disease, but it is known that infection with SARS-CoV-2 can also damage the heart. In rare cases, SARS-CoV-2 triggers a multisystemic inflammatory syndrome in children and young adults. Myocarditis is the most common clinical feature.

The pandemic offered researchers at the Max Delbrück Center, the Berlin Institute of Health at Charité (BIH) and Charité - Universitätsmedizin Berlin a unique opportunity to investigate whether heart muscle inflammation also differs from one another at the cellular and molecular level, depending on the cause.

Hübner's working group has been researching heart disease at the single-cell level for a long time. For the study, the scientists collaborated with Professor Carsten Tschöpe, cardiologist at Charité's German Heart Center (DHZC), head of the BIH Immunocardiology research group and researcher at the German Center for Cardiovascular Research (DZHK). His team had taken biopsies from patients with suspected myocarditis. "We have a renowned outpatient clinic for severe heart failure and cardiomyopathies at the DHZC. The doctors are specialized in performing endomyocardial biopsies in individual cases," says Tschöpe.

"The research program initiated by Charité during the COVID-19 crisis was integrated into the care plan and is part of the PERSONIFY program funded by the DZHK. Patients with myocarditis are examined very specifically and in a targeted manner in this program. This enables comprehensive and advanced approaches for clinical and scientific evaluation," says Tschöpe. "We are very grateful to the patients for their trust and their invaluable contribution. The same applies to the performance of our nursing staff specializing in heart failure. The nurses played a crucial role in identifying patients, carefully managing data, handling tissue and blood and, above all, caring for the patients."

Significant differences in immune activation

The researchers at the Max Delbrück Center used the heart tissue from the biopsies to sequence the RNA in the cell nuclei (snRNA-seq). This enabled them to analyze gene expression, create transcription profiles of each individual cell and use the profiles to identify the different cell types of the heart. They examined the molecular changes in each cell and the frequency of the different cell types in the heart muscle tissue of three different groups: samples that were COVID-19 positive, cases caused by mRNA vaccines, and non-COVID-induced myocarditis that could be traced back to viral infections before the pandemic.

The scientists found that some changes in gene expression were similar in all three groups. However, there were significant differences in the gene expression of the immune cells. In addition, the transcription profiles showed that the immune cells were present at different frequencies depending on the cause of the myocarditis.

"Such differences were surprising," says Dr. Eric Lindberg, co-first author of the study and former postdoc in Hübner's research team. He now heads his own working group at the LMU Clinic in Munich. For example, the researchers observed that CD4 T cells were more common after vaccination, while CD8 T cells tended to dominate after SARS-CoV-2 infection. In the samples of myocarditis without COVID, the ratio of CD4 to CD8 cells was around 50:50. The gene expression data also indicated that the CD8 T cells appeared more aggressive in the COVID-19 group than in myocarditis without COVID disease. The researchers also found a small population of T cells in post-COVID myocarditis that had previously only been observed in the blood of severely ill COVID-19 patients.

"Overall, these results indicate a stronger immune response in COVID-19 myocarditis compared to forms of myocarditis that we knew before the pandemic. In contrast, the inflammation of the heart muscle after vaccination appears to be less pronounced," says Professor Norbert Hübner from the Max Delbrück Center and Charité - Universitätsmedizin Berlin. He is also a researcher at the DZHK and corresponding author of the study. "The sample size for myocarditis after vaccination was small. But the results match those of other studies on myocarditis after vaccination."

Significance for the treatment

Being able to distinguish between inflammations caused by different infections and vaccinations paves the way for better treatment, explains Maatz. It would then be tailored to the respective inflammation. New therapies could also be developed based on this research, for example to control the side effects of vaccines.

Samples from heart biopsies are also usually tiny, often no bigger than the head of a pin. It was a challenge to make the snRNA-seq technique possible with such small amounts of tissue, recalls Maatz: "But the richness of detail and the depth of focus of the findings obtained show how powerful this method is - possibly also for diagnosis in the future."

Originalpublikation: Henrike Maatz, Eric L. Lindberg, et al. (2024): „The cellular and molecular cardiac tissue responses in human inflammatory cardiomyopathies following SARS-CoV-2 infection and COVID-19 vaccination.“ Nature Cardiovascular Research, DOI: 10.1038/s44161-025-00612-6