Myocarditis, or inflammation of the heart muscle, is relatively rare, with one or two cases per 100,000 children each year. Yet it is one of the most common causes of cardiac insufficiency and heart failure in children. The inflammation may be caused by a viral infection and mostly affects young children under the age of two and adolescents over the age of 13. "The latter age group are usually admitted to A&E with heart arrhythmia or cardiac pain that feels like angina pectoris. They exhibit typical ECG changes. In infants, the symptoms are less specific. They feel unwell, they're lethargic and they refuse to drink," says Professor Sabine Klaassen, last author of the study and head of the Clinical Cardiogenetics research team at the Experimental and Clinical Research Center (ECRC ), a joint facility of the Max Delbrück Center for Molecular Medicine (MDC) and the Charité – Universitätsmedizin Berlin.
But while bed rest, avoidance of exertion and the administration of immunoglobulins is enough for some children, others require medication to support the heart or even an artificial heart or heart transplant at short notice. "The disease is usually most serious in the youngest age group. More than half of these young children also have dilated cardiomyopathy. This means that their heart function is restricted because the muscle of the left ventricle is enlarged," says Dr Franziska Seidel, first author of the study and an assistant doctor in paediatric cardiology at the Charité and the Clinic for Congenital Heart Defects – Pediatric Cardiology of the German Heart Center Berlin.
Genetic diagnostics could provide important information
Until recently, there was no reliable way of predicting what course the disease would take. The Berlin scientists want to address this issue with their work: To find out whether genetic factors affect individual prognosis, the two researchers, together with other colleagues from the German Heart Center Berlin and the Competence Network for Congenital Heart Defects, analyzed tissue and blood samples from 42 children with myocarditis. The study involved 20 children with dilated cardiomyopathy and 22 children without. All were diagnosed with myocarditis by means of a heart muscle biopsy. ECRC researcher Dr Jirko Kühnisch sequenced the DNA extracted from the patients' blood and performed a bioinformatic analysis of the data obtained.
As the team has now reported in "Circulation: Genomic and Precision Medicine", a cluster of rare, disease-causing gene variants was detected in patients with myocarditis and dilated cardiomyopathy. These genetic defects mostly occurred in young children with serious disease progression. "We found variants in disease-causing genes for dilated cardiomyopathy. These genes code for components of the contractile units of the heart muscle cells, such as titin and cardiac troponin I. But we also found genetic defects in genes with other cell functions, such as desmoplakin and BAG3," says Kühnisch, last author of the study along with Sabine Klaassen. The gene variants follow Mendelian inheritance and were assessed as disease-causing in accordance with bioinformatic criteria, which is why the researchers refer to them as 'pathogenic'.
"Our findings indicate that children who have dilated cardiomyopathy in addition to myocarditis have a higher risk of developing and even dying of long-term cardiac insufficiency. So in future, genetic analysis should be part of the diagnostic process, especially in younger children. This will make it possible to tailor medication-based treatment to the individual patient at an early stage and use a heart assist system like the Berlin HeartÓ," says Klaassen. Genetic diagnostics could also provide important information to support a successful transition away from an artificial heart.
The next step: gathering more data
"At 42, the number of patients involved in this pilot study in Berlin was relatively small due to the fact that heart muscle biopsies are difficult to perform on children. But we can already see that the differences are very clear, both between the age groups, young children and adolescents, and the different forms of the disease – dilated and non-dilated," Klaassen adds. She was surprised by this, particularly as there is little genetic data on myocarditis in adults.
To gather more data, the researchers now intend to expand their work across Germany with the help of the Register for Children and Adolescents with Suspected Myocarditis – MYKKE, established at the German Heart Center Berlin in 2013. "With over 550 patients, it's now the largest register for paediatric myocarditis in the world," says Franziska Seidel, a doctor involved in the MYKKE project – together with Dr. Daniel Messroghli of the German Heart Center Berlin and Professor Stephan Schubert of the Heart and Diabetes Center North Rhine-Westphalia.
Text: Catarina Pietschmann
- Mykke: (German only)
Franziska Seidel et al. (2021): „Pathogenic Variants Associated with Dilated Cardiomyopathy Predict Outcome in Pediatric Myocarditis“. Circulation: Genomic and Precision Medicine, DOI: