Researchers at the German Centre for Cardiovascular Research (DZHK) within the Stem Cell Unit at Göttingen University Hospital (UMG) have identified a key mechanism that contributes to the development of severe cardiac abnormalities in the inherited condition known as Noonan syndrome. The findings have now been published in a recent study in the journal "Circulation".
Noonan syndrome is a genetic condition which, according to the US National Institutes of Health, occurs at a rate of approximately one in every 1,000 to 2,500 births. Many people affected develop what is known as hypertrophic cardiomyopathy. This involves thickening of the heart muscle, which can impair the heart’s pumping function. There is an increased risk of heart failure, particularly when the condition develops at an early age. Treatment options are currently limited and are mainly symptomatic.
Noonan syndrome is caused by genetic changes in the RAS-MAPK signalling pathway. This pathway regulates fundamental processes such as cell growth and cell division. However, it has not yet been fully understood how these changes lead to the characteristic structural changes in the heart.
A research team in Göttingen led by Dr Lukas Cyganek, Head of the Stem Cell Unit at the Department of Cardiology and Pulmonology at Göttingen University Hospital (UMG), has demonstrated that connective tissue cells in the heart – known as cardiac fibroblasts – play a key role in causing disease. In people with the condition, these cells produce increased levels of the signalling molecule interleukin-8, which regulates communication between cells and is normally only activated during inflammatory processes. By specifically blocking this signalling pathway, it has now been possible to significantly reduce the damage to heart tissue in human stem cell models. The findings were published in the journal "Circulation".
In the models investigated, interleukin-8 acts directly within the heart tissue and independently of the immune system. It mediates a dysregulated interaction between connective tissue cells and cardiac muscle cells. As a result, there is an increased formation of connective tissue, known as fibrosis, which contributes to the stiffening of the heart tissue, as well as an enlargement of the cardiac muscle cells, referred to as hypertrophy. Both processes play a major role in the deterioration of cardiac function.
For their investigations, the researchers used so-called induced pluripotent stem cells. These are derived from patients’ body cells and reprogrammed in the laboratory so that they can develop into different types of heart cells. This approach makes it possible to recreate the disease realistically in the laboratory – both in simple cell cultures and in three-dimensional tissue models resembling human heart tissue.
“One of the key findings of the study is that the pathological process can be specifically halted. By inhibiting a specific binding site of interleukin-8 using the drug Reparixin, both the connective tissue changes in the heart and the pathological enlargement of cardiac muscle cells were significantly reduced,” says Dr Cyganek. Functional properties of the heart tissue also normalised in the models.
The findings demonstrate that interleukin-8-mediated signalling is a central driver of the disease. At the same time, they open up the prospect of a new therapeutic approach that specifically targets this mechanism.
“As corresponding compounds have already been investigated in other clinical contexts, translation into early clinical trials for initial studies in patients with Noonan syndrome could take place comparatively quickly,” says Dr Cyganek.
Source: Press release University Medical Center Göttingen
Original publication: Fell J, Pavez-Giani M, Koitka F et al. Targeting Interleukin-8 mediated cellular crosstalk reverses hypertrophic cardiomyopathy and cardiac fibrosis in Noonan syndrome. Circulation (2026). DOI: 10.1161/CIRCULATIONAHA.125.074155
