Scientists at Heidelberg University Hospital, led by first author Maarten van den Hoogenhof, have described a key mechanism underlying a hereditary form of heart failure in Nature Cardiovascular Research. Their study shows that the condition is not driven solely by impaired gene processing in the heart. Rather, the overactivation of a signalling protein plays a central role. The work thus opens up the prospect, for the first time, of a cause-oriented therapy for patients with RBM20 cardiomyopathy and highlights the potential of genetically tailored treatment strategies in cardiology.
When gene splicing goes wrong
For cells to function, genes are first transcribed in a raw form. In a second step, known as splicing, this raw transcript is edited: unnecessary sections are removed, whilst others are rearranged. This creates the blueprint for a protein. This process takes place in almost all cells, but is regulated differently depending on the tissue.
In the heart, the RBM20 protein plays a key role in regulating splicing. If the gene responsible is altered, this finely tuned process becomes unbalanced. The result is a particularly severe form of dilated cardiomyopathy, which often occurs early in life and is associated with an increased risk of cardiac arrhythmias.
This form of heart failure is rare: only a small proportion of patients with heart failure are affected. Within the group of genetically caused dilated cardiomyopathies, RBM20 mutations account for only a few per cent – yet the course of the disease is often severe and affects many patients from a young age.
The key finding: an overactive signalling pathway
The new study now shows that the condition is not caused solely by altered splicing. Although the RBM20 defect influences the composition of various protein variants, including the important signalling protein CaMKIIδ, the crucial factor is that CaMKIIδ subsequently becomes overactive. This protein controls key processes in the heart muscle, particularly calcium homeostasis, and acts as an amplifier for cellular signals.
Using mouse models, the researchers were able to demonstrate that animals with an RBM20 defect develop severe heart failure. However, if CaMKIIδ is inactivated, heart function remains largely intact. When the protein is reactivated, the disease returns. The data thus confirm that the overactivity of CaMKIIδ is the key pathogenic step.
The exact molecular link between altered splicing and increased activity of the signalling protein has not yet been fully elucidated. What is clear, however, is that the overactivity of CaMKIIδ is the point at which the disease takes hold. The disrupted splicing sets the process in motion, but does not drive the disease on its own.
Therapeutic prospects
In further experiments, the team treated a mouse model carrying a human RBM20 mutation with a compound that inhibits CaMKII. Heart function improved significantly – even though the genetic defect remained unchanged.
The compound used is not an approved drug, but a research tool. However, it demonstrates that the principle works: if the excessive activity of CaMKIIδ is inhibited, the disease can be influenced.
The findings are also significant because CaMKII is already being targeted as a therapeutic target. More selective inhibitors are currently in clinical development, albeit for other heart conditions at present. This study now provides a clear rationale for specifically testing these approaches in patients with RBM20 mutations.
A potential path towards cause-oriented therapies
To date, genetic heart failure has mostly been treated with general standard therapies. The study points to a different approach: it links a clearly defined genetic cause to a treatable signalling pathway. The results thus also highlight the importance of genetic diagnostics in dilated cardiomyopathy. Only if the underlying mutation is known will patients be able to benefit specifically from such cause-oriented therapies in the future.
The results are still at the preclinical stage. Further research is needed before they can be applied in clinical practice. Nevertheless, this work opens up the prospect of being able to treat certain forms of heart failure in a cause-oriented manner in the future.
Original publication:
van den Hoogenhof MMG, Duran J, Britto-Borges T, et al. CAMK2D causes heart failure in mice with RBM20 cardiomyopathy. Nat Cardiovasc Res. 2026;5(5):479-491. doi:10.1038/s44161-026-00818-2
