A potential new drug for stiff hearts 

Michael Gotthardt at the Max Delbrück Center and collaborators are developing a drug to treat a common type of heart failure characterized by impaired cardiac filling. In “Cardiovascular Research,” his group and a US team showed the therapy improves cardiac function in a mouse model of the disease. 

As we age, our muscles tend to stiffen, including one of the most vital muscles in our bodies: the heart. This is why older adults often suffer from a specific type of heart failure whereby the organ continues to pump blood, but becomes too stiff to relax and to fully fill between beats. 

“There’s currently no effective medication that lowers mortality in this form of heart failure – heart failure with preserved ejection fraction, or HFpEF,” says Professor Michael Gotthardt, Group Leader of the Translational Cardiology and Functional Genomics lab at the Max Delbrück Center in Berlin. For more than a decade, Gotthardt’s research has focused on uncovering the molecular mechanisms of HFpEF and developing therapeutic strategies to counteract them. 

In the journal “Cardiovascular Research,” he and a team led by Professor Henk Granzier from the College of Medicine, Tucson at the University of Arizona – a longtime collaborator – report that a drug they developed, called RBM20-ASO, improves heart muscle elasticity and cardiac filling in a mouse model that better reproduces the multifactorial pathology of human HFpEF than any previously established model. “After treatment with RBM20-ASO, the mice’s hearts were markedly more compliant and capable of expanding and filling with blood after contracting,” Gotthardt explains. 

Elastic forms of the protein titin  

“Most people with HFpEF have comorbid conditions such as obesity, high blood pressure, elevated blood lipids or high blood sugar,” says Dr. Mei Methawasin, first author of the study who now leads her own group at the University of Missouri at Columbia. “For the first time, we tested the drug in mice that not only developed HFpEF, but also had these comorbidities – to better simulate the human disease.” 

The drug is an antisense oligonucleotide (ASO) – a short, single-stranded nucleic acid molecule designed to reduce the amount, and therefore the activity, of the splicing regulator RBM20. This factor plays a critical role in determining whether heart muscle cells produce a more elastic or stiffer version of the giant protein titin, which functions as a molecular spring in cardiac muscle. Gotthardt and colleagues had previously demonstrated that RBM20-ASO prompts heart cells to express more of the elastic titin variant – similar to what’s seen in very young hearts – completely reversing HFpEF-like symptoms in genetic animal models of the disease. 

High doses not required 

“The current study also aimed to determine the optimal dose of the drug to minimize side effects, including immune system disturbances,” says Methawasin. The team found that reducing RBM20 levels by about half was enough to improve the heart's diastolic function – its ability to fill with blood – without impairing its pumping strength, or systolic function.  

“Our treatment significantly reduced left ventricular stiffness and abnormal thickening of the heart muscle, even in the presence of persistent comorbidities,” adds Gotthardt. Moreover, side effects in treated animals were moderate. The researchers believe they can reduce these effects even further by increasing the dosing interval – an approach they plan to test in future studies. 

“Our results suggest that using ASOs to modulate RBM20 protein levels could be a viable alternative or complementary therapy for HFpEF – one capable of restoring diastolic function and limiting further organ damage, either as a standalone or adjunctive treatment” says Gotthardt. Supported by the Deutsches Zentrum für Herz-Kreislauf-Forschung and the German Research Foundation, he is planning to bring this treatment to HFpEF patients in collaboration with colleagues from the Deutsches Herzzentrum der Charité in Berlin. Before clinical translation, however, the therapeutic strategy will undergo further evaluation in a porcine model to validate its safety and efficacy. 

Further information 

Gotthardt lab 

Granzier Lab 

Resorting the elasticity of heart muscle 

How to fill a heart 

Max Delbrück Center  

The Max Delbrück Center for Molecular Medicine in the Helmholtz Association lays the foundation for the medicine of tomorrow through our discoveries of today. At locations in Berlin-Buch, Berlin-Mitte, Heidelberg, and Mannheim, interdisciplinary teams investigate the complexity of disease at the systems level – from molecules and cells to organs and entire organisms. Together with academic, clinical, and industry partners, and as part of global networks, we turn biological insights into innovations for early detection, personalized therapies, and disease prevention. Founded in 1992, the Max Delbrück Center is home to a vibrant, international research community of around 1,800 people from over 70 countries. We are 90 percent funded by the German federal government and 10 percent by the state of Berlin.