MHH researcher aims to stop harmful effect of chemotherapy on heart muscle

Wants to stop heart injuries caused by chemotherapy and SARS-CoV-2 infections: Professor Dr. Dr. Thomas Thum.

EU funds research project to elucidate pathological cardiac remodeling caused by cancer drugs with around 2.5 million euros

Heart failure is one of the most common causes of death worldwide. The disease, known in medical terms as heart failure, affects around four million people in Germany. One of the main causes is remodeling processes in the heart muscle, which can be triggered for a variety of reasons - for example, by the side effects of chemotherapy or infection with the SARS-CoV-2 coronavirus. To date, there is no treatment option that can stop or even reverse the course of the disease. Professor Dr. Dr. Thomas Thum, head of the Institute for Molecular and Translational Therapeutic Strategies at Hannover Medical School (MHH), is now looking for such a strategy with his research project REVERSE. The European Research Council (ERC) has awarded him an ERC Advanced Grant, one of the most highly endowed prizes for absolute top-level research, and is supporting the project with 2.5 million euros over five years.

Circular RNA controls processes in body cells

In his project, the scientist focuses on so-called circular RNAs (circRNA). They belong to the group of non-coding RNAs (ncRNA), so they do not function as a blueprint for protein production and therefore do not transcribe genetic information. However, they are not “garbage” either, but regulate many processes within the cells. Professor Thum has been studying the functions of these RNAs in cells for a long time. “Within the family of non-coding RNAs, circRNAs are particularly stable and species-conserved, i.e. largely unchanged in the course of evolution,” the cardiologist explains. “This makes them ideal drug targets.”

Chemotherapy damages the heart

In the REVERSE project, Professor Thum and his research team will initially search for circRNAs that control the cardiac remodeling process. This side effect on the heart is caused, for example, by certain drugs used in cancer treatment. “Cardiotoxicity caused by chemotherapy often depends on the dosage of the drug,” the cardiologist points out. In this case, the heart muscle is attacked to such an extent that the heart can no longer pump at its full capacity. “There is a risk that after treatment the tumor is gone, but the heart is permanently damaged.” Too low a dosage, on the other hand, increases the risk that the tumor will not disappear completely. Many cancer patients are therefore closely monitored by ultrasound to determine whether there is any deterioration in heart function. But SARS-CoV-2 also attacks the heart muscle. “In up to ten percent of severely affected COVID-19 sufferers, new heart failure that was not present before the infection can occur within a year because the virus attacks and destroys heart muscle cells, among other things.”

Verification of circRNAs in “living heart slices”.

Identifying the circRNAs involved is like the famous search for a needle in a haystack. There are probably an estimated 20,000 to 30,000 different circRNAs in our cells, and only about ten are known to date about their mode of action. In a first step, an automated screening high-throughput procedure will be used to search a circRNA library for suitable candidates that could be involved in the cardiac damage caused by chemotherapy or by the SARS-CoV2 infection. The cardiologist then wants to verify whether the selected RNA structures actually control cardiac remodeling in each case. To do this, the research team uses the method of “living heart slices.” These are wafer-thin slices of damaged heart muscle tissue that has been removed during surgery. In nutrient solution, these heart muscle slices live and continue to beat for many days to weeks. “We first test the mode of action of our circRNA candidates in the living heart slices,” says the scientist. In a next step, the research team then wants to investigate how they can stop the two different forms of cardiotoxicity. In this way, the researchers hope to find new therapeutic approaches for both causes of cardiac injury, for which there is currently no specific treatment.