After surviving a heart attack, the immune system quickly gets going. Dead cells are removed and the wound begins to heal. In some cases, however, an excessive immune reaction causes disproportionately large scarring, which can result in persistent heart failure. Researchers in Graz have now investigated how the healing process can be better estimated at an early stage – and in doing so have discovered new approaches for future diagnostic procedures.
A heart attack is a turning point in many people’s lives. Aside from lifestyle, which often requires fundamental rethinking, even with timely and good treatment, persistent heart failure can occur. The reason for this is extensive scarring of the heart muscle, which reduces the pumping power. The result: despite a mild emergency and the best of intentions, there may be little chance of feeling healthy and fit again in the long term.
Excessive inflammatory reactions of the immune system
However, it is difficult to predict whether heart failure will actually occur in an individual case. Excessive scarring is triggered by excessive inflammatory reactions of the immune system. Doctors lack both the diagnostic and therapeutic means to prevent these in time. Medical researchers have now provided a new approach in this area in the EU project “The role of the adaptive immune response after myocardial infarction”, which was funded in Austria by the Austrian Science Fund FWF.
Peter Rainer and his team from the University Heart Center at the Medical University of Graz, together with colleagues from the University Hospital in Würzburg and the Sorbonne Université in Paris, investigated the complex immunological processes that are involved in the “wound healing” of the heart and are ultimately responsible for scarring. “An important starting point for our research is the realization that the adaptive immune system – that is, the system acquired over the course of life – which is different in each person, plays a key role in the healing process,” emphasizes Rainer. “That is why our goal was to find biomarkers or patterns in the individual immunological processes that provide information about the expected course of the disease.”
The project “The role of the adaptive immune response after myocardial infarction” was carried out within the framework of the European Research Network ERA-CVD and co-financed by the Austrian Science Fund FWF with 300,000 euros.
Complex immune dynamics
A heart attack is most often caused by a clot, triggered by an injury to the vessel walls due to arteriosclerosis – i.e. the “calcification” of the blood vessels. This cuts off the blood and oxygen supply to the heart. Chest pain and shortness of breath occur, and after a few minutes heart cells die. In the worst case, the heart attack is followed by cardiac arrest. At the same time, the death of the cells also triggers a reaction from the body’s own immune system. Tissue regeneration, which takes weeks after the emergency has been overcome, is extremely dynamic. “The processes at the beginning are completely different from those in a later stage,” explains Rainer. “The combination of immune and messenger substances involved changes in each phase. A better understanding of these processes is needed for effective treatment.”
Right at the beginning of the immune reaction, T lymphocytes – they are part of the acquired immune system – come into play. They play an important role in regulating the inflammatory reaction, which is why they were particularly interesting for the studies by Rainer and colleagues. They were analyzed using single-cell sequencing, among other things. In this method, the genetic material examined does not come from a large number of cell nuclei, but can be specifically extracted from an individual cell. “We were able to really break down the work of the immune system into the function of the individual cell – and thus of the proteins that the DNA produces in it,” emphasizes Rainer. What was particularly interesting here was which proteins and antigens are recognized by the receptors on the T cells.
Investigations on human tissue
Further access to the immunological processes was provided by the analysis of human tissue forms that were available as part of the project. This includes not only blood, but also samples of the heart muscles of diseased people. “Thanks to access to these materials, we were able to verify findings from immunological research using animal models for humans,” the doctor emphasizes.
Single-cell sequencing and other methods ultimately helped to understand the different healing processes in a small group of selected and very well-characterized test subjects. All participants had just had their first “major” heart attack and, according to current knowledge, had very similar healing requirements. Nevertheless, the tissue scarred better in some than in others.
Notes on the healing process
In the analysis of the immunological processes involved, a relevant signature was actually found that allows these differences in recovery to be identified at an early stage, explains Rainer. “Our data showed a different immunological footprint in patients with good healing than in those with severe scarring,” emphasizes the researcher. “However, these results would now have to be confirmed in a more extensive study with a larger and more diverse group of heart attack patients.” A detailed understanding of the mechanisms behind the signature found and the associated sequelae also remains the subject of future research. Ultimately, however, the approach offers the prospect of a new diagnostic marker that could make timely interventions possible.
Rainer and colleagues are also approaching the problem with new research approaches. On the one hand, a new project supported by the FWF is using artificial intelligence to search through large amounts of patient data – from laboratory findings to X-ray images – in order to identify connections with later heart attacks and to derive risk assessments and preventive recommendations. On the other hand, researchers in the flagship project “VascHealth” at the Medical University of Graz are investigating a kind of feedback effect that a heart attack brings with it. This is because inflammation levels in the body often rise suddenly, thereby accelerating arteriosclerosis – the beginning of a vicious circle that makes further heart attacks more likely. The complex interplay between cardiovascular diseases and the immune system still holds many unanswered questions.
To person
Peter P. Rainer studied medicine in Graz and Florence before becoming a postdoc fellow at Johns Hopkins University in Baltimore, USA. From 2018, he worked as an associate professor at the Medical University of Graz and as senior physician and head of the cardiology outpatient clinics and the heart failure program at the University Heart Center Graz. Rainer is now head of the internal medicine department at the St. Johann District Hospital in Tirol.
Publications
Delgobo M., Weiß E., Ashour D., Richter L. et al.: Myocardial Milieu Favors Local Differentiation of Regulatory T Cellsin: Circulation Research 2023
Sattler S., Ramos GC, Ludewig B., Rainer P: Cardioimmunology: the new frontier!in: European Heart Journal 2023
Le Gouge K., Ashour D., Heinrichs M., Stys P. et al.: A distinct T cell receptor signature associates with cardiac outcome in myocardial infarction patientsin: medRxiv 2023 (pre-print)
Austrian Science Fund FWF Ingrid Ladner, scilog editorial team Phone: +43 676 83487 8117 Email: [email protected] Website:
