Scientists from Heidelberg University Hospital (UKHD) and the German Centre for Cardiovascular Research (DZHK) have investigated the damaging effects of stress hormones on the heart and the underlying mechanisms in an animal model of broken heart syndrome ─ the medical term is Takotsubo syndrome (TTS). They identified a signaling pathway that promotes inflammation in the heart. Two immunosuppressive drugs that inhibit this pathway showed a protective effect on the hearts of mice in experiments. A DZHK-funded phase II clinical trial has been approved to test the use of one of these drugs in the treatment of TTS patients.
TTS, also known as broken-heart syndrome, is a medical phenomenon and an unmet medical need that can occur upon intense emotional stress, such as grief or trauma. It causes symptoms similar to a heart attack, but cannot be treated like one because the coronary arteries are not closed. Traditionally, TTS has been regarded as a benign disease due to recovery of cardiac function. However, recent studies show impaired short- and long-term outcome comparable to myocardial infarction. In survivors, subclinical organ dysfunction persists for reasons that are not well understood yet. The disease is most common in postmenopausal women. "However, men often have a more severe course than women," says Dr. Bastian Bruns, first author of the paper. Current treatment is supportive, as there are no evidence-based therapies available. "We have now developed a model that reflects the complexity of human TTS and allows us to explore the molecular basis and test treatment approaches," reports Professor Johannes Backs, head of the Institute of Experimental Cardiology at the UKHD, spokesperson for the Collaborative Research Centre 1550 "Molecular Circuits of Heart Disease" and the DZHK Heidelberg/Mannheim partner site.
In experiments, the scientists studied the effect of different doses of stress hormones on cardiac function. A high dose of the stress hormone epinephrine led to heart failure in the mice within 30 minutes and an increase in the biomarker troponin, which indicates damage to the heart muscle. Remarkably, the same dose caused less heart damage in female mice than in male mice.
Molecular analyses showed that stress hormones stimulate inflammatory pathways. In particular, the calcineurin-dependent signaling cascade is activated, which adversely affects cardiac function. Two drugs already on the market can inhibit this specific pathway. In a series of experiments, the research team showed that these two immunosuppressants protected the hearts from damage, even when the animals were exposed to stress hormones.
Since the signaling pathway is also present in human heart muscle cells, a clinical trial funded by the DZHK will now test whether cyclosporin A, which is used after organ transplantation, is suitable for the treatment of TTS. The study will be led by Dr. Bastian Bruns and the Director of the Department of Cardiology at the UKHD, Professor Norbert Frey. "This shows how excellent experimental work at the DZHK can lead to important clinical studies when basic science is closely linked to clinical questions," says Professor Johannes Backs.
Original publication: Bruns, B., Antoniou, M., Baier, I. et al. Calcineurin signaling promotes takotsubo syndrome. Nat Cardiovasc Res 2, 645–655 (2023). https://doi.org/10.1038/s44161-023-00296-w
Scientific contact: Prof. Dr. med. Johannes Backs (johannes.backs(at)med.uni-heidelberg.de), Head of the Institute for Experimental Cardiology, University of Heidelberg