Impaired calcium buffering in heart muscle cells promotes the progression and perpetuation of atrial fibrillation. This was discovered by researchers from the Heart Center of the University Medical Center Göttingen (UMG) and the German Centre for Cardiovascular Research (DZHK). The findings offer potential starting points for new therapies. The results have been published in the renowned scientific journal ‘Circulation’.
According to the German Heart Foundation, around two million people in Germany suffer from atrial fibrillation, the most common form of cardiac arrhythmia. A Göttingen research team led by MBExC member Prof Dr Niels Voigt, Professor of Molecular Pharmacology at the Institute of Pharmacology and Toxicology at the University Medical Center Göttingen (UMG), has discovered new mechanisms that cause atrial fibrillation to become chronic. It is already known that the cause is a disturbed electrical excitation of the atria. Instead of contracting evenly, the atria begin to fibrillate at a high frequency. At the beginning of the disease, the arrhythmia often only occurs occasionally and can become permanent over time. A normal heart rhythm can only be restored through medical intervention. If this is not successful, the condition is referred to as permanent atrial fibrillation. As a result, it can happen that the blood is not pumped completely out of the heart and clots. This blood clot can in turn lead to a stroke. Anticoagulant medication is administered to prevent this. It is estimated that around 35,000 strokes in Germany are caused by atrial fibrillation every year.
The Göttingen researchers discovered that this cardiac arrhythmia leads to a breakdown of muscle proteins in the heart muscle cells of the atria over time. These proteins are important buffers for calcium ions. ‘Similar to a shock absorber in a car that compensates for bumps in the road, calcium buffers mitigate fluctuations in the calcium concentration in heart muscle cells, which also occur to a small extent in healthy cells. In atrial fibrillation, however, these shock absorbers do not function properly,’ explains Prof Voigt, who is also a member of the Göttingen Cluster of Excellence Multiscale Bioimaging: from molecular machines to networks of excitable cells (MBExC). ‘Even small fluctuations in calcium concentration can then build up into so-called calcium waves, which travel through the entire cell and generate an electrical impulse. This faulty electrical impulse helps to ensure that the irregular heartbeats in the atria persist.’
Possible treatment options with already authorised drugs
‘At the same time, we were able to identify possible treatment options for atrial fibrillation with the already approved drugs levosimendan and omecamtiv, which increase calcium binding to muscle proteins in the heart muscle cells, in order to replace the impaired calcium buffer in the heart muscle cells,’ adds first author Dr Funsho Fakuade, postdoctoral researcher in the Voigt working group and member of the Hertha-Sponer-College at MBExC. The results of the study have now been published in the current August issue of the renowned journal Circulation.
Original publication:
Impaired Intracellular Calcium Buffering Contributes to the Arrhythmogenic Substrate in Atrial Myocytes From Patients With Atrial Fibrillation. Fakuade et al., Circulation. Volume 150, Issue 7, 13 August 2024; Pages 544-559.
DOI: 10.1161/CIRCULATIONAHA.123.066577
About the study
For the study, which was conducted in collaboration with the UMG’s Department of Cardiothoracic and Vascular Surgery, the researchers analysed tissue that was produced during heart surgery. They isolated the heart muscle cells, also known as myocytes, from the tissue and used special microscopes to measure the calcium waves within the cells. They also used artificial atrial cells produced from induced stem cells to investigate the role of muscle proteins in calcium buffering. For this purpose, the muscle protein troponin C was specifically switched off in the cells using genetic methods in order to investigate the effects on calcium buffering. Troponin C plays an important role in the contraction of the heart muscle. If it is missing, no calcium is bound and the heart muscle cannot contract. The researchers found that these modified cells not only exhibited a similarly defective calcium buffering as the cells of patients with atrial fibrillation, but also showed increased calcium waves, which contribute to the development of atrial fibrillation.
‘The data we have obtained indicate that new strategies that specifically target intracellular calcium buffering could offer promising therapeutic approaches for the prevention and treatment of atrial fibrillation,’ explains Prof Voigt. ‘The research results thus open up new perspectives for the treatment of atrial fibrillation and could improve the course of the disease in patients with cardiac arrhythmia.’
Contact:
University Medical Centre Göttingen, Georg-August-University,
Institute of Pharmacology and Toxicology
Prof Dr Niels Voigt
Robert-Koch-Straße 40, 37075 Göttingen
phone 0551 / 39-65174
niels.voigt[at]med.uni-goettingen.de
www.molecular-pharmacology.de
