Atrial fibrillation is the most common form of persistent cardiac arrhythmia. According to the German Heart Foundation, around two million people in Germany are affected. The condition affects the electrical activity of the heart and can lead to irregular heartbeats, shortness of breath and, in the long term, serious complications such as heart failure or stroke. Until now, it was not fully understood why the heart muscle cells lose their rhythm in atrial fibrillation.
A research team at Göttingen University Medical Centre (UMG) led by Prof. Dr. Niels Voigt, Professor of Molecular Pharmacology at the Institute of Pharmacology and Toxicology at UMG, and the University Hospital of Würzburg (UKW) led by Prof. Dr. Christoph Maack, Head of the Department of Translational Research at the German Centre for Heart Failure (DZHI) at the UKW, has now found new evidence that impaired communication between central cell structures of the heart muscle contributes significantly to the development of arrhythmia.
The research focuses on mitochondria, the ‘powerhouses of the cell’, and the sarcoplasmic reticulum, a fine tubular system within the heart muscle cell that stores calcium and releases it with every heartbeat. This calcium causes the heart muscle to contract. The mitochondria use this calcium signal to generate energy, especially when the heart is under stress. Normally, the sarcoplasmic reticulum and the mitochondria are closely linked, but in patients with atrial fibrillation, this link appears to be disrupted. The team was able to show that mitochondrial calcium uptake is reduced in atrial fibrillation and that the regeneration of important energy carriers remains limited. High-resolution microscopy images also show that the spatial proximity between the sarcoplasmic reticulum and mitochondria is lost in diseased cells, causing the energy supply to the heart muscle to become unbalanced.
‘We suspect that the loss of calcium communication contributes to the electrical instability of the heart muscle and is therefore a key mechanism in arrhythmia,’ explain Prof. Voigt and Prof. Maack.
Cholesterol reducers support calcium absorption
In their investigations, the team analysed heart muscle samples from patients with and without atrial fibrillation. In addition to biochemical measurements, high-resolution imaging techniques such as electron tomography and STED nanoscopy were also used. Electron tomography allows cell structures to be visualised in three dimensions down to the nanometre level. Using this method, the researchers were able to precisely measure the spatial proximity between the mitochondria and the sarcoplasmic reticulum. STED nanoscopy (stimulated emission depletion microscopy) also made it possible to visualise the fine structure of the cells with a significantly higher resolution than conventional light microscopy. In this way, the scientists were able to show that mitochondria lose their orderly structure during atrial fibrillation and detach from the sarcoplasmic reticulum.
The working groups investigated whether the impaired function of the heart could be influenced – with surprising results: an already approved cholesterol-lowering drug was able to partially normalise calcium uptake by the mitochondria in heart muscle cells. An evaluation of patient data also showed that people who took this drug were less likely to suffer from atrial fibrillation.
‘Our findings open up new perspectives for the treatment of atrial fibrillation,’ says lead author Dr Julius Pronto, postdoctoral researcher at the Institute of Pharmacology and Toxicology at UMG. ‘If we succeed in stabilising the mitochondria in a targeted manner and improving their calcium uptake, this could reduce the risk of cardiac arrhythmia in the long term.’
Focus on calcium
In an earlier study conducted in collaboration with Würzburg University Hospital, the research group was able to show that calcium can also serve as a marker to better predict the risk of dangerous cardiac arrhythmias after heart surgery. The new study now goes one step further and sheds light on the fundamental cellular mechanisms that may underlie such disorders.
Research funding
The research project was financially supported by the German Centre for Cardiovascular Research (DZHK), the German Research Foundation (DFG) and the Göttingen Cluster of Excellence ‘Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells’ (MBExC).
Original publication: Julius Ryan D. Pronto, et al. Impaired Atrial Mitochondrial Calcium Handling in Patients With Atrial Fibrillation. Circulation Research (2025). DOI:https://doi.org/10.1161/CIRCRESAHA.124.325658
Source: Press release Universiy medical centre Göttingen
