https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 2Kath. Klinikum Bochum Cellular Physiology Bochum, Deutschland; 3Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland
Introduction
The exact mechanisms of Takotsubo syndrome (TTS) are so far unclear. The role of lactate in cardiovascular disease is gradually being recognized. This study is designed to explore roles and mechanisms of lactate in pathogenesis of TTS.
Method
Human induced pluripotent stem cell derived cardiomyocytes(hiPSC-CMs) generated from one healthy donor and one TTS-patient were used as a study platform. 100uM epinephrine (Epi) was applied to hiPSC-CMs to mimic the TTS setting. The qPCR, western blot, ELISA, immunostaining and patch clamp, metabolomics analysis, transcriptomics analysis and Mitochondrial Oxygen Consumption Rate Detection were performed.
Results
Epi-treatment increased lactate levels in both healthy (control) and TTS-hiPSC-CMs, detected by ELISA. WB and immunofluorescence further confirmed that the Epi elevated the level of histone (H3K18LA) lactylation through the NF-KB pathway. By using lactate dehydrogenase inhibitor(10uM), a significant reduction in ROS levels was found. In the Epi and TTS groups, significant prolongation of action potentials and increased arrhythmic events were found, which were significantly alleviated by lactate dehydrogenase inhibitors. Transcriptome results showed that ASIC1a (an acid-sensitive ion channel type1a) gene was significantly increased in the Epi treated cells. WB and qPCR further verified the result. By measuring intracellular PH value and ASIC current, it was found that lactate activated ASIC current through reducing PH value.
Conclusion
Lactate plays important roles for arrhythmogenesis of TTS via affecting ASIC1a channel. Lactate blockers might be clinically helpful for treating arrhythmias in patients with TTS.