https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Tübingen Innere Medizin III, Kardiologie und Kreislauferkrankungen Tübingen, Deutschland; 2Helmholtz Zentrum Munich Research Unit Analytical Pathology Neuherberg, Deutschland; 3Universitätsklinikum Tübingen Kardiopathologie Tübingen, Deutschland; 4Ostalb-Klinikum Aalen Innere Medizin II, Kardiologie und Angiologie Aalen, Deutschland
Aims: Arrhythmia-induced tachycardiomyopathy (TCM) is commonly encountered in clinical practice. However, diagnostic and prognostic parameters for clinical outcome are largely unknown. In this prospective study we investigated whether the previously described rearrangement of mitochondria in cardiomyocytes (EMID-sign) prospectively predicts outcome and whether it is associated with altered myocardial metabolism.
Methods and Results: In the EMPATHY study (ClinicalTrials.gov: #NCT03418467) 51 patients with newly diagnosed HFrEF due to suspected TCM and planned rhythm control strategy and endomyocardial biopsy were enrolled after valvular or ischemic heart disease had been ruled out. The main outcome was defined as recovery of left ventricular ejection fraction (LVEF). LVEF changed from 32.1% (±9.5) to 44.6% (±9.1) at follow-up.
Analysis of mitochondrial distribution in cardiomyocytes showed, as previously described, an enrichment of mitochondria at the intercalated discs (EMID-sign) in 50% of endomyocardial biopsies and the intensity of the EMID-sign was found to be predictive for LVEF recovery (p<0.05). Using MALDI-FT-ICR imaging as well as spatial Raman spectrometry we were able to identify distinct metabolic changes in the cardiomyocytes. EMID-sign intensity was correlated to glucose-6-phosphate levels as well as phosphopantothenate, the latter being the most prominent regulator of Acetyl-CoA synthesis (p<0.05, respectively). Using high-resolution Raman spectroscopy revealed gradient-like patterns for glucose, pyruvate, and lactate mimicking the intensity of mitochondrial distribution that results in the EMID-sign (p<0.05, respectively). Depending on the presence of the EMID-sign we observed changes in cytochrome distribution and oxidation states, which are critical for ATP regeneration in mitochondria.
Conclusion: With this prospective observational study we provide novel insight into the pathophysiological mechanisms that drive heart failure in patients with TCM. As cutting-edge analysis methods allow us to associate the EMID-sign with numerous metabolic changes in the myocardium we provide unprecedented insight into this poorly understood pathophysiology of heart failure.