Tachycardiomyopathy is associated with metabolic changes that predict LVEF recovery - results from the EMPATHY study

Abstract Aims Tachycardiomyopathy (TCM) is common in clinical practice. To date, diagnostic and prognostic parameters for clinical outcome are, however, still 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 54 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 primary outcome was defined as the recovery of left ventricular ejection fraction (LVEF). LVEF improved from 32.1% (±9.5) to 44.6% (±9.1) at follow-up. Mitochondrial distribution in cardiomyocytes confirmed the previously described pattern of enrichment of mitochondria at the intercalated discs (EMID-sign) in 50% of endomyocardial biopsies. The intensity of the EMID-sign was predictive for LVEF recovery (p0.05). Using MALDI-FT-ICR imaging as well as spatial Raman spectrometry were were able to correlate distinct metabolic changes in the cardiomyocytes to mitochondrial redistribution and LVEF recovery. 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 (p0.05, respectively). High-resolution Raman spectroscopy revealed gradient-like patterns for glucose, pyruvate, and lactate paralleling the mitochondrial redistribution within the cardiomyocytes (p0.05, respectively). EMID-sign-positive cells showed changes in cytochrome distribution and their oxidation states, which are critical for ATP regeneration in mitochondria. Conclusion This prospective observational study offers novel metabolic insight into the mechanisms that drive heart failure and predict outcome in patients with TCM. Leveraging cutting-edge analysis methods allowed us to associate the EMID-sign with numerous metabolic changes and investigating spatial alterations within cardiomyocytes that provide unprecedented insight into this poorly understood pathophysiology of heart failure.