Aims: Arrhythmia-induced tachycardiomyopathy (TCM) is commonly suspected in patients presenting with impaired left ventricular ejection fraction (LVEF) and tachycardia. However, the mechanisms that result in progressive heart failure are largely unknown and diagnostic and prognostic parameters for clinical outcome are not well established. As tachycardia is associated with increased energy demand we prospectively investigated the impact of metabolic changes and enrichment of mitochondria at the intercalated discs (EMID-sign) on outcome in patients with suspected TCM.
Methods and Results: In this prospective, observational study (ClinicalTrials.gov: #NCT03418467) 51 patients with newly onset HFrEF due to suspected TCM were enrolled. Valvular as well as ischemic heart disease were ruled out prior to recruitment. A rhythm control strategy and endomyocardial biopsy were planned in all patients. The primary outcome was defined as recovery of left ventricular ejection fraction (LVEF). LVEF at baseline was 32% (±9.5) recovering to 46% (±8.7) at follow-up.
Analysis of endomyocardial biopsy specimen (EMB) confirmed the previously described EMID-sign in 50% of endomyocardial biopsies. The EMID-sign intensity was found to be predictive for LVEF recovery (p<0.05). With high mass-resolution matrix assisted laser desorption ionisation-imaging (MALDI-FT-ICR-MS) as well as spatial Raman spectrometry metabolic changes within the cardiomyocyte were assessed. EMID-sign intensity correlated with glucose-6-phosphate and phosphopantothenate levels, with the latter being regarded as the pivotal regulator of acetyl-CoA synthesis (p<0.05, respectively). Following the altered mitochondrial distribution, we observed a gradient-like distribution of cytochrome levels and differences in their oxidation states. The glucose, pyruvate, and lactate distribution within cardiomyocytes paralleled the EMID-sign (p<0.05, respectively), which could explain reduced contractility due to a lack of ATP regeneration.
Conclusion: By leveraging cutting-edge analysis methods to probe metabolic changes within cardiomyocytes of patients with suspected TCM we provide deep insights into spatial metabolic alterations in this poorly understood pathophysiology of heart failure.
