Non-targeted metabolomics identified a common metabolic signature of lethal ventricular tachyarrhythmia (LVTA) in two rat models

Abstract

Lethal ventricular tachyarrhythmia (LVTA) is the predominant underlying mechanism of sudden cardiac death (SCD). The aim of this study is to characterize the metabolic features of myocardia following LVTA, and identify potential biomarkers to diagnose LVTA. We developed two LVTA rat models induced by aconitine injection or coronary artery ligation, which represent cardiac ion channel disease-related and cardiac ischemia-related SCD, respectively. The myocardial metabolic profile was investigated by gas chromatography-mass spectrometry and proton nuclear magnetic resonance-based metabolomics. Twenty-three aconitine-injected and 14 coronary artery ligation-treated rats developed LVTA SCD. A total of 38 differential metabolites of myocardia were identified in aconitine-induced LVTA rats, of which 31 metabolites showed a similar change in coronary artery ligation-related LVTA rats. Fatty acids (stearic, palmitic, linoleic, elaidic, and myristic) and branched-chain amino acids (valine, leucine, and isoleucine) were the most down-regulated metabolites. Furthermore, elevated ADP, phosphate, lactate, glutamate, aspartate, threonine, choline and arginine were also observed. Major pathways regarding these dysregulated metabolites post LVTA are energy excessive consumption and deficit, ionic imbalance, oxidative stress, cardiac cytotoxicity and membrane injury. Valine, stearic acid and leucine collectively enable a precision of 92.9% to distinguish LVTA from its control, and are correlated with several arrhythmia indices. Our results uncovered a common metabolic feature of LVTA in myocardia in two rat models, which represent cardiac ion channel disease and cardiac ischemia, respectively. L-Valine, L-leucine and stearic acid jointly confer good potential for distinguishing LVTA, which might be potential biomarkers of LVTA-related SCD.