A circulating extracellular vesicle-bound fraction of cardiac troponin discriminates myocardial homeostasis and disease states

Abstract Background Various cardiovascular diseases are associated with transient troponin elevation, warranting further potentially invasive diagnostic measures to rule out myocardial ischemia. The origin of circulating cardiac troponins in the absence of overt myocardial necrosis remains unclear. Extracellular vesicles (EV) secreted by cardiomyocytes were found to contain cardiac troponins of unknown significance to date. Objectives We aim to investigate the presence of distinct distribution patterns of cardiac troponins in circulating EV and free plasma. Methods H9c2 cardiomyocytes exposed to hypoxia were investigated for troponin disintegration and vesicular troponin secretion. In a murine model of myocardial infarction and porcine model of atrial fibrillation, EV secretion into blood and EV-bound troponin fraction were studied. In two patient cohorts encompassing patients with myocardial infarction, tachyarrhythmia and healthy controls, EV- and non-EV-fraction troponin patterns were quantified. Results Hypoxic conditioning of cardiomyocytes enhanced EV-bound troponin T secretion. Minimal invasive myocardial infarction in mice caused pronounced systemic EV release. Induction of atrial fibrillation in pigs induced EV release and a shift in relative circulating troponin T compartmentalization. In patients presenting with tachyarrhythmia and myocardial infarction, elevated circulating EV concentrations were observed, concomitant with disease-specific relative EV-troponin fractional signatures in blood, concurrent with observations made in animal models. Circulating EV-troponin compartmental signatures could robustly discriminate myocardial infarction from tachyarrhythmia-induced myocardial injury, and further distinguish first diagnosis from recurrent tachyarrhythmia. Conclusions This study introduces the relative EV-troponin fraction as a novel biomarker in cardiovascular disease, improving diagnostic specificity for ischemic and non-ischemic myocardial disease entities.