Abstract 11964: Circulating Levels of 2-Aminobutyric Acid Reflect Myocardial Redox State in Patients With Atrial Septal Defects

Abstract

Heart failure (HF) is a major cause of morbidity and mortality worldwide. However, conventional biomarkers are insufficient to detect early stage of HF and identification of more sensitive markers is an urgent task. We conducted the comprehensive quantification of water-soluble metabolites in blood of atrial septal defect (ASD) patients using a gas chromatograph-mass spectrometry. We found the mean level of 2-Aminobutyric acid (2-AB) in ASD patients was significantly higher than that in healthy volunteers, and 1 month after transcatherter closure of ASD using the Amplatzer septal occluder, serum 2-AB levels in patients decreased to almost the same levels as healthy volunteers (healthy-volunteers: 15.74±1.75 μM, ASD (pre-closure): 22.38±1.99 μM, ASD (post-closure):15.50±1.50 μM, P=0.017). In contrast, serum levels of brain natriuretic peptide (BNP), frequently used as the biomarker in heart disease, did not show such relationships. In addition, 2-AB concentration had a significant correlation with tricuspid regurgitation peak gradient (TRPG) (R2=0.517, P=0.029). Because TRPG reflects right ventricular loading conditions, we examined whether mechanical stress to cardiomyocyte induces 2-AB. Mechanical stretch induced an accumulation of 2-AB, suggesting that circulating 2-AB increased in ASD patients were derived from their hearts. Next, we tried to identify the 2-AB synthesis pathway. 2-AB is known as a key molecule in the biosynthesis of ophthalmic acid that is an analogue of glutathione (GSH) and indicates GSH depletion under oxidative stress. We revealed that 2-AB was produced as the byproduct of GSH synthesis reactions. We also demonstrated that oxidative stress lead to 2-AB production by H2O2 stimulation in cardiomyocyte. Mechanical stress-induced 2-AB accumulation might be mediated by oxidative stress. In summary, circulating 2-AB levels changed before and after closure of ASD and indicated heart condition more efficiently than BNP. We also demonstrated that 2-AB reflects myocardial redox state. Thus, 2-AB monitoring may facilitate the early diagnosis strategy for HF.