Identification of serum predictors of n-acetyl-l-cysteine and isoproterenol induced remodelling in cardiac hypertrophy

Abstract

Cardiac hypertrophy (CH), leading to cardiac failure is due to chronic metabolic alterations occurring during cellular stress. Besides the already known relationship between oxidative stress and CH, there are implications of reductive stress leading to CH. This study attempted to develop reductive stress-based CH rat model using n-acetyl-L-cysteine (NAC), a glutathione agonist that was compared with typical isoproterenol (ISO) induced CH model. The main objective was to identify serum metabolites that can serve as potent predictors for seven routine clinical and diagnostic parameters in CH: 3-hydroxybutyrate (3-HB), lactic acid (LA), urea, and ECG-CH parameters (QRS complex, R-amplitude, R-R interval, heart rate) that were hypothesized to underlie metabolic remodelling in this study. CH was assessed using electrocardiography, hypertrophic index and histopathological analysis (H&E stain) in both ventricles after 2 weeks. Gas chromatography mass spectroscopy analysis (GC-MS) identified unique metabolite finger-prints. Correlation and pattern analysis revealed strong relationships between specific metabolites and parameters (Pearson’s score > 0.7) of this study. Multiple regression analysis (MRA) for the strongly related metabolites (independent variables) with each of the seven parameters (dependent variables) identified significant predictors for the latter namely fructose, valine, butanoic acid in NAC and cholesterol, erythrose, isoleucine in ISO models, with proline and succinic acid as common for both models. Metabolite set enrichment analysis (MSEA) of those significant predictors (p