Metabolomic distinction and insights into the pathogenesis of human primary dilated cardiomyopathy

Abstract

Metabolomics, the comprehensive profile of small-molecule metabolites found in biological specimens, has the potential to provide insights into the pathogenesis of disease states and lead to the identification of new biomarkers. We analysed 451 plasma metabolites by liquid chromatography/mass spectroscopy and gas chromatography/mass spectroscopy in 39 patients with primary dilated cardiomyopathy (DCM) and 31 age-, sex- and body mass index-matched controls. Sixty-one metabolites were significantly different between primary DCM and control individuals [false discovery rate (FDR) < 0·05]. Plasma levels of steroid metabolites, glutamine, threonine and histidine were reduced while levels of citric acid cycle intermediates and lipid β-oxidation products were increased in patients with primary DCM when compared to controls. Medications, particularly furosemide and angiotensin-1 converting enzyme-1 inhibitors, had significant effects on the plasma metabolites. Reduced levels of glutamine in conjunction with increased 3-methyhistidine and prolylhydroxyproline levels suggested enhanced myofibrillar and collagen degradation in DCM patients. Likewise, increased stachydrine and reduced indole-3-propionate implicated a role for intestinal-derived antioxidant molecules. Changes in steroid metabolites were notable for the loss of metabolic distinction between men and women in patients with primary DCM. Cortisol and cortisone levels were increased while androgen metabolites were decreased significantly, implying metabolic 'feminization' of men with primary DCM. Metabolomic profiling identifies biologically active metabolites that could serve as markers of primary DCM and impart protective or harmful effects on cardiac structure and function.