Metabolomics reveals the mechanism of Zhilong Huoxue Tongyu capsule in the treatment of heart failure

Energy deprivation in cardiomyocytes is a pivotal factor in the progression of heart failure (HF). Zhilong Huoxue Tongyu capsule (ZL) is a widely used Chinese patent medicine that has been employed in the treatment of various cardiovascular diseases. However, its effects on HF and its impact on cardiac metabolism remain to be elucidated. This study aims to validate the therapeutic effects of ZL on heart failure and analyze its influence on human cardiac metabolism through clinical trials and untargeted metabolomics research. A cohort of 80 HF patients was enrolled, all of whom received conventional treatment (CT) in conjunction with ZL. Primary therapeutic endpoints included left ventricular ejection fraction, brain natriuretic peptide levels, 6-min walking distance, the Minnesota Living with Heart Failure Questionnaire score, and traditional Chinese medicine (TCM) syndrome scores. Ultra-high performance liquid chromatography-tandem mass spectrometry was utilized to identify key compounds, core targets, and pathways implicated in the anti-HF effects of CT combined with ZL. Seventy-six subjects completed the clinical study. Post-treatment, significant improvements were observed in heart function, exercise endurance, quality of life, and TCM syndrome scores. Untargeted metabolomics screening identified 57 differential metabolites in the serum of subjects pre- and post-treatment, including PC 20:2_20:2 and cyclic acid, among others. Of these, 25 metabolites were upregulated, while 32 were downregulated. Pathway analysis indicated that these differential metabolites were involved in riboflavin metabolism, the citrate cycle, alanine, aspartate and glutamate metabolism, arginine biosynthesis, butanoate metabolism, lipoic acid metabolism, and fatty acid biosynthesis. The combination of CT and ZL for HF treatment exhibits promising clinical efficacy, potentially mediated through the optimization of cardiac energy metabolism.