[Similarities and differences of myocardial metabolic characteristics between HFpEF and HFrEF mice based on LC-MS/MS metabolomics].

Objective: To reveal the similarities and differences in myocardial metabolic characteristics between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) mice using metabolomics. Methods: The experimental mice were divided into 4 groups, including control, HFpEF, sham and HFrEF groups (10 mice in each group). High fat diet and Nω-nitroarginine methyl ester hydrochloride (L-NAME) were applied to construct a"two-hit"HFpEF mouse model. Transverse aortic constriction (TAC) surgery was used to construct the HFrEF mouse model. The differential expression of metabolites in the myocardium of HFpEF and HFrEF mice was detected by untargeted metabolomics (UHPLC-QE-MS). Variable importance in projection>1 and P<0.05 were used as criteria to screen and classify the differentially expressed metabolites between the mice models. KEGG functional enrichment and pathway impact analysis demonstrated significantly altered metabolic pathways in both HFpEF and HFrEF mice. Results: One hundred and nine differentially expressed metabolites were detected in HFpEF mice, and 270 differentially expressed metabolites were detected in HFrEF mice. Compared with the control group, the most significantly changed metabolite in HFpEF mice was glycerophospholipids, while HFrEF mice presented with the largest proportion of carboxylic acids and their derivatives. KEGG enrichment and pathway impact analysis showed that the differentially expressed metabolites in HFpEF mice were mainly enriched in pathways such as biosynthesis of unsaturated fatty acids, ether lipid metabolism, amino sugar and nucleotide sugar metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and arginine and proline metabolism. The differentially expressed metabolites in HFrEF mice were mainly enriched in arginine and proline metabolism, glycine, serine and threonine metabolism, pantothenate and CoA biosynthesis, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism and arachidonic acid metabolism, etc. Conclusions: HFpEF mice have a significantly different myocardial metabolite expression profile compared with HFrEF mice. In addition, biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, glycerophospholipid metabolism and arginine and proline metabolism are significantly altered in both HFpEF and HFrEF mice, suggesting that these metabolic pathways may play an important role in disease progression in both types of heart failure.目的： 采用代谢组学揭示射血分数保留的心力衰竭（HFpEF）与射血分数降低的心力衰竭（HFrEF）小鼠心肌代谢特征的异同。 方法： 将实验小鼠分为对照组、HFpEF组、假手术组以及HFrEF组共4组，每组10只。采用高脂饮食与Nω-硝基-L-精氨酸甲基脂（L-NAME）干预构建“two-hit”HFpEF小鼠模型，主动脉弓缩窄术（TAC）构建HFrEF小鼠模型。采用非靶向代谢组学（UHPLC-QE-MS）检测HFpEF与HFrEF小鼠心肌组织中差异代谢物的表达情况。以变量投影重要度>1，P<0.05为标准对这两种小鼠中的差异代谢物进行筛选与分类。KEGG功能富集与通路影响分析展示在这两种小鼠中发生了显著变化的代谢通路。 结果： HFpEF小鼠中共有109个差异代谢物，HFrEF小鼠中共有270个差异代谢物。与对照组相比，HFpEF小鼠心肌组织中甘油磷脂的改变最为显著，而HFrEF小鼠中则以羧酸及其衍生物的占比最多。KEGG富集与通路影响分析显示HFpEF小鼠中的差异代谢物主要富集在不饱和脂肪酸的生物合成、醚脂代谢、氨基糖与核苷糖代谢、甘油磷脂代谢、花生四烯酸代谢以及精氨酸与脯氨酸代谢等通路上，而HFrEF小鼠中的差异代谢物则主要富集在精氨酸与脯氨酸代谢、甘氨酸和丝苏氨酸代谢、泛酸盐和CoA的生物合成、甘油磷脂代谢、烟酸盐和烟酰胺代谢以及花生四烯酸代谢等通路上。 结论： HFpEF小鼠与HFrEF小鼠相比具有显著不同的心肌代谢物表达谱。此外，不饱和脂肪酸的生物合成、花生四烯酸代谢、甘油磷脂代谢以及精氨酸和脯氨酸代谢在HFpEF与HFrEF小鼠中都出现了显著改变，提示这些代谢通路可能在这两类心力衰竭的疾病进展中都发挥着重要作用。.