Proteomic and metabolomic profiling in human peripartum cardiomyopathy

Pregnancy imposes significant cardiovascular adaptations including progressive increases in plasma volume and cardiac output. For most women, this physiological adaptation resolves at the end of pregnancy, but some women develop pathological dilatation and ultimately heart failure late in pregnancy or in the postpartum period manifesting as peripartum cardiomyopathy (PPCM). Despite the mortality risk of this form of heart failure, the molecular mechanisms underlying PPCM have not been extensively examined in human hearts. We examined protein and metabolite expression in PPCM compared to familial dilated cardiomyopathy (DCM) and non-failing donors using unbiased quantitative mass spectrometry. Proteomics analysis identified uniquely downregulated proteins, such as SBSPON and TNS3, in PPCM relative to both DCM and donors. KEGG analysis of PPCM proteins identified key pathways associated with intracellular signalling cascades, protein folding and neurohormonal pathways that can directly impact the contractility of the heart. Metabolomics demonstrated uniquely expressed metabolites, such as upregulated homogentisate and deoxycholate, and downregulated lactate and alanine, along with reduced alanine, aspartate and glutamate metabolism are involved in the PPCM phenotype. Therefore, this study is the first to isolate unique molecular features underlying PPCM at the protein and metabolite level which may hold promise as future therapeutic candidate targets.

妊娠会引发显著的心血管适应性变化，包括血浆容量与心输出量的进行性升高。多数女性的此类生理性适应会在妊娠结束后恢复，但部分女性会出现病理性心脏扩张，最终在妊娠晚期或产后阶段发生心力衰竭，临床表现为围产期心肌病（peripartum cardiomyopathy, PPCM）。尽管此类心力衰竭存在致死风险，但围产期心肌病的潜在分子机制尚未在人类心脏中得到广泛研究。本研究采用无偏倚定量质谱技术，对比分析了围产期心肌病、家族性扩张型心肌病（familial dilated cardiomyopathy, DCM）以及非衰竭供体心脏中的蛋白质与代谢物表达情况。蛋白质组学分析显示，相较于家族性扩张型心肌病患者与非衰竭供体，围产期心肌病患者体内存在独特的下调蛋白，如SBSPON与TNS3。对围产期心肌病相关蛋白的KEGG分析显示，其关键通路与细胞内信号级联反应、蛋白质折叠以及神经体液通路密切相关，这些通路可直接影响心脏收缩功能。代谢组学分析发现，围产期心肌病表型存在独特的差异代谢物：包括上调的尿黑酸（homogentisate）与脱氧胆酸（deoxycholate）、下调的乳酸与丙氨酸，同时丙氨酸、天冬氨酸与谷氨酸代谢通路活性降低。综上，本研究首次在蛋白质与代谢物层面揭示了围产期心肌病独特的分子特征，这些特征有望成为未来潜在的治疗靶点。