Lovell Jana P, Bermea Kevin, Yu Jinsheng, Rousseau Sylvie, Cohen Charles D, Bhalodia Aashik, Zita Marcelle Dina, Head Richard D, Blumenthal Roger S, Alharethi Rami, Damp Julie, Boehmer John, Alexis Jeffrey, McNamara Dennis M, Sharma Garima, Adamo Luigi
Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Genetics, McDonnell Genome Institute, Washington University, St. Louis, Missouri, USA.
JACC Heart Fail. 2023 Sep;11(9):1231-1242. doi: 10.1016/j.jchf.2023.05.031. Epub 2023 Aug 2.
The pathophysiology of peripartum cardiomyopathy (PPCM) and its distinctive biological features remain incompletely understood. High-throughput serum proteomic profiling, a powerful tool to gain insights into the pathophysiology of diseases at a systems biology level, has never been used to investigate PPCM relative to nonischemic cardiomyopathy.
The aim of this study was to characterize the pathophysiology of PPCM through serum proteomic analysis.
Aptamer-based proteomic analysis (SomaScan 7K) was performed on serum samples from women with PPCM (n = 67), women with nonischemic nonperipartum cardiomyopathy (NPCM) (n = 31), and age-matched healthy peripartum and nonperipartum women (n = 10 each). Serum samples were obtained from the IPAC (Investigation of Pregnancy-Associated Cardiomyopathy) and IMAC2 (Intervention in Myocarditis and Acute Cardiomyopathy) studies.
Principal component analysis revealed unique clustering of each patient group (P for difference <0.001). Biological pathway analyses of differentially measured proteins in PPCM relative to NPCM, before and after normalization to pertinent healthy controls, highlighted specific dysregulation of inflammatory pathways in PPCM, including the upregulation of the cholesterol metabolism-related anti-inflammatory pathway liver-X receptor/retinoid-X receptor (LXR/RXR) (P < 0.01, Z-score 1.9-2.1). Cardiac recovery by 12 months in PPCM was associated with the downregulation of pro-inflammatory pathways and the upregulation of LXR/RXR, and an additional RXR-dependent pathway involved in the regulation of inflammation and metabolism, peroxisome proliferator-activated receptor α/RXRα signaling.
Serum proteomic profiling of PPCM relative to NPCM and healthy controls indicated that PPCM is a distinct disease entity characterized by the unique dysregulation of inflammation-related pathways and cholesterol metabolism-related anti-inflammatory pathways. These findings provide insight into the pathophysiology of PPCM and point to novel potential therapeutic targets.
围产期心肌病（PPCM）的病理生理学及其独特的生物学特征仍未完全明确。高通量血清蛋白质组分析作为一种在系统生物学水平深入了解疾病病理生理学的强大工具，从未被用于研究PPCM与非缺血性心肌病的关系。
本研究旨在通过血清蛋白质组分析来描述PPCM的病理生理学特征。
对来自PPCM患者（n = 67）、非缺血性非围产期心肌病（NPCM）患者（n = 31）以及年龄匹配的健康围产期和非围产期女性（各n = 10）的血清样本进行基于适配体的蛋白质组分析（SomaScan 7K）。血清样本取自IPAC（妊娠相关心肌病研究）和IMAC2（心肌炎和急性心肌病干预研究）。
主成分分析显示每个患者组都有独特的聚类（差异P<0.001）。在根据相关健康对照进行标准化前后，对PPCM相对于NPCM中差异测量的蛋白质进行生物学通路分析，突出了PPCM中炎症通路的特定失调，包括胆固醇代谢相关抗炎通路肝X受体/视黄醇X受体（LXR/RXR）的上调（P<0.01，Z分数1.9 - 2.1）。PPCM患者在12个月时心脏恢复与促炎通路的下调、LXR/RXR的上调以及另一个参与炎症和代谢调节的RXR依赖性通路过氧化物酶体增殖物激活受体α/RXRα信号传导有关。
PPCM相对于NPCM和健康对照的血清蛋白质组分析表明，PPCM是一种独特的疾病实体，其特征在于炎症相关通路和胆固醇代谢相关抗炎通路的独特失调。这些发现为PPCM的病理生理学提供了见解，并指出了新的潜在治疗靶点。
