Dixit Gunjan, Blair John, Ozcan Cevher
Department of Medicine, Section of Cardiology, Heart and Vascular Center, University of Chicago 5841 S. Maryland Avenue, MC 6080, Chicago 60637, IL, USA.
Am J Cardiovasc Dis. 2022 Apr 15;12(2):81-91. eCollection 2022.
The clinical association between atrial fibrillation (AF), coronary microvascular disease (CMD) and heart failure with preserved ejection fraction (HFpEF) is highly prevalent, however the mechanism behind this association is not known. We hypothesized that plasma proteomic analysis can identify novel biomarkers and the mechanistic pathways in concomitant AF, CMD and HFpEF. To discover circulating biomarkers for the association between AF, CMD and HFpEF, an unbiased label-free quantitative proteomics approach was used in plasma derived from patients who underwent coronary physiology studies (n=18). Circulating proteins were analyzed by liquid chromatography-mass spectrometry and screened to determine candidate biomarkers of the concomitant AF, CMD and HFpEF. We identified 130 dysregulated proteins across the groups with the independent patient replicates. Among those, 35 proteins were candidate biomarkers of the association between AF, CMD and HFpEF. We found significantly elevated SAA1, LRG1 and APOC3 proteins in the coexistence of AF, CMD and HFpEF, whereas LCP1, PON1 and C1S were markedly downregulated in their associations. AF was associated with reduced LCP1, KLKB1 and C4A in these patients. Combined downregulation of PON1 and C1S was a marker of concurrent HFpEF and CMD. PON1 was associated with HFpEF while C1S was a marker of CMD. These proteins are related to inflammation, extra cellular remodeling, oxidative stress, and coagulation. In conclusion, plasma proteomic profile provides biomarkers and mechanistic insight into the association of AF, CMD and HFpEF. SAA1, LRG1, APOC3, LCP1, PON1 and C1S are candidate markers for the risk stratification of their associations and potential underlying mechanistic pathways.
心房颤动（AF）、冠状动脉微血管疾病（CMD）和射血分数保留的心力衰竭（HFpEF）之间的临床关联非常普遍，然而这种关联背后的机制尚不清楚。我们假设血浆蛋白质组学分析可以识别伴随AF、CMD和HFpEF的新型生物标志物和机制途径。为了发现AF、CMD和HFpEF之间关联的循环生物标志物，我们对接受冠状动脉生理学研究的患者（n = 18）的血浆采用了无偏倚的无标记定量蛋白质组学方法。通过液相色谱 - 质谱分析循环蛋白，并进行筛选以确定伴随AF、CMD和HFpEF的候选生物标志物。我们在独立的患者重复样本中识别出130种各分组间失调的蛋白质。其中，35种蛋白质是AF、CMD和HFpEF之间关联的候选生物标志物。我们发现，在AF、CMD和HFpEF共存时，血清淀粉样蛋白A1（SAA1）、富含亮氨酸α-2糖蛋白1（LRG1）和载脂蛋白C3（APOC3）蛋白显著升高，而淋巴细胞胞质蛋白1（LCP1）、对氧磷酶1（PON1）和补体C1s（C1S）在它们的关联中显著下调。在这些患者中，AF与LCP1、激肽释放酶激肽原1（KLKB1）和补体C4a（C4A）降低有关。PON1和C1S的联合下调是并发HFpEF和CMD的标志物。PON1与HFpEF有关，而C1S是CMD的标志物。这些蛋白质与炎症、细胞外重塑、氧化应激和凝血有关。总之，血浆蛋白质组学图谱为AF、CMD和HFpEF之间的关联提供了生物标志物和机制性见解。SAA1、LRG1、APOC3、LCP1、PON1和C1S是它们关联的风险分层以及潜在潜在机制途径的候选标志物。
