Comparative Analysis of Plasma Protein Dynamics in Women with ST-Elevation Myocardial Infarction and Takotsubo Syndrome

Abstract

Background: ST-elevation myocardial infarction (STEMI) and Takotsubo syndrome (TS) are two distinct cardiac conditions that both result in sudden loss of cardiac dysfunction and that are difficult to distinguish clinically. This study compared plasma protein changes in 24 women with STEMI and 12 women with TS in the acute phase (days 0-3 post symptom onset) and the stabilization phase (days 7, 14, and 30) to examine the molecular differences between these conditions.

Methods: Plasma proteins from STEMI and TS patients were extracted during the acute and stabilization phases and analyzed via quantitative proteomics. Differential expression and functional significance were assessed. Data are accessible on ProteomeXchange, ID PXD051367.

Results: During the acute phase, STEMI patients showed higher levels of myocardial inflammation and tissue damage proteins compared to TS patients, along with reduced tissue repair and anti-inflammatory proteins. In the stabilization phase, STEMI patients exhibited ongoing inflammation and disrupted lipid metabolism. Notably, ADIPOQ was consistently downregulated in STEMI patients in both phases. When comparing the acute to the stabilization phase, STEMI patients showed increased inflammatory proteins and decreased structural proteins. Conversely, TS patients showed increased proteins involved in inflammation and the regulatory response to counter excessive inflammation. Consistent protein changes between the acute and stabilization phases in both conditions, such as SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE, suggest shared underlying pathophysiological mechanisms.

Conclusions: This study presents protein changes in women with STEMI or TS and identifies ADIPOQ, SAA2, CRP, SAA1, LBP, FGL1, AGT, MAN1A1, APOA4, COMP, and PCOLCE as candidates for further exploration in both therapeutic and diagnostic contexts.

Keywords: ST-elevation myocardial infarction; Takotsubo syndrome; biomarkers; energy metabolism; plasma proteomics; temporal changes; tissue remodeling.

Figure 1

Alterations in plasma protein expression between STEMI and TS patients during the acute phase. (A) Study design and workflow of nLC-MS-based proteomics. (B) Volcano plot depicting the significant proteins in terms of their significance levels and fold changes in expression. Proteins with p-values less than 0.05 were considered to be statistically significant (red and blue points in the plot). Of these, those with more than a two-fold expression are additionally demarcated (proteins denoted in red). The proteins represented in black (NS) and green (log2FC) points denote the ones that were not statistically significant and were not considered for downstream analyses. (C) Box plots represent the top 5 most significant proteins. (D–G) Gene Ontology term enrichment analysis of upregulated proteins in STEMI compared to TS based on Biological Process, Cellular Component, Molecular Function, and KEGG Pathway. (H,I) GO term enrichment analysis of downregulated proteins in STEMI compared to TS based on Biological Process and Molecular Function. The bubble plot diagrams provide information on the top 10 pathways in terms of GO fold enrichment, significance (FDR in log10), and the number of proteins in each pathway.

Figure 2

Alterations in plasma protein expression between STEMI and TS patients during the stabilization phase. (A) Volcano plot representing proteins based on significance and expression fold changes. Statistically significant proteins (p < 0.05) are highlighted in red and blue, with those exceeding two-fold change in red. Non-significant proteins are shown in black (NS), and proteins not meeting fold change criteria are in green (log2FC). (B) Box plots illustrating the expression levels of the top 5 most significant proteins. (C–E) GO enrichment analysis for upregulated proteins in STEMI, categorized by Biological Process, Cellular Component, and Molecular Function. (F–I) GO enrichment for downregulated proteins, encompassing Biological Process, Cellular Component, Molecular Function, and KEGG Pathway. The bubble plot diagrams highlight the top 10 enriched pathways with details on fold enrichment, significance, and protein count.

Figure 3

Plasma protein changes in patients with STEMI between the acute phase and stabilization. (A) Volcano plot displays proteins by their significance and fold changes. Proteins with p < 0.05 are shown in red (those with over two-fold change) and blue. Proteins not meeting significance are in black (NS), and those not reaching the fold change threshold are in green (log2FC). (B) Box plots of the top 5 significantly altered proteins. (C–F) GO enrichment analysis of upregulated proteins, categorized by Biological Process, Cellular Component, Molecular Function, and KEGG Pathway. (G–J) GO analysis for downregulated proteins, broken down into Biological Process, Cellular Component, Molecular Function, and KEGG Pathway. Bubble plot diagrams spotlight the top 10 enriched pathways, detailing fold enrichment, significance level, and protein constituents.

Figure 4

Plasma protein changes in patients with TS between the acute phase and stabilization. (A) Volcano plot representing proteins based on significance and expression fold changes. Statistically significant proteins (p < 0.05) are highlighted in red and blue, with those exceeding two-fold change in red. Non-significant proteins are shown in black (NS), and proteins not meeting fold change criteria are in green (log2FC). (B) Box plots showing the top 5 significant protein changes. (C–E) Gene Ontology term enrichment analysis of upregulated proteins in the TS acute phase compared to the TS stabilization phase based on Biological Process, Cellular Component, and KEGG Pathway. (F–I) GO term enrichment analysis of downregulated proteins in TS acute phase compared to TS stabilization phase based on Biological Process, Cellular Component, Molecular Function, and KEGG Pathway. The lollipop diagrams provide information on the top 10 pathways in terms of GO fold enrichment, significance (FDR in log10), and the number of proteins in each pathway.

Figure 5

Venn diagrams showing the overlap of differentially expressed plasma proteins quantified in the study comparisons. (A) Overlapping upregulated (UP) and downregulated (DW) proteins between patients with STEMI and patients with TS in the acute phase (AC) and stabilization phase (STAB). (B) Overlapping UP and DW proteins between patients with STEMI AC and STAB and between patients with TS AC and STAB.