Exploratory transcriptomic analysis of 7-day outcomes in patients receiving extracorporeal membrane oxygenation for cardiogenic shock after acute myocardial infarction

Abstract

Background: We performed an exploratory secondary analysis of a public transcriptomic dataset to identify gene-expression patterns associated with 7-day outcome among 14 patients receiving ECMO for cardiogenic shock after acute myocardial infarction.
Methods: The microarray dataset (GSE93101, n = 14) was retrieved from the Gene Expression Omnibus online database. Differential expression, weighted gene co-expression network analyses (WGCNA), Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed. To identify the top five hub genes, we used the mutual construction of the protein–protein interaction network and the Cytoscape software. Subsequently, a gene–microRNA (miRNA) network was established to identify the miRNAs that potentially regulate these hub genes.
Results: Ten genes were obtained when those in the two highest correlation modules of WGCNA were intersected with the differentially expressed genes. A total of 104 differentially expressed genes were found to be associated with oxidoreductase activity and metabolic pathways. We found the top five hub genes using the Cytoscape software: CD68, C8A, NR1H4, and ADGRE1 genes were downregulated, while TMPRSS6 was upregulated. TMPRSS6 had the highest degree of affinity and was regulated by 29 miRNAs, while CD68, NR1H4, CD163, and C8A were regulated by 18, 14, 14, and 2 miRNAs, respectively. Although CD163 was not in the top five hub genes, it is regulated by more miRNAs.
Conclusion: Through comprehensive analysis, CD68, which was regulated by 18 miRNAs, emerged as a promising prognostic biomarker for ECMO after AMI, and the mechanism may reflect macrophage activation and differentiation, thereby modulating postinfarction inflammatory responses and tissue repair.

Keywords

Acute myocardial infarction / Bioinformatics analysis / Extracorporeal membrane oxygenation / Hub gene / miRNA / WGCNA

References

[1] Udell JA, Bahit MC, Campbell P, et al. Prevention of heart failure after acute myocardial infarction. Lancet. 2025; 406(10508): 1154-1170. doi: 10.1016/S0140-6736(25)01394-7

[2] Samsky MD, Morrow DA, Proudfoot AG, Hochman JS, Thiele H, Rao SV. Cardiogenic shock after acute myocardial infarction: a review. JAMA. 2021; 326(18): 1840-1850. doi: 10.1001/jama.2021.18323

[3] Tarantini G, Honton B, Paradies V, et al. ; TARGET-FIRST Investigators. Early discontinuation of aspirin after PCI in low-risk acute myocardial infarction. N Engl J Med. 2025; 393(21): 2083-2094. doi: 10.1056/NEJMoa2508808

[4] Zeymer U, Westermann D. Veno-arterial extracorporeal membrane oxygenation. Curr Opin Crit Care. 2025; 31(4): 473-479. doi: 10.1097/MCC.0000000000001295

[5] Agapito G, Arbitrio M. Microarray data analysis protocol. Methods Mol Biol. 2022; 2401: 263-271. doi: 10.1007/978-1-0716-1839-4_17

[6] Carulli JP, Artinger M, Swain PM, et al. High throughput analysis of differential gene expression. J Cell Biochem Suppl. 1998; 30-31: 286-296. doi: 10.1002/(SICI)1097-4644(1998)72:30/31+<286::AID-JCB35>3.0.CO;2-D

[7] Shen W, Song Z, Zhong X, et al. Sangerbox: a comprehensive, interaction-friendly clinical bioinformatics analysis platform. Imeta. 2022; 1(3): e36. doi: 10.1002/imt2.36

[8] Moller JE, Thiele H, Zeymer U, Proudfoot A, Hassager C. Mechanical circulatory support for patients with infarct-related cardiogenic shock: a state-of-the-art review. Heart. 2025; 111(10): 445-453. doi: 10.1136/heartjnl-2024-324883

[9] Shaffer A, Cogswell R, John R. Future developments in left ventricular assist device therapy. J Thorac Cardiovasc Surg. 2021; 162(2): 605-611. doi: 10.1016/j.jtcvs.2020.07.125

[10] Gill G, Patel JK, Casali D, et al. Outcomes of venoarterial extracorporeal membrane oxygenation for cardiac arrest in adult patients in the United States. J Am Heart Assoc. 2021; 10(20): e021406. doi: 10.1161/JAHA.121.021406

[11] Murakami T, Sakakura K, Jinnouchi H, et al. Complications related to veno-arterial extracorporeal membrane oxygenation in patients with acute myocardial infarction: VA-ECMO complications in AMI. J Cardiol. 2022; 79(2): 170-178. doi: 10.1016/j.jjcc.2021.10.003

[12] Vakil D, Soto C, D’Costa Z, et al. Short-term and intermediate outcomes of cardiogenic shock and cardiac arrest patients supported by venoarterial extracorporeal membrane oxygenation. J Cardiothorac Surg. 2021; 16(1): 290. doi: 10.1186/s13019-021-01674-w

[13] Du X, She E, Gelbart T, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science. 2008; 320(5879): 1088-1092. doi: 10.1126/science.1157121

[14] Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306(5704): 2090-2093. doi: 10.1126/science.1104742

[15] Roemhild K, von Maltzahn F, Weiskirchen R, et al. Iron metabolism: pathophysiology and pharmacology. Trends Pharmacol Sci. 2021; 42(8): 640-656. doi: 10.1016/j.tips.2021.05.001

[16] Buerkli S, Pei SN, Hsiao SC, et al. The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption-a stable iron isotope study in Taiwanese women. Haematologica. 2021; 106(11): 2897-2905. doi: 10.3324/haematol.2020.264556

[17] Maurer E, Gütschow M, Stirnberg M. Matriptase-2 (TMPRSS6) is directly up-regulated by hypoxia inducible factor-1: identification of a hypoxia-responsive element in the TMPRSS6 promoter region. Biol Chem. 2012; 393(6): 535-540. doi: 10.1515/hsz-2011-0221

[18] Lakhal S, Schödel J, Townsend AR, Pugh CW, Ratcliffe PJ, Mole DR. Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signaling and iron homeostasis. J Biol Chem. 2011; 286(6): 4090-4097. doi: 10.1074/jbc.M110.173096

[19] Chaston TB, Matak P, Pourvali K, Srai SK, McKie AT, Sharp PA. Hypoxia inhibits hepcidin expression in HuH7 hepatoma cells via decreased SMAD4 signaling. Am J Physiol Cell Physiol. 2011; 300(4): C888-C895. doi: 10.1152/ajpcell.00121.2010

[20] Chistiakov DA, Killingsworth MC, Myasoedova VA, Orekhov AN, Bobryshev YV. CD68/macrosialin: not just a histochemical marker. Lab Invest. 2017; 97(1): 4-13. doi: 10.1038/labinvest.2016.116

[21] Bernier ED, Bartnicki E, Khanna KM. Macrophages: sentinels, warriors, and healers. Hum Mol Genet. 2025; 34(R1): R110-R120. doi: 10.1093/hmg/ddaf087

[22] Yang W, Lin J, Zhou J, et al. Innate lymphoid cells and myocardial infarction. Front Immunol. 2021; 12: 758272. doi: 10.3389/fimmu.2021.758272

[23] Zhang Z, Tang J, Cui X, et al. New insights and novel therapeutic potentials for macrophages in myocardial infarction. Inflammation. 2021; 44(5): 1696-1712. doi: 10.1007/s10753-021-01467-2