Identification of Anesthetic-Induced Cardiovascular Biomarkers in Off-Pump Coronary Artery Bypass Grafting Surgery Using Weighted Gene Co-Expression Network Analysis and Machine Learning
DOI:
https://doi.org/10.59958/hsf.6809Keywords:
biomarker, machine learning, off-pump coronary artery bypass grafting, weighted gene co-expression network analysisAbstract
Background: This study aimed to select anesthesia-induced zinc finger protein-related gene biomarkers that predict cardiovascular function during off-pump coronary artery bypass grafting (OPCABG). Methods: Gene expression data from GSE4386 included 20 post-anesthesia and 20 pre-anesthesia atrial tissue samples. Zinc finger protein-related genes (ZFPRGs) were searched in the UniProt database and anesthesia-induced differentially expressed genes (DEGs) were identified Weighted gene co-expression network analysis (WGCNA) was used to screen hub genes, and three machine learning algorithms were used to further screen for cardiovascular biomarkers. Diagnostic accuracy was evaluated using a nomogram model. Gene set enrichment analysis was used to analyze the pathways enriched by the biomarkers. A microRNA (miRNA)-mRNA-transcription factor (TF) regulatory network was established to explore the potential regulatory mechanisms of these biomarkers. Disease-related drugs were predicted using the Comparative Toxicogenomics Database (CTD). Results: A total of 1102 cardioprotection-related DEGs were selected between the pre- and post-anesthesia groups. Additionally, 1095 hub genes were obtained based on WGCNA, and 2274 ZFPRGs were downloaded from the UniProt database. After Venn analysis and machine learning, ZNF420, RNF135, and BNC2 were selected as cardioprotection-related zinc finger biomarkers during OPCABG. Receiver operating characteristic (ROC) curves and nomogram models confirmed the diagnostic value and accuracy of the three cardioprotective biomarkers. Pathway enrichment analysis revealed that ZNF420 is involved in the cell cycle and the tricarboxylic acid cycle. RNF135 and BNC2 were enriched in the oxidative phosphorylation pathway. In the constructed miRNA-mRNA-TF network, miR-182-5p and miR-16-5p simultaneously regulated three cardioprotective biomarkers. Conclusion: Three cardioprotection-related zinc finger protein biomarkers (ZNF420, RNF135, and BNC2) were identified using OPCABG samples.
References
Lucchinetti E, Hofer C, Bestmann L, Hersberger M, Feng J, Zhu M, et al. Gene regulatory control of myocardial energy metabolism predicts postoperative cardiac function in patients undergoing off-pump coronary artery bypass graft surgery: inhalational versus intravenous anesthetics. Anesthesiology. 2007; 106: 444–457.
Mirhafez SR, Khadem SH, Sahebkar A, Movahedi A, Rahsepar AA, Mirzaie A, et al. Comparative effects of on-pump versus off-pump coronary artery bypass grafting surgery on serum cytokine and chemokine levels. IUBMB Life. 2021; 73: 1423–1431.
Pawliszak W, Kowalewski M, Raffa GM, Malvindi PG, Kowalkowska ME, Szwed KA, et al. Cerebrovascular Events After No-Touch Off-Pump Coronary Artery Bypass Grafting, Conventional Side-Clamp Off-Pump Coronary Artery Bypass, and Proximal Anastomotic Devices: A Meta-Analysis. Journal of the American Heart Association. 2016; 5: e002802.
Kusurin M, Majnaric M, Unic D, Baric D, Blazekovic R, Varvodic J, et al. Comparison between OPCABG and CABG Surgical Revascularization Using Transit Time Flow Measurement (TTFM). The Heart Surgery Forum. 2021; 2021: E963–E967.
Rajakaruna C, Rogers C, Pike K, Alwair H, Cohen A, Tomkins S, et al. Superior haemodynamic stability during off-pump coronary surgery with thoracic epidural anaesthesia: results from a prospective randomized controlled trial. Interactive Cardiovascular and Thoracic Surgery. 2013; 16: 602–607.
Dhurandhar V, Saxena A, Parikh R, Vallely MP, Wilson MK, Butcher JK, et al. Comparison of the Safety and Efficacy of On-Pump (ONCAB) versus Off-Pump (OPCAB) Coronary Artery Bypass Graft Surgery in the Elderly: A Review of the ANZSCTS Database. Heart, Lung & Circulation. 2015; 24: 1225–1232.
Pruna R, Artells R, Lundblad M, Maffulli N. Genetic biomarkers in non-contact muscle injuries in elite soccer players. Knee Surgery, Sports Traumatology, Arthroscopy: Official Journal of the ESSKA. 2017; 25: 3311–3318.
Selvanayagam JB, Petersen SE, Francis JM, Robson MD, Kardos A, Neubauer S, et al. Effects of off-pump versus on-pump coronary surgery on reversible and irreversible myocardial injury: a randomized trial using cardiovascular magnetic resonance imaging and biochemical markers. Circulation. 2004; 109: 345–350.
Zhao H, Wang W, Liu L, Wang J, Yan Q. Functional Modular Network Identifies the Key Genes of Preoperative Inhalation Anesthesia and Intravenous Anesthesia in Off-Pump Coronary Artery Bypass Grafting. Computational and Mathematical Methods in Medicine. 2020; 2020: 4574792.
Likhvantsev VV, Landoni G, Levikov DI, Grebenchikov OA, Skripkin YV, Cherpakov RA. Sevoflurane Versus Total Intravenous Anesthesia for Isolated Coronary Artery Bypass Surgery With Cardiopulmonary Bypass: A Randomized Trial. Journal of Cardiothoracic and Vascular Anesthesia. 2016; 30: 1221–1227.
Pasin L, Landoni G, Cabrini L, Borghi G, Taddeo D, Saleh O, et al. Propofol and survival: a meta-analysis of randomized clinical trials. Acta Anaesthesiologica Scandinavica. 2015; 59: 17–24.
Huang Z, Zhong X, Irwin MG, Ji S, Wong GT, Liu Y, et al. Synergy of isoflurane preconditioning and propofol postconditioning reduces myocardial reperfusion injury in patients. Clinical Science (London, England: 1979). 2011; 121: 57–69.
Lin S, Neelankavil J, Wang Y. Cardioprotective Effect of Anesthetics: Translating Science to Practice. Journal of Cardiothoracic and Vascular Anesthesia. 2021; 35: 730–740.
De Hert SG, Van der Linden PJ, Cromheecke S, Meeus R, Nelis A, Van Reeth V, et al. Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology. 2004; 101: 299–310.
Cassandri M, Smirnov A, Novelli F, Pitolli C, Agostini M, Malewicz M, et al. Zinc-finger proteins in health and disease. Cell Death Discovery. 2017; 3: 17071.
Ozyildirim S, Baltaci SB. Cardiovascular Diseases and Zinc. Biological Trace Element Research. 2023; 201: 1615–1626.
Li F, Yang Y, Xue C, Tan M, Xu L, Gao J, et al. Zinc Finger Protein ZBTB20 protects against cardiac remodelling post-myocardial infarction via ROS-TNFα/ASK1/JNK pathway regulation. Journal of Cellular and Molecular Medicine. 2020; 24: 13383–13396.
Meng XY, Yu HL, Zhang WC, Wang TH, Mai X, Liu HT, et al. ZFP580, a novel zinc-finger transcription factor, is involved in cardioprotection of intermittent high-altitude hypoxia against myocardial ischemia-reperfusion injury. PLoS ONE. 2014; 9: e94635.
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008; 9: 559.
Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics: a Journal of Integrative Biology. 2012; 16: 284–287.
Yuan GX, Ho CH, Lin CJ. An improved glmnet for l1-regularized logistic regression. Journal of Machine Learning Research. 2012; 13: 1999–2030.
Meyer D, Dimitriadou E, Hornik K, Weingessel A, Leisch F, Chang C, et al. e1071: Misc functions of the Department of Statistics (e1071), TU Wien. R Package Version. 2014; 1: 9.
Levinson N. The Wiener (root mean square) error criterion in filter design and prediction. Journal of Mathematics and Physics. 1946; 25: 261–278.
Bhaskaran K, Arumugam G, Vinay Kumar PV. A prospective, randomized, comparison study on effect of perioperative use of chloride liberal intravenous fluids versus chloride restricted intravenous fluids on postoperative acute kidney injury in patients undergoing off-pump coronary artery bypass grafting surgeries. Annals of Cardiac Anaesthesia. 2018; 21: 413–418.
Brown JM, Poston RS, Gammie JS, Cardarelli MG, Schwartz K, Sikora JAH, et al. Off-pump versus on-pump coronary artery bypass grafting in consecutive patients: decision-making algorithm and outcomes. The Annals of Thoracic Surgery. 2006; 81: 555–561.
Tian C, Xing G, Xie P, Lu K, Nie J, Wang J, et al. KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis. Nature Cell Biology. 2009; 11: 580–591.
Sato M, Jiao Q, Honda T, Kurotani R, Toyota E, Okumura S, et al. Activator of G protein signaling 8 (AGS8) is required for hypoxia-induced apoptosis of cardiomyocytes: role of G betagamma and connexin 43 (CX43). The Journal of Biological Chemistry. 2009; 284: 31431–31440.
Kang PM, Haunstetter A, Aoki H, Usheva A, Izumo S. Morphological and molecular characterization of adult cardiomyocyte apoptosis during hypoxia and reoxygenation. Circulation Research. 2000; 87: 118–125.
von Harsdorf R, Li PF, Dietz R. Signaling pathways in reactive oxygen species-induced cardiomyocyte apoptosis. Circulation. 1999; 99: 2934–2941.
Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. The Journal of Biological Chemistry. 2002; 277: 30409–30412.
Martínez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nature Communications. 2020; 11: 102.
Müller OJ, Heckmann MB, Ding L, Rapti K, Rangrez AY, Gerken T, et al. Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in cardiac hypertrophy and failure. Cardiovascular Research. 2019; 115: 1296–1305.
Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiological Reviews. 2005; 85: 1093–1129.
Santos JL, Ruiz-Canela M, Razquin C, Clish CB, Guasch-Ferré M, Babio N, et al. Circulating citric acid cycle metabolites and risk of cardiovascular disease in the PREDIMED study. Nutrition, Metabolism, and Cardiovascular Diseases: NMCD. 2023; 33: 835–843.
Pohjoismäki JL, Goffart S. The role of mitochondria in cardiac development and protection. Free Radical Biology & Medicine. 2017; 106: 345–354.
Piper HM, Noll T, Siegmund B. Mitochondrial function in the oxygen depleted and reoxygenated myocardial cell. Cardiovascular Research. 1994; 28: 1–15.
Solaini G, Harris DA. Biochemical dysfunction in heart mitochondria exposed to ischaemia and reperfusion. The Biochemical Journal. 2005; 390: 377–394.
Oshiumi H, Matsumoto M, Hatakeyama S, Seya T. Riplet/RNF135, a RING finger protein, ubiquitinates RIG-I to promote interferon-beta induction during the early phase of viral infection. The Journal of Biological Chemistry. 2009; 284: 807–817.
Wu Y, Zhang X, Liu Y, Lu F, Chen X. Decreased Expression of BNC1 and BNC2 Is Associated with Genetic or Epigenetic Regulation in Hepatocellular Carcinoma. International Journal of Molecular Sciences. 2016; 17: 153.
Vanhoutteghem A, Messiaen S, Hervé F, Delhomme B, Moison D, Petit JM, et al. The zinc-finger protein basonuclin 2 is required for proper mitotic arrest, prevention of premature meiotic initiation and meiotic progression in mouse male germ cells. Development. 2014; 141: 4298–4310.
Xu Y, Lv X, Cai R, Ren Y, He S, Zhang W, et al. Possible implication of miR-142-3p in coronary microembolization induced myocardial injury via ATXN1L/HDAC3/NOL3 axis. Journal of Molecular Medicine (Berlin, Germany). 2022; 100: 763–780.
Zhang X, Xiao C, Liu H. Ganoderic Acid A Protects Rat H9c2 Cardiomyocytes from Hypoxia-Induced Injury via Up-Regulating miR-182-5p. Cellular Physiology and Biochemistry: International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology. 2018; 50: 2086–2096.
Lee SY, Lee S, Choi E, Ham O, Lee CY, Lee J, et al. Small molecule-mediated up-regulation of microRNA targeting a key cell death modulator BNIP3 improves cardiac function following ischemic injury. Scientific Reports. 2016; 6: 23472.
Calderon-Dominguez M, Mangas A, Belmonte T, Quezada-Feijoo M, Ramos M, Toro R. Ischemic dilated cardiomyopathy pathophysiology through microRNA-16-5p. Revista Espanola De Cardiologia (English Ed.). 2021; 74: 740–749.
Toro R, Pérez-Serra A, Mangas A, Campuzano O, Sarquella-Brugada G, Quezada-Feijoo M, et al. miR-16-5p Suppression Protects Human Cardiomyocytes against Endoplasmic Reticulum and Oxidative Stress-Induced Injury. International Journal of Molecular Sciences. 2022; 23: 1036.
