Postoperative Organ Dysfunction Risk Stratification Using Extracellular Vesicle-Derived circRNAs in Pediatric Congenital Heart Surgery
Abstract
:1. Introduction
2. Material and Methods
2.1. Study Design and Setting
2.2. Patient Selection and Perioperative Course
2.3. Clinical Data Collection
2.4. Blood Sample Collection
2.5. Plasma Collection and EVs Isolation
2.6. Nanoparticle Tracking Analysis (NTA)
2.7. EV Proteomic Antibody Array
2.8. EV RNA Extraction
2.9. RNA Library Preparation and Small RNA Sequencing
2.10. Bioinformatic Analysis
2.11. Statistical Analysis
3. Results
3.1. Altered Plasma EV circRNA Expression Profiles in Individuals with Respiratory Dysfunction Following Pediatric Congenital Heart Surgery
3.2. Biological Pathways and Processes Associated with the Altered EV circRNAs
3.3. Tissue Specificity of the Altered EV circRNAs and Their Potential Clinical Associations
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Brown, K.L.; Ridout, D.; Pagel, C.; Wray, J.; Anderson, D.; Barron, D.J.; Cassidy, J.; Davis, P.J.; Rodrigues, W.; Stoica, S.; et al. Incidence and Risk Factors for Important Early Morbidities Associated with Pediatric Cardiac Surgery in a UK Population. J. Thorac. Cardiovasc. Surg. 2019, 158, 1185–1196.e7. [Google Scholar] [CrossRef] [PubMed]
- Salvin, J.W.; Scheurer, M.A.; Laussen, P.C.; Wypij, D.; Polito, A.; Bacha, E.A.; Pigula, F.A.; McGowan, F.X.; Costello, J.M.; Thiagarajan, R.R. Blood Transfusion after Pediatric Cardiac Surgery Is Associated with Prolonged Hospital Stay. Ann. Thorac. Surg. 2011, 91, 204–210. [Google Scholar] [CrossRef]
- Redlin, M.; Kukucka, M.; Boettcher, W.; Schoenfeld, H.; Huebler, M.; Kuppe, H.; Habazettl, H. Blood Transfusion Determines Postoperative Morbidity in Pediatric Cardiac Surgery Applying a Comprehensive Blood-Sparing Approach. J. Thorac. Cardiovasc. Surg. 2013, 146, 537–542. [Google Scholar] [CrossRef] [PubMed]
- Iyengar, A.; Scipione, C.N.; Sheth, P.; Ohye, R.G.; Riegger, L.; Bove, E.L.; Devaney, E.J.; Hirsch-Romano, J.C. Association of Complications with Blood Transfusions in Pediatric Cardiac Surgery Patients. Ann. Thorac. Surg. 2013, 96, 910–916. [Google Scholar] [CrossRef]
- Faraoni, D.; Nasr, V.G.; DiNardo, J.A. Overall Hospital Cost Estimates in Children with Congenital Heart Disease: Analysis of the 2012 Kid’s Inpatient Database. Pediatr. Cardiol. 2016, 37, 37–43. [Google Scholar] [CrossRef] [PubMed]
- Alhamwe, B.A.; Potaczek, D.P.; Miethe, S.; Alhamdan, F.; Hintz, L.; Magomedov, A.; Garn, H. Extracellular Vesicles and Asthma-More Than Just a Co-Existence. Int. J. Mol. Sci. 2021, 22, 4984. [Google Scholar] [CrossRef]
- Scrimgeour, L.A.; Potz, B.A.; Aboul Gheit, A.; Shi, G.; Stanley, M.; Zhang, Z.; Sodha, N.R.; Ahsan, N.; Abid, M.R.; Sellke, F.W. Extracellular Vesicles Promote Arteriogenesis in Chronically Ischemic Myocardium in the Setting of Metabolic Syndrome. J. Am. Heart Assoc. 2019, 8, e012617. [Google Scholar] [CrossRef]
- Alhamdan, F.; Greulich, T.; Daviaud, C.; Marsh, L.M.; Pedersen, F.; Thölken, C.; Pfefferle, P.I.; Bahmer, T.; Potaczek, D.P.; Tost, J.; et al. Identification of Extracellular Vesicle MicroRNA Signatures Specifically Linked to Inflammatory and Metabolic Mechanisms in Obesity-Associated Low Type-2 Asthma. Allergy 2023, 78, 2944–2958. [Google Scholar] [CrossRef]
- Schindler, V.E.M.; Alhamdan, F.; Preußer, C.; Hintz, L.; Alhamwe, B.A.; Nist, A.; Stiewe, T.; von Strandmann, E.P.; Potaczek, D.P.; Thölken, C.; et al. Side-Directed Release of Differential Extracellular Vesicle-Associated MicroRNA Profiles from Bronchial Epithelial Cells of Healthy and Asthmatic Subjects. Biomedicines 2022, 10, 622. [Google Scholar] [CrossRef]
- Ikeda, Y.; Morikawa, S.; Nakashima, M.; Yoshikawa, S.; Taniguchi, K.; Sawamura, H.; Suga, N.; Tsuji, A.; Matsuda, S. CircRNAs and RNA-Binding Proteins Involved in the Pathogenesis of Cancers or Central Nervous System Disorders. Noncoding RNA 2023, 9, 23. [Google Scholar] [CrossRef]
- Huang, S.; Yang, B.; Chen, B.J.; Bliim, N.; Ueberham, U.; Arendt, T.; Janitz, M. The Emerging Role of Circular RNAs in Transcriptome Regulation. Genomics 2017, 109, 401–407. [Google Scholar] [CrossRef] [PubMed]
- Wu, W.; Zhang, J.; Cao, X.; Cai, Z.; Zhao, F. Exploring the Cellular Landscape of Circular RNAs Using Full-Length Single-Cell RNA Sequencing. Nat. Commun. 2022, 13, 3242. [Google Scholar] [CrossRef] [PubMed]
- Sharma, A.R.; Bhattacharya, M.; Bhakta, S.; Saha, A.; Lee, S.S.; Chakraborty, C. Recent Research Progress on Circular RNAs: Biogenesis, Properties, Functions, and Therapeutic Potential. Mol. Ther. Nucleic Acids 2021, 25, 355. [Google Scholar] [CrossRef]
- Von Elm, E.; Altman, D.G.; Egger, M.; Pocock, S.J.; Gøtzsche, P.C.; Vandenbroucke, J.P. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. BMJ 2007, 335, 806. [Google Scholar] [CrossRef]
- Seghaye, M.C.; Engelhardt, W.; Grabitz, R.G.; Faymonville, M.E.; Hörnchen, H.; Messmer, B.J.; von Bernuth, G. Multiple system organ failure after open heart surgery in infants and children. Thorac Cardiovasc Surg. 1993, 41, 49–53. [Google Scholar] [CrossRef] [PubMed]
- Montgomery, V.L.; Strotman, J.M.; Ross, M.P. Impact of multiple organ system dysfunction and nosocomial infections on survival of children treated with extracorporeal membrane oxygenation after heart surgery. Crit Care Med. 2000, 28, 526–531. [Google Scholar] [CrossRef]
- Russell, R.A.; Ghanayem, N.S.; Kuhn, E.M.; Jeffries, H.E.; Scanlon, M.C.; Rice, T.B. Relationship between risk-adjustment tools and the pediatric logistic organ dysfunction score. World J Pediatr Congenit Heart Surg. 2014, 5, 16–21. [Google Scholar] [CrossRef]
- Gulla, K.M.; Sachdev, A. Illness severity and organ dysfunction scoring in Pediatric Intensive Care Unit. Indian J Crit Care Med. 2016, 20, 27–35. [Google Scholar]
- Glažar, P.; Papavasileiou, P.; Rajewsky, N. CircBase: A Database for Circular RNAs. RNA 2014, 20, 1666–1670. [Google Scholar] [CrossRef]
- Fehlmann, T.; Kern, F.; Laham, O.; Backes, C.; Solomon, J.; Hirsch, P.; Volz, C.; Müller, R.; Keller, A. MiRMaster 2.0: Multi-Species Non-Coding RNA Sequencing Analyses at Scale. Nucleic Acids Res. 2021, 49, W397–W408. [Google Scholar] [CrossRef]
- Gillespie, M.; Jassal, B.; Stephan, R.; Milacic, M.; Rothfels, K.; Senff-Ribeiro, A.; Griss, J.; Sevilla, C.; Matthews, L.; Gong, C.; et al. The Reactome Pathway Knowledgebase 2022. Nucleic Acids Res. 2022, 50, D687–D692. [Google Scholar] [CrossRef] [PubMed]
- Aleksander, S.A.; Balhoff, J.; Carbon, S.; Cherry, J.M.; Drabkin, H.J.; Ebert, D.; Feuermann, M.; Gaudet, P.; Harris, N.L.; Hill, D.P.; et al. The Gene Ontology Knowledgebase in 2023. Genetics 2023, 224, iyad031. [Google Scholar] [CrossRef] [PubMed]
- Huang, R.; Grishagin, I.; Wang, Y.; Zhao, T.; Greene, J.; Obenauer, J.C.; Ngan, D.; Nguyen, D.T.; Guha, R.; Jadhav, A.; et al. The NCATS BioPlanet–An Integrated Platform for Exploring the Universe of Cellular Signaling Pathways for Toxicology, Systems Biology, and Chemical Genomics. Front. Pharmacol. 2019, 10, 437284. [Google Scholar] [CrossRef]
- Zhong, Z.; Jiao, Z.; Yu, F.X. The Hippo Signaling Pathway in Development and Regeneration. Cell Rep. 2024, 43, 113926. [Google Scholar] [CrossRef] [PubMed]
- Fischer, J.W.; Leung, A.K.L. CircRNAs: A Regulator of Cellular Stress. Crit. Rev. Biochem. Mol. Biol. 2017, 52, 220–233. [Google Scholar] [CrossRef]
- Joaquim, V.H.A.; Pereira, N.P.; Fernandes, T.; Oliveira, E.M. Circular RNAs as a Diagnostic and Therapeutic Target in Cardiovascular Diseases. Int. J. Mol. Sci. 2023, 24, 2125. [Google Scholar] [CrossRef]
- Goina, C.A.; Goina, D.M.; Farcas, S.S.; Andreescu, N.I. The Role of Circular RNA for Early Diagnosis and Improved Management of Patients with Cardiovascular Diseases. Int. J. Mol. Sci. 2024, 25, 2986. [Google Scholar] [CrossRef]
- He, A.T.; Liu, J.; Li, F.; Yang, B.B. Targeting Circular RNAs as a Therapeutic Approach: Current Strategies and Challenges. Signal Transduct. Target. Ther. 2021, 6, 185. [Google Scholar] [CrossRef]
- Huang, Y.; Su, D.; Ye, B.; Huang, Y.; Qin, S.; Chen, C.; Zhao, Y.; Pang, Y. Expression and Clinical Significance of Circular RNA Hsa_circ_0003416 in Pediatric Pulmonary Arterial Hypertension Associated with Congenital Heart Disease. J. Clin. Lab. Anal. 2022, 36, e24273. [Google Scholar] [CrossRef]
- Yu, H.; Wang, X.; Cao, H. Construction and Investigation of a CircRNA-Associated CeRNA Regulatory Network in Tetralogy of Fallot. BMC Cardiovasc. Disord. 2021, 21, 1–11. [Google Scholar] [CrossRef]
- Huang, S.; Li, X.; Zheng, H.; Si, X.; Li, B.; Wei, G.; Li, C.; Chen, Y.; Chen, Y.; Liao, W.; et al. Loss of Super-Enhancer-Regulated CircRNA Nfix Induces Cardiac Regeneration after Myocardial Infarction in Adult Mice. Circulation 2019, 139, 2857–2876. [Google Scholar] [CrossRef] [PubMed]
- Cai, L.; Qi, B.; Wu, X.; Peng, S.; Zhou, G.; Wei, Y.; Xu, J.; Chen, S.; Liu, S. Circular RNA Ttc3 Regulates Cardiac Function after Myocardial Infarction by Sponging MiR-15b. J. Mol. Cell Cardiol. 2019, 130, 10–22. [Google Scholar] [CrossRef] [PubMed]
- Yates, L.L.; Schnatwinkel, C.; Murdoch, J.N.; Bogani, D.; Formstone, C.J.; Townsend, S.; Greenfield, A.; Niswander, L.A.; Dean, C.H. The PCP Genes Celsr1 and Vangl2 Are Required for Normal Lung Branching Morphogenesis. Hum. Mol. Genet. 2010, 19, 2251–2267. [Google Scholar] [CrossRef]
- Zeng, X.Y.; Yuan, J.; Wang, C.; Zeng, D.; Yong, J.H.; Jiang, X.Y.; Lan, H.; Xiao, S.S. CircCELSR1 Facilitates Ovarian Cancer Proliferation and Metastasis by Sponging MiR-598 to Activate BRD4 Signals. Mol. Med. 2020, 26, 1–14. [Google Scholar] [CrossRef]
- Wang, L.; Liang, W.; Wang, S.; Wang, Z.; Bai, H.; Jiang, Y.; Bi, Y.; Chen, G.; Chang, G. Circular RNA Expression Profiling Reveals That Circ-PLXNA1 Functions in Duck Adipocyte Differentiation. PLoS ONE 2020, 15, e0236069. [Google Scholar] [CrossRef]
- He, K.; Han, S.; An, L.; Zhang, J. Inhibition of MicroRNA-214 Alleviates Lung Injury and Inflammation via Increasing FGFR1 Expression in Ventilator-Induced Lung Injury. Lung 2021, 199, 63–72. [Google Scholar] [CrossRef]
- Fu, M.; Hu, Y.; Lan, T.; Guan, K.L.; Luo, T.; Luo, M. The Hippo Signalling Pathway and Its Implications in Human Health and Diseases. Signal Transduct. Target. Ther. 2022, 7, 1–20. [Google Scholar] [CrossRef]
- Zhou, B.; Flodby, P.; Luo, J.; Castillo, D.R.; Liu, Y.; Yu, F.X.; McConnell, A.; Varghese, B.; Li, G.; Chimge, N.O.; et al. Claudin-18–Mediated YAP Activity Regulates Lung Stem and Progenitor Cell Homeostasis and Tumorigenesis. J. Clin. Investig. 2018, 128, 970. [Google Scholar] [CrossRef] [PubMed]
- Jia, X.; Wu, B.; Huang, J.; Fan, L.; Yang, M.; Xu, W. YAP and Wnt3a Independently Promote AECIIs Proliferation and Differentiation by Increasing Nuclear Β-catenin Expression in Experimental Bronchopulmonary Dysplasia. Int. J. Mol. Med. 2021, 47, 195–206. [Google Scholar] [CrossRef]
- Aspal, M.; Zemans, R.L. Mechanisms of ATII-to-ATI Cell Differentiation during Lung Regeneration. Int. J. Mol. Sci. 2020, 21, 3188. [Google Scholar] [CrossRef]
Organ Dysfunction (OD) | Non-Organ Dysfunction (Ctrl) | p Value | |
---|---|---|---|
Age (mo) | 6.53 ± 5.47 | 6.61 ± 5.79 | 0.39 |
Male (%) | 10 | 20 | 0.27 |
OP time (min) | 487.50 ± 84.80 | 396.00 ± 137.57 | 0.14 |
CPB time (min) | 264.75 ± 31.57 | 196.00 ± 79.46 | 0.08 |
X-clamp time (min) | 152.25 ± 38.30 | 83.00 ± 70.74 | 0.06 |
Circulatory arrest (%) | 25% (1/4) | 60% (3/5) | 0.18 |
Regional perfusion (%) | 25% (1/4) | 60% (3/5) | 0.18 |
MV duration (h) | 325.58 ± 368.99 | 72.58 ± 17.60 | 0.08 |
ICU stay (h) | 442.75 ± 314.65 | 99.00 ± 13.02 | 0.02 * |
LOS (d) | 41.13 ± 24.20 | 13.02 ± 6.53 | 0.02 * |
PELOD 0 | 10.00 ± 2.82 | 7.40 ± 1.40 | 0.05 * |
PELOD 1 | 4.25 ± 0.96 | 5.20 ± 1.10 | 0.11 |
PELOD 2 | 5.00 ± 0.82 | 4.40 ± 2.51 | 0.33 |
Salvaged RBCs (mL/kg) | 39.59 ± 17.55 | 20.62 ± 13.57 | 0.05 * |
Platelets (mL/kg) | 27.75 ± 17.75 | 17.24 ± 5.90 | 0.12 |
Cryoprecipitate (mL/kg) | 10.41 ± 8.80 | 7.30 ± 7.16 | 0.29 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Alhamdan, F.; Yuki, K. Postoperative Organ Dysfunction Risk Stratification Using Extracellular Vesicle-Derived circRNAs in Pediatric Congenital Heart Surgery. Cells 2024, 13, 1417. https://doi.org/10.3390/cells13171417
Alhamdan F, Yuki K. Postoperative Organ Dysfunction Risk Stratification Using Extracellular Vesicle-Derived circRNAs in Pediatric Congenital Heart Surgery. Cells. 2024; 13(17):1417. https://doi.org/10.3390/cells13171417
Chicago/Turabian StyleAlhamdan, Fahd, and Koichi Yuki. 2024. "Postoperative Organ Dysfunction Risk Stratification Using Extracellular Vesicle-Derived circRNAs in Pediatric Congenital Heart Surgery" Cells 13, no. 17: 1417. https://doi.org/10.3390/cells13171417