General Review|Articles in Press

Circulating miRNAs as biomarkers for diagnosis, surveillance and post-operative follow-up of abdominal aortic aneurysms

  • Kalliopi - Maria Tasopoulou
    Corresponding author: Kalliopi - Maria Tasopoulou Department of Vascular Surgery, Democritus University of Thrace, University General Hospital of Alexandroupolis, Dragana Area, Alexandroupolis, Greece, 68100, Tel: +30 6939682259,
    Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece
    Search for articles by this author
  • Christos Argiriou
    Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece
    Search for articles by this author
  • Alexandra K Tsaroucha
    Laboratory of Experimental Surgery and Surgical Research, School of Medicine, Democritus University of Thrace, Alexandroupolis, Greece
    Search for articles by this author
  • George S Georgiadis
    Department of Vascular Surgery, Medical School, Democritus University of Thrace, University General Hospital of Evros, Alexandroupolis, Greece
    Search for articles by this author
Published:March 13, 2023DOI:


      • MiRNAs are good candidates as circulating biomarkers (stability in human blood and high sensitivity/ specificity of expression evaluation).
      • Numerous reports have recently demonstrated differential expression of miRNAs in Cardiovascular, Peripheral Arterial and Aneurysmal disease.
      • A total of 25 reports, published from 2012 to 2022, were included in this review (N=1259 patients with AAA, 90% men).
      • The following miRNAs were identified in more than two references: miR-145, miR-24, miR-33, miR-125, let-7, miR-15, miR-191, miR-29 and miR-133.
      • These nine miRNAs are implicated in known pathogenetic mechanisms for AAA.



      To provide a summary of the current state of research in English medical literature on circulating miRNAs, as biomarkers for AAA. Additionally, for the most commonly mentioned circulating miRNAs in the literature, to attempt a documentation of the biological mechanisms underlying their role in AAA development.


      A literature search was undertaken in the MEDLINE database. Only reports that involved peripheral blood samples (whole blood, plasma, serum) were included. The following terms were used in combination: microrna, mirna, abdominal aortic aneurysm, human, circulating, plasma, serum, endovascular and EVAR.


      A total of 25 reports, published from 2012 to 2022 were included with a total of 1259 patients with AAA, predominantly men (N= 1040, 90%). Six of these reports recruited healthy donors who underwent ultrasound screening for AAA as control samples. The majority of studies were undertaken in plasma samples and the most preferred microRNA profiling method was Real - Time quantitative polymerase chain reaction (qRT-PCR). The following nine miRNAs (out of a total of 76) were studied in more than two references: miR-145, miR-24, miR-33, miR-125, let-7, miR-15, miR-191, miR-29 and miR-133.


      The nine miRNAs described in this study, are implicated in known pathogenetic mechanisms of AAA such as atherosclerosis, vascular smooth muscle cell phenotype switch and apoptosis, vascular inflammation, extracellular matrix degradation and lipid metabolism. Identifying disease-specific miRNAs, in combination with other clinical parameters, as indicators of AAA, is crucial for early diagnosis as well as follow-up of AAAs. For future research on miRNAs as AAA biomarkers, strict case and control group definitions, sample acquisition protocols, and miRNA expression profiling techniques are warranted.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Annals of Vascular Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      9. References

        • Sprynger M
        • Willems M
        • Van Damme H
        • et al.
        Screening Program of Abdominal Aortic Aneurysm.
        Angiology. 2019; 70: 407-413
        • Howard DPJ
        • Banerjee A
        • Fairhead JF
        • et al.
        Age-specific incidence, risk factors and outcome of acute abdominal aortic aneurysms in a defined population.
        Br J Surg. 2015; 102: 907-915
        • Kumar S
        • Boon RA
        • Maegdefessel L
        • et al.
        Role of Noncoding RNAs in the Pathogenesis of Abdominal Aortic Aneurysm: Possible Therapeutic Targets?.
        Circ Res. 2019; 124: 619-630
        • Gurung R
        • Choong AM
        • Woo CC
        • et al.
        Genetic and Epigenetic Mechanisms Underlying Vascular Smooth Muscle Cell Phenotypic Modulation in Abdominal Aortic Aneurysm.
        Int J Mol Sci. 2020; 21: 6334
        • Kabłak-Ziembicka A
        • Badacz R
        • Przewłocki T
        Clinical Application of Serum microRNAs in Atherosclerotic Coronary Artery Disease.
        J Clin Med. 2022; 11: 6849
        • Zampetaki A
        • Mayr M
        Analytical challenges and technical limitations in assessing circulating MiRNAs.
        Thromb Haemost. 2012; 108: 592-598
        • Hasemaki N
        • Andreou N-P
        • Legaki E
        • et al.
        Association of miRNA-145 Single Nucleotide Polymorphisms in Abdominal Aortic Aneurysms.
        In Vivo. 2022; 36: 1120-1125
        • Wågsäter D
        • Ravn H
        • Wanhainen A
        • et al.
        Circulating microRNA in patients with popliteal and multiple artery aneurysms.
        JVS Vasc Sci. 2021; 2: 129-135
        • Courtois A
        • Nusgens B
        • Garbacki N
        • et al.
        Circulating microRNAs signature correlates with positive [18F]fluorodeoxyglucose-positron emission tomography in patients with abdominal aortic aneurysm.
        J Vasc Surg. 2018; 67: 585-595.e3
        • Hildebrandt A
        • Kirchner B
        • Meidert AS
        • et al.
        Detection of Atherosclerosis by Small RNA-Sequencing Analysis of Extracellular Vesicle Enriched Serum Samples.
        Front Cell Dev Biol. 2021; 9729061
        • Lareyre F
        • Clément M
        • Moratal C
        • et al.
        Differential micro-RNA expression in diabetic patients with abdominal aortic aneurysm.
        Biochimie. 2019; 162: 1-7
        • Zalewski DP
        • Ruszel KP
        • Stępniewski A
        • et al.
        Dysregulation of microRNA Modulatory Network in Abdominal Aortic Aneurysm.
        J Clin Med. 2020; 9: 1974
        • Spear R
        • Boytard L
        • Blervaque R
        • et al.
        Adventitial Tertiary Lymphoid Organs as Potential Source of MicroRNA Biomarkers for Abdominal Aortic Aneurysm.
        Int J Mol Sci. 2015; 16: 11276-11293
        • Tenorio EJR
        • Braga AFF
        • Tirapelli DPDC
        • et al.
        Expression in Whole Blood Samples of miRNA-191 and miRNA-455-3p in Patients with AAA and Their Relationship to Clinical Outcomes after Endovascular Repair.
        Ann Vasc Surg. 2018; 50: 209-217
        • Missae L
        • Rossoni B
        • Tenorio EJR
        • et al.
        Expression of MicroRNA-1281, C-Reactive Protein, and Renal Function in Individuals with Abdominal Aortic Aneurysm and their Clinical Correlation after Endovascular Repair.
        Braz J Cardiovasc Surg. 2021; 36 (Epub ahead of print)
        • Torres-Do Rego A
        • Barrientos M
        • Ortega-Hernández A
        • et al.
        Identification of a Plasma Microrna Signature as Biomarker of Subaneurysmal Aortic Dilation in Patients with High Cardiovascular Risk.
        J Clin Med. 2020; 9: 2783
        • Stather PW
        • Sylvius N
        • Sidloff DA
        • et al.
        Identification of microRNAs associated with abdominal aortic aneurysms and peripheral arterial disease.
        Br J Surg. 2015; 102: 755-766
        • Spear R
        • Boytard L
        • Blervaque R
        • et al.
        Let-7f: A New Potential Circulating Biomarker Identified by miRNA Profiling of Cells Isolated from Human Abdominal Aortic Aneurysm.
        Int J Mol Sci. 2019; 20: 5499
        • Biros E
        • Moran CS
        • Wang Y
        • et al.
        microRNA profiling in patients with abdominal aortic aneurysms: the significance of miR-155.
        Clin Sci. 2014; 126: 795-803
        • Peng J
        • He X
        • Zhang L
        • et al.
        MicroRNA-26a protects vascular smooth muscle cells against H2O2-induced injury through activation of the PTEN/AKT/mTOR pathway.
        Int J Mol Med. 27 June 2018; (Epub ahead of print)
        • Maegdefessel L
        • Spin JM
        • Raaz U
        • et al.
        miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development.
        Nat Commun. 2014; 5: 5214
        • Li Y
        • Lv M
        • Lu M
        • et al.
        miR-124a Involves in the Regulation of Wnt/β-Catenin and P53 Pathways to Inhibit Abdominal Aortic Aneurysm via Targeting BRD4.
        Comput Math Methods Med 2022. 2022; : 1-11
        • Zhang C
        • Wang H
        • Yang B
        miR-146a regulates inflammation and development in patients with abdominal aortic aneurysms by targeting CARD10.
        Int Angiol. October 2020; 39 (Epub ahead of print)
        • Lichołai S
        • Studzińska D
        • Plutecka H
        • et al.
        MiR-191 as a Key Molecule in Aneurysmal Aortic Remodeling.
        Biomolecules. 2021; 11: 1611
        • Ma X
        • Yao H
        • Yang Y
        • et al.
        miR-195 suppresses abdominal aortic aneurysm through the TNF-α/NF-κB and VEGF/PI3K/Akt pathway.
        Int J Mol Med. 25 January 2018; (Epub ahead of print)
        • Zhou F
        • Zheng Z
        • Zha Z
        • et al.
        Nuclear Paraspeckle Assembly Transcript 1 Enhances Hydrogen Peroxide-Induced Human Vascular Smooth Muscle Cell Injury by Regulating miR-30d-5p/A Disintegrin and Metalloprotease 10.
        Circ J. 2022; 86: 1007-1018
        • Zhang W
        • Shang T
        • Huang C
        • et al.
        Plasma microRNAs serve as potential biomarkers for abdominal aortic aneurysm.
        Clin Biochem. 2015; 48: 988-992
        • Zampetaki A
        • Attia R
        • Mayr U
        • et al.
        Role of miR-195 in Aortic Aneurysmal Disease.
        Circ Res. 2014; 115: 857-866
        • Wanhainen A
        • Mani K
        • Vorkapic E
        • et al.
        Screening of circulating microRNA biomarkers for prevalence of abdominal aortic aneurysm and aneurysm growth.
        Atherosclerosis. 2017; 256: 82-88
        • Kin K
        • Miyagawa S
        • Fukushima S
        • et al.
        Tissue‐ and Plasma‐Specific MicroRNA Signatures for Atherosclerotic Abdominal Aortic Aneurysm.
        J Am Heart Assoc. 2012; 1e000745
        • Han Z-L
        • Wang H-Q
        • Zhang T-S
        • et al.
        Up-regulation of exosomal miR-106a may play a significant role in abdominal aortic aneurysm by inducing vascular smooth muscle cell apoptosis and targeting TIMP-2, an inhibitor of metallopeptidases that suppresses extracellular matrix degradation.
        Eur Rev Med Pharmacol Sci. 2020; 24: 8087-8095
        • Davis FM
        • Rateri DL
        • Daugherty A
        Mechanisms of aortic aneurysm formation: translating preclinical studies into clinical therapies.
        Heart. 2014; 100: 1498-1505
        • Cheng Y
        • Liu X
        • Yang J
        • et al.
        MicroRNA-145, a Novel Smooth Muscle Cell Phenotypic Marker and Modulator, Controls Vascular Neointimal Lesion Formation.
        Circ Res. 2009; 105: 158-166
      1. Mirbase (accessed December 14, 2022).

        • Elia L
        • Quintavalle M
        • Zhang J
        • et al.
        The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease.
        Cell Death Differ. 2009; 16: 1590-1598
        • Liao M
        • Zou S
        • Weng J
        • et al.
        A microRNA profile comparison between thoracic aortic dissection and normal thoracic aorta indicates the potential role of microRNAs in contributing to thoracic aortic dissection pathogenesis.
        J Vasc Surg. 2011; 53: 1341-1349.e3
        • Boettger T
        • Beetz N
        • Kostin S
        • et al.
        Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster.
        J Clin Invest. 2009; 119: 2634-2647
        • Maegdefessel L
        • Rayner KJ
        • Leeper NJ
        MicroRNA Regulation of Vascular Smooth Muscle Function and Phenotype: Early Career Committee Contribution.
        Arterioscler Thromb Vasc Biol. 2015; 35: 2-6
        • Tang Y
        • Fan W
        • Zou B
        • et al.
        TGF-β signaling and microRNA cross-talk regulates abdominal aortic aneurysm progression.
        Clin Chim Acta. 2021; 515: 90-95
        • Araujo NNF de
        • Lin-Wang HT
        • Germano J de F
        • et al.
        Dysregulation of microRNAs and target genes networks in human abdominal aortic aneurysm tissues.
        PLoS One. 2019; 14e0222782
        • Moushi A
        • Michailidou K
        • Soteriou M
        • et al.
        MicroRNAs as possible biomarkers for screening of aortic aneurysms: a systematic review and validation study.
        Biomarkers. 2018; 23: 253-264
        • Santoro MM
        • Nicoli S
        miRNAs in endothelial cell signaling: The endomiRNAs.
        Exp Cell Res. 2013; 319: 1324-1330
        • Fiedler J
        • Jazbutyte V
        • Kirchmaier BC
        • et al.
        MicroRNA-24 Regulates Vascularity After Myocardial Infarction.
        Circulation. 2011; 124: 720-730
        • Wang S
        • Cao N
        Uncovering potential differentially expressed miRNAs and targeted mRNAs in myocardial infarction based on integrating analysis.
        Mol Med Rep. 17 September 2020; (Epub ahead of print)
        • Mangum KD
        • Farber MA
        Genetic and epigenetic regulation of abdominal aortic aneurysms.
        Clin Genet. 2020; 97: 815-826
        • Gelissen IC
        • Jessup W
        MicroRNA-33: natureʼs own RNAi controls cholesterol homeostasis.
        Curr Opin Lipidol. 2010; 21: 464-465
        • Xie Q
        • Peng J
        • Guo Y
        • et al.
        MicroRNA-33-5p inhibits cholesterol efflux in vascular endothelial cells by regulating citrate synthase and ATP-binding cassette transporter A1.
        BMC Cardiovasc Disord. 2021; 21: 433
        • Niesor EJ
        • Schwartz GG
        • Perez A
        • et al.
        Statin-Induced Decrease in ATP-Binding Cassette Transporter A1 Expression via microRNA33 Induction may Counteract Cholesterol Efflux to High-Density Lipoprotein.
        Cardiovasc Drugs Ther. 2015; 29: 7-14
        • Ouimet M
        • Ediriweera HN
        • Gundra UM
        • et al.
        MicroRNA-33–dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis.
        J Clin Invest. 2015; 125: 4334-4348
        • Ouimet M
        • Ediriweera H
        • Afonso MS
        • et al.
        microRNA-33 Regulates Macrophage Autophagy in Atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2017; 37: 1058-1067
        • Huang K
        • Bao H
        • Yan Z-Q
        • et al.
        MicroRNA-33 protects against neointimal hyperplasia induced by arterial mechanical stretch in the grafted vein.
        Cardiovasc Res. 2017; 113: 488-497
        • Nakao T
        • Horie T
        • Baba O
        • et al.
        Genetic Ablation of MicroRNA-33 Attenuates Inflammation and Abdominal Aortic Aneurysm Formation via Several Anti-Inflammatory Pathways.
        Arterioscler Thromb Vasc Biol. 2017; 37: 2161-2170
        • Chen Z
        • Wang M
        • Huang K
        • et al.
        MicroRNA-125b Affects Vascular Smooth Muscle Cell Function by Targeting Serum Response Factor.
        Cell Physiol Biochem. 2018; 46: 1566-1580
        • Wang Y
        • Tan J
        • Wang L
        • et al.
        MiR-125 Family in Cardiovascular and Cerebrovascular Diseases.
        Front Cell Dev Biol. 2021; 9799049
        • Wang X
        • Chen S
        • Gao Y
        • et al.
        MicroRNA-125b inhibits the proliferation of vascular smooth muscle cells induced by platelet-derived growth factor BB.
        Exp Ther Med. 2021; 22: 791
        • Knappich C
        • Spin JM
        • Eckstein H-H
        • et al.
        Involvement of Myeloid Cells and Noncoding RNA in Abdominal Aortic Aneurysm Disease.
        Antioxid Redox Signal. 2020; 33: 602-620
        • Hao L
        • Wang X
        • Cheng J
        • et al.
        The up-regulation of endothelin-1 and down-regulation of miRNA-125a-5p, -155, and -199a/b-3p in human atherosclerotic coronary artery.
        Cardiovasc Pathol. 2014; 23: 217-223
        • Lee H
        • Han S
        • Kwon CS
        • et al.
        Biogenesis and regulation of the let-7 miRNAs and their functional implications.
        Protein Cell. 2016; 7: 100-113
        • Stather PW
        • Sylvius N
        • Wild JB
        • et al.
        Differential MicroRNA Expression Profiles in Peripheral Arterial Disease.
        Circ Cardiovasc Genet. 2013; 6: 490-497
        • Bao M-H
        • Feng X
        • Zhang Y-W
        • et al.
        Let-7 in Cardiovascular Diseases, Heart Development and Cardiovascular Differentiation from Stem Cells.
        Int J Mol Sci. 2013; 14: 23086-23102
        • Ji R
        • Cheng Y
        • Yue J
        • et al.
        MicroRNA Expression Signature and Antisense-Mediated Depletion Reveal an Essential Role of MicroRNA in Vascular Neointimal Lesion Formation.
        Circ Res. 2007; 100: 1579-1588
        • Li T
        • Cao H
        • Zhuang J
        • et al.
        Identification of miR-130a, miR-27b and miR-210 as serum biomarkers for atherosclerosis obliterans.
        Clin Chim Acta. 2011; 412: 66-70
        • Ghafouri-Fard S
        • Khoshbakht T
        • Hussen BM
        • et al.
        A Comprehensive Review on Function of miR-15b-5p in Malignant and Non-Malignant Disorders.
        Front Oncol. 2022; 12870996
        • Quann K
        • Jing Y
        • Rigoutsos I
        Post-transcriptional regulation of BRCA1 through its coding sequence by the miR-15/107 group of miRNAs.
        Front Genet. 24 July 2015; 6 (Epub ahead of print)
        • Sun C-Y
        • She X-M
        • Qin Y
        • et al.
        miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF.
        Carcinogenesis. 2013; 34: 426-435
        • Gao P
        • Si J
        • Yang B
        • et al.
        Upregulation of MicroRNA-15a Contributes to Pathogenesis of Abdominal Aortic Aneurysm (AAA) by Modulating the Expression of Cyclin-Dependent Kinase Inhibitor 2B (CDKN2B).
        Med Sci Monit. 2017; 23: 881-888
        • Gan S
        • Mao J
        • Pan Y
        • et al.
        hsa-miR-15b-5p regulates the proliferation and apoptosis of human vascular smooth muscle cells by targeting the ACSS2/PTGS2 axis.
        Exp Ther Med. 2021; 22: 1208
        • Borek A
        • Drzymała F
        • Botor M
        • et al.
        Roles of microRNAs in abdominal aortic aneurysm pathogenesis and the possibility of their use as biomarkers.
        Kardiochir Torakochirurgia Pol. 2019; 16: 124-127
        • Prinz C
        • Frese R
        • Grams M
        • et al.
        Emerging Role of microRNA Dysregulation in Diagnosis and Prognosis of Extrahepatic Cholangiocarcinoma.
        Genes. 2022; 13: 1479
        • Jing X
        • Du L
        • Shi S
        • et al.
        Hypoxia-Induced Upregulation of lncRNA ELFN1-AS1 Promotes Colon Cancer Growth and Metastasis Through Targeting TRIM14 via Sponging miR-191-5p.
        Front Pharmacol. 2022; 13806682
        • Kazempour Dizaji M
        • Farzanegan B
        • Bahrami N
        • et al.
        Expression of miRNA1, miRNA133, miRNA191, and miRNA24, as Good Biomarkers, in Non-Small Cell Lung Cancer Using Real-Time PCR Method.
        Asian Pac J Cancer Prev. 2022; 23: 1565-1570
        • Wu Y
        • Yang S
        • Zheng Z
        • et al.
        MiR-191-5p Disturbed the Angiogenesis in a Mice Model of Cerebral Infarction by Targeting Inhibition of BDNF.
        Neurol India. 2021; 69: 1601
        • Gu Y
        • Ampofo E
        • Menger MD
        • et al.
        miR‐191 suppresses angiogenesis by activation of NF‐kB signaling.
        FASEB J. 2017; 31: 3321-3333
        • Mott JL
        • Kobayashi S
        • Bronk SF
        • et al.
        mir-29 regulates Mcl-1 protein expression and apoptosis.
        Oncogene. 2007; 26: 6133-6140
        • Park S-Y
        • Lee JH
        • Ha M
        • et al.
        miR-29 miRNAs activate p53 by targeting p85α and CDC42.
        Nat Struct Mol Biol. 2009; 16: 23-29
        • Quintana RA
        • Taylor WR
        Cellular Mechanisms of Aortic Aneurysm Formation.
        Circ Res. 2019; 124: 607-618
        • Maegdefessel L
        • Azuma J
        • Tsao PS
        MicroRNA-29b regulation of abdominal aortic aneurysm development.
        Trends Cardiovac Med. 2014; 24: 1-6
        • Maegdefessel L
        • Azuma J
        • Toh R
        • et al.
        Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development.
        J Clin Invest. 2012; 122: 497-506
        • Boon RA
        • Seeger T
        • Heydt S
        • et al.
        MicroRNA-29 in Aortic Dilation: Implications for Aneurysm Formation.
        Circ Res. 2011; 109: 1115-1119
        • Liu N
        • Bezprozvannaya S
        • Williams AH
        • et al.
        microRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart.
        Genes Dev. 2008; 22: 3242-3254
        • Abdellatif M
        Differential Expression of MicroRNAs in Different Disease States.
        Circ Res. 2012; 110: 638-650
        • Carè A
        • Catalucci D
        • Felicetti F
        • et al.
        MicroRNA-133 controls cardiac hypertrophy.
        Nat Med. 2007; 13: 613-618
        • Torella D
        • Iaconetti C
        • Catalucci D
        • et al.
        MicroRNA-133 Controls Vascular Smooth Muscle Cell Phenotypic Switch In Vitro and Vascular Remodeling In Vivo.
        Circ Res. 2011; 109: 880-893
        • Iyer V
        • Rowbotham S
        • Biros E
        • et al.
        A systematic review investigating the association of microRNAs with human abdominal aortic aneurysms.
        Atherosclerosis. 2017; 261: 78-89
        • Pahl MC
        • Derr K
        • Gäbel G
        • et al.
        MicroRNA expression signature in human abdominal aortic aneurysms.
        BMC Med Genomics. 2012; 5: 25
        • Carvalho LSF
        Can microRNAs improve prediction of abdominal aortic aneurysm growth?.
        Atherosclerosis. 2017; 256: 131-133
        • Georgiadis GS
        • Antoniou GA
        • Argyriou C
        • et al.
        Correlation of Baseline Plasma and Inguinal Connective Tissue Metalloproteinases and Their Inhibitors With Late High-Pressure Endoleak After Endovascular Aneurysm Repair: Long-term Results.
        J Endovasc Ther. 2019; 26: 826-835
        • Wang Y
        • Ge W
        • Niu L
        • et al.
        Combined Detection of Plasma Tumor Necrosis Factor-α Converting Enzyme and Notch1 is Valuable in Screening Endoleak After Endovascular Abdominal Aortic Aneurysms Repair.
        Ann Vasc Surg. 2021; 76: 302-308