Microangiopathic disease in the diabetic neuro-ischemic feet: A threatening, often understated contributor, for tissue and limb loss Microangiopathy in the diabetic foot syndrome
Main Article Content
Vlad Adrian Alexandrescu, MD, PhD
http://orcid.org/0000-0002-9181-7993
Arnaud Kerzmann, MD
http://orcid.org/0000-0002-9434-3076
Evelyne Boesmans, MD
Vincent Tchana-Sato, MD, PhD
http://orcid.org/0000-0001-8838-814X
http://orcid.org/0000-0002-9181-7993
Arnaud Kerzmann, MD
http://orcid.org/0000-0002-9434-3076
Evelyne Boesmans, MD
Vincent Tchana-Sato, MD, PhD
http://orcid.org/0000-0001-8838-814X
Abstract
Conventionally, vessels exhibiting diameters between 100 μm and 5 μm are related to the ubiquitarian microcirculatory realm that gathers the arterioles, the capillaries and the venules. This important network represents a fundamental anatomical and functional unit involved in all vital processes of human tissues. The microcirculatory system secures and regulates the microvascular flow and intraluminal pressure within specific organs (including the lower extremities). These purposes are achieved by harmonising the luminal diameter of regional microvessels to the changing metabolic needs, oxygen demand, neurologic signals, and eventual pathological surrounding conditions. Particularly in patients with diabetes mellitus, hyperglycaemia can generate characteristic microcirculatory damage through molecular, biochemical, structural, and functional alterations, which add reactional, self-unfolding, hypoxic and pro-coagulant local tissue conditions. Among various localisations of diabetic microvascular disease (retinopathy, nephropathy, peripheral neuropathy, etc.), diabetic foot microangiopathy essentially produces aberrant arteriolar wall remodelling, coupled with progressive thickening and stiffness of the concerned microvessels, which can lead to increased regional blood flow occlusions and increasing local tissue ischemia. Progressive structural and functional impairment of endothelial cells in arterioles and capillaries is well known in diabetes mellitus and mirrors the gradual loss of microvascular repair ability. Recent video-capillaroscopy research specifically conducted in patients with diabetes documented that the duration of diabetes and the severity of chronic hyperglycaemic levels, significantly influenced the spread and gravity of peripheral diabetic microangiopathy. This latest combined with peripheral macrovascular arterial disease manifested a 12-fold higher risk for major amputation, while suboptimal glycaemic control during and post-revascularization showed a significantly higher propensity for major adverse limb events in patients with chronic arterial disease and diabetic microangiopathy. This review equally avails a succinct overview of current diagnostic and treatment methods applied to diabetic microangiopathy concomitantly to prompt macrovascular revascularization, owing systematic surveillance by a multidisciplinary diabetic foot team. Significant clinical implications of inferior limb microangiopathy isolated, versus associated to diabetic arteriopathy and neuropathy, or to other parallel systemic microvascular manifestations are developed in distinct paragraphs, following referred recommendations, for better clinical knowledge and applicability.
Keywords:
chronic limb-threatening ischemia, hyperglycaemia, diabetic microangiopathy, microcirculation, diabetic peripheral neuropathy, diabetic foot syndrome, arterial calcification, capillary disease, peripheral angioplasty, inferior limb salvage
Article Details
How to Cite
ALEXANDRESCU, Vlad Adrian et al.
Microangiopathic disease in the diabetic neuro-ischemic feet: A threatening, often understated contributor, for tissue and limb loss.
Medical Research Archives, [S.l.], v. 13, n. 7, july 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6730>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i7.6730.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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24. Mustapha JA, Diaz-Sandoval LJ, Saab F. Infra- popliteal calcification patterns in critical limb ischemia: diagnostic, pathologic and therapeutic implications in the search for the endovascular holy grail. J Cardiovasc Surg (Torino). 2017;58: 383–401.
25. Alexandrescu VA, Kerzmann A, Boesmans E, et al. Singularities of the pedal circulation in CLTI: time for novel merging guidelines. J Crit Limb Ischem. 2023;3:E1-E8.
26. O’Neal LW. Surgical pathology of the foot and clinicopathologic correlations. The end-artery occlusive disease conception. In: Bowker JH, Pfeifer MA. Levin and O’Neal’s The Diabetic Foot. 7th Ed. Mosby Elsevier, Philadelphia. 2007:367-401.
27. Conte MS, Bradbury AW, Kolh P, et al. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. Eur. J. Vasc. Endovasc. Surg.2019, 58, S1-S109.e133.
28. Thiruvoipati T, Kielhorn CE Armstrong EJ. Peripheral artery disease in patients with diabetes: epidemiology, mechanisms, and outcomes. World J. Diabetes. 2015; 6: 961–969.
29. Jude EB, Oyibo SO, Chalmers N, Boulton AJ. Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Diabetes Care. 2001; 24: 1433–1437.
30. Kris K, Olesen W, Anand S, Thim T, Gyldenkerne C, Maeng M. Microvascular disease increases the risk of lower limb amputation - a western danish cohort study. Eur J Clin Invest. 2022; 52(10): e13812 doi: 10.1111/eci.13812.
31. Arya S, Binney ZO, Khakharia A, et al. High haemoglobin A. J. Vasc. Surg. 2018; 67: 217–228.e211.
32. Cha JJ, Kim H, Ko YG, et al. Influence of preprocedural glycemic control on clinical outcomes of endovascular therapy in diabetic patients with lower extremity artery disease: an analysis from a Korean multicenter retrospective registry cohort. Cardiovasc. Diabetol. 2020; 19: 1–10.
33. Chen L, Chen D, Gong H et al. Pedal medial arterial calcification in diabetic foot ulcers: a significant risk factor of amputation and mortality. Journal of Diabetes. 2024;16:e13527. https://doi.org/10.1111/1753-0407.13527
34. Ferraresi R, Ucci A, Pizzuto A, et al. A novel scoring system for small artery disease and medial arterial calcification is strongly associated with major adverse Limb events in patients with chronic limb-threatening ischemia. J Endovasc Ther. 2021; 28(2):194-207.
35. Alexandrescu VA, Brochier S, Schoenen S, et al. Grades of below-the-ankle arterial occlusive disease following the angiosome perfusion: a new morphological assessment and correlations with the inframalleolar GVG stratification in CLTI patients. Ann Vasc Surg. 2022.1;1-20. https://doi.org/10.1016/j.avsg.2021.09.031
36. Biscetti F, Nardella E, Rando MM, et al. Outcomes of lower extremity endovascular revascularization: Potential predictors and prevention strategies. Int. J. Mol. Sci. 2021; 22: 2002. https://doi.org/10.3390/ ijms22042002
37. Lowry D, Saeed M, Narendran P, Tiwari A. The difference between the healing and the nonhealing diabetic foot ulcer: a review of the role of the microcirculation. Journal of Diabetes Science and Technology. 2017;11(5): 914–923
38. LoGerfo FW, Coffman JD. Vascular and microvascular disease of the foot in diabetes. Implications for foot care. N Engl J Med. 1984; 311:1615–1619.
39. Song K, Chambers AR. Diabetic foot care. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. 2025, PMID: 31971750.
40. Farber A. Chronic limb-threatening ischemia. N Engl J Med. 2018;379:171– 180. doi: 10.1056/ NEJMcp1709326
41. Teso D, Sommerset J, Dally M, et al. Pedal acceleration time (PAT): A novel predictor of limb salvage. Ann Vasc Surg 2021; 75: 189–193. https://doi.org/10.1016/j.avsg.2021.02.038
42. Li FM, Liang HL, Wu TH. Pulsatility-index adjusted doppler flow measurement of pedal arteries in peripheral artery disease patients. J. Clin. Med. 2021, 10, x. https://doi.org/10.3390/xxxxx
43. Utsunomiya M, Nakamura M, Nagashima Y, et al. Predictive value of skin perfusion pressure after endovascular therapy for wound healing in critical limb ischemia. J Endovasc Ther 2014; 21: 662–670.
44. Boezeman RP, Becx BP, van den Heuvel D, et al. Monitoring of foot oxygenation with near-infrared spectroscopy in patients with critical limb ischemia undergoing percutaneous transluminal angioplasty: a pilot study. Eur J Vasc Endovasc Surg 2016; 52: 650–656.
45. Chiang N, Jain JK, Sleigh J, et al. Evaluation of hyper- spectral imaging technology in patients with peripheral vascular disease. J Vasc Surg 2017; 66: 1192–1201.
46. Guven G, Dijkstra A, Kuijper TM, et al. Comparison of laser speckle contrast imaging with laser Doppler perfusion imaging for tissue perfusion measurement. Microcirculation. 2023;30:e12795. https://doi.org/10.1111/micc.12795
47. Venermo M, Settembre N, Alback A, et al. Pilot assessment of the repeatability of indocyanine green fluores- cence imaging and correlation with traditional foot perfusion assessments. Eur J Vasc Endovasc Surg 2016; 52: 527–533.
48. Pantoja JL, Ali F, Baril DT, et al. Arterial spin labeling magnetic resonance imaging quantifies tissue perfusion around foot ulcers. J Vasc Surg Cases Innov Tech. 2022;3;8(4):817-824. doi: 10.1016/j.jvscit.2022.09.015.
49. Stacy MR, Zhou W, Sinusas AJ. Radiotracer imaging of peripheral vascular disease. J Nucl Med Technol 2015; 43: 185–192.
50. Alexandrescu VA, Neville RF, Kerzmann A, et al. Applicability of intentional topographic revascularization following the angiosome model in patients with chronic limb-threatening ischemia: from theory, to current clinical challenges. Clin Surg. 2024;9: 3701. DOI: https://dx.doi.org/10.25107/cis-v9-id3701
51. Diehm N. Commentary: Intra-arterial subtraction angiography: what you see is not always what you get. J Endovasc Ther 22: 252-253.
52. Lyssenko V, Vaag A. Genetics of diabetes‐associated microvascular complications. Diabetologia (2023) 66:1601–1613. https://doi.org/10.1007/s00125-023-05964-x
53. Katsui S, Inoue Y, Yamamoto Y et al. In patients with severe peripheral arterial disease, revascularization-induced improvement in lower extremity ischemia can be detected by laser speckle contrast imaging of the fluctuation in blood perfusion after local heating. Ann Vasc Surg. 2018; 48: 67-74. doi: 10.1016/j.avsg.2017.09.022.
54. Montero-Baker MF, Au-Yeung KY, Wisniewski NA, et al. The First-in-Man "Si Se Puede" Study for the use of micro-oxygen sensors (MOXYs) to determine dynamic relative oxygen indices in the feet of patients with limb-threatening ischemia during endovascular therapy. J Vasc Surg. 2015; 61(6):1501-9.e1.doi: 10.1016/j.jvs.2014.12.060.
55. Ahmed Z, Ochoa-Prieto M, Bhalla A, Strosberg DS, Dardik A, Altin SE. How much flow is enough: the use of fractional flow reserve in chronic limb-threatening ischemia in a series of patients with isolated occlusive tibial disease. J Vasc Surg Cases Innov Tech. 2023; 9:101017. https://doi.org/10.1016/j.jvscit.2022.08.022
2. Mansour A, Mousa M, Abdelmannan D, Tay G, Hassoun A, Alsafar A. Microvascular and macrovascular complications of type 2 diabetes mellitus: exome wide association analyses. Front. Endocrinol. 14:1143067. doi: 10.3389/fendo.2023.1143067
3. Hinchliffe RJ, Andros G, Apelqvist J, et al. A systematic review of the effectiveness of revascularization of the ulcer- ated foot in patients with diabetes and peripheral disease. Diabetes Metab Res Rev. 2012;28(suppl 1):179–217.
4. Alexandrescu VA, Van Overmeire L, Makrygiannis G, et al. Clinical implications of diabetic peripheral neuropathy in primary infrapopliteal angioplasty approach for neuro-ischemic foot wounds. J Endovasc Ther. 2022;1-11. DOI: 10.1177/15266028221106312
5. Smith AD, Hawkins AT, Schaumeier MJ, et al. Predictors of major amputation despite patent bypass grafts. J Vasc Surg. 2016; 63: 1279-88. http://dx.doi.org/10.1016/j.jvs.2015.10.101
6. Alexandrescu VA, Pottier M, Balthazar S, Azdad K. The foot angiosomes as integrated level of lower limb arterial perfusion: amendments for chronic limb threatening ischemia presentations. J Vasc Endovasc Ther. 2019;4(1):1-7. http://vascular-endovascular- surgery.imedpub.com/
7. Behroozian A, Beckman JA. Microvascular disease increases amputation in patients with peripheral artery disease. Arterioscler Thromb Vasc Biol. 202 0;40:534-540. www.ahajournals.org/journal/atvb. DOI: 10.1161/ATVBAHA.119.312859
8. Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care. 2015;19(3):S8.
9. Sharma S, Schaper N, Rayman G. Microangiopathy: is it relevant to wound healing in diabetic foot disease? Diabetes Metab Res Rev. 2020;36(S1): e3244 https://doi.org/10.1002/dmrr.3244
10. Hingorani A, LaMuraglia GM, Henke P, et al. The management of the diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63(2 Suppl):3S–21S. doi: 10.1016/j.jvs.2015.10.003.
11. Jett S, Thompson MR, Awasthi S, et al. Stratification of microvascular disease severity in the foot using spatial frequency domain imaging. J Diabetes Science Technology. 2023;17(1):25-34.
12. Alexandrescu VA, Kerzmann A, Tchana-Sato V. Diabetic neuro-ischaemic foot syndrome and the key underlying interactions between chronic arterial disease and peripheral neuropathy. Medical Research Archives, 2025;13(2). ISSN 2375-1924
13. Yang P, Feng J, Peng Q, Liu X, Fan Zhongcai. Advanced glycation end products: potential mechanism and therapeutic target in cardiovascular complications under diabetes. Hindawi, Oxidative Medicine and Cellular Longevity Volume 2019, ID: 9570616, 12 pages https://doi.org/10.1155/2019/9570616
14. Kintrup S, Listkiewicz L, Arnemann PH, Wagner NM. Nailfold videocapillaroscopy – a novel method for the assessment of hemodynamic incoherence on the ICU. Critical care. 2024;28:400. https://doi.org/10.1186/s13054-024-05194-6
15. Neubauer-Geryk J, Wielicka M, Hoffmann M, Mysliwiec M, Bieniaszewski. The impact of disease duration on microcirculatory dysfunction in young patients with uncomplicated type 1 diabetes. Biomedicines. 2024, 12, 1020. https://doi.org/10.3390/ biomedicines12051020
16. Madonna R, Balistreri CR, Geng YJ, De Caterina R. Diabetic microangiopathy: pathogenetic insights and novel therapeutic approaches. Vascul Pharmacol. 2017;90:1-7. doi: 10.1016/j.vph.2017.01.004.
17. Guven, G.; Hilty, M.P.; Ince, C. Microcirculation: physiology, pathophysiology, and clinical application. Blood Purif. 2020, 49,143–150.
18. Siperstein M, Unger RH, Madison L. Studies of muscle capillary basement membranes in normal subjects, diabetic, and prediabetic patients. J Clin Investig.1968;47(9):1973-1999.
19. Jaalouk DE, Lammerding J. Mechano- transduction gone awry. Nat Rev Mol Cell Biol. 2009;10:63–73.
20. Lanzer P, Hannan FM, Lanzer D, et al. Medial arterial calcification JACC state-of-the art review. JACC.2021;78(11): 1146-1165. https://doi.org/10.1016/j.jacc.2021.06.049
21. Ngai D, Lino M, Rothenberg KE, Simmons CA, Fernandez-Gonzalez R, Bendeck MP. DDR1 (discoidin domain receptor-1)-RhoA (Ras homolog family member A) axis senses matrix stiffness to promote vascular calcification. Arterioscler Thromb Vasc Biol. 2020;40:1763–1776.
22. Edmonds ME, Morrison N, Laws JW, et al. Medial arte- rial calcification and diabetic neuropathy. Br Med J. 1982;284(6320):928–930. doi:10.1136/bmj.284.6320.928.
23. Duque A, Mediano MF, De Lorenzo A, et al. Cardiovascular autonomic neuropathy in diabetes: pathophysiology, clinical assessment and implications. World J Diabetes.2021;12(6):855–867. doi:10.4239/wjd.v12.i6.855.
24. Mustapha JA, Diaz-Sandoval LJ, Saab F. Infra- popliteal calcification patterns in critical limb ischemia: diagnostic, pathologic and therapeutic implications in the search for the endovascular holy grail. J Cardiovasc Surg (Torino). 2017;58: 383–401.
25. Alexandrescu VA, Kerzmann A, Boesmans E, et al. Singularities of the pedal circulation in CLTI: time for novel merging guidelines. J Crit Limb Ischem. 2023;3:E1-E8.
26. O’Neal LW. Surgical pathology of the foot and clinicopathologic correlations. The end-artery occlusive disease conception. In: Bowker JH, Pfeifer MA. Levin and O’Neal’s The Diabetic Foot. 7th Ed. Mosby Elsevier, Philadelphia. 2007:367-401.
27. Conte MS, Bradbury AW, Kolh P, et al. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. Eur. J. Vasc. Endovasc. Surg.2019, 58, S1-S109.e133.
28. Thiruvoipati T, Kielhorn CE Armstrong EJ. Peripheral artery disease in patients with diabetes: epidemiology, mechanisms, and outcomes. World J. Diabetes. 2015; 6: 961–969.
29. Jude EB, Oyibo SO, Chalmers N, Boulton AJ. Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Diabetes Care. 2001; 24: 1433–1437.
30. Kris K, Olesen W, Anand S, Thim T, Gyldenkerne C, Maeng M. Microvascular disease increases the risk of lower limb amputation - a western danish cohort study. Eur J Clin Invest. 2022; 52(10): e13812 doi: 10.1111/eci.13812.
31. Arya S, Binney ZO, Khakharia A, et al. High haemoglobin A. J. Vasc. Surg. 2018; 67: 217–228.e211.
32. Cha JJ, Kim H, Ko YG, et al. Influence of preprocedural glycemic control on clinical outcomes of endovascular therapy in diabetic patients with lower extremity artery disease: an analysis from a Korean multicenter retrospective registry cohort. Cardiovasc. Diabetol. 2020; 19: 1–10.
33. Chen L, Chen D, Gong H et al. Pedal medial arterial calcification in diabetic foot ulcers: a significant risk factor of amputation and mortality. Journal of Diabetes. 2024;16:e13527. https://doi.org/10.1111/1753-0407.13527
34. Ferraresi R, Ucci A, Pizzuto A, et al. A novel scoring system for small artery disease and medial arterial calcification is strongly associated with major adverse Limb events in patients with chronic limb-threatening ischemia. J Endovasc Ther. 2021; 28(2):194-207.
35. Alexandrescu VA, Brochier S, Schoenen S, et al. Grades of below-the-ankle arterial occlusive disease following the angiosome perfusion: a new morphological assessment and correlations with the inframalleolar GVG stratification in CLTI patients. Ann Vasc Surg. 2022.1;1-20. https://doi.org/10.1016/j.avsg.2021.09.031
36. Biscetti F, Nardella E, Rando MM, et al. Outcomes of lower extremity endovascular revascularization: Potential predictors and prevention strategies. Int. J. Mol. Sci. 2021; 22: 2002. https://doi.org/10.3390/ ijms22042002
37. Lowry D, Saeed M, Narendran P, Tiwari A. The difference between the healing and the nonhealing diabetic foot ulcer: a review of the role of the microcirculation. Journal of Diabetes Science and Technology. 2017;11(5): 914–923
38. LoGerfo FW, Coffman JD. Vascular and microvascular disease of the foot in diabetes. Implications for foot care. N Engl J Med. 1984; 311:1615–1619.
39. Song K, Chambers AR. Diabetic foot care. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing. 2025, PMID: 31971750.
40. Farber A. Chronic limb-threatening ischemia. N Engl J Med. 2018;379:171– 180. doi: 10.1056/ NEJMcp1709326
41. Teso D, Sommerset J, Dally M, et al. Pedal acceleration time (PAT): A novel predictor of limb salvage. Ann Vasc Surg 2021; 75: 189–193. https://doi.org/10.1016/j.avsg.2021.02.038
42. Li FM, Liang HL, Wu TH. Pulsatility-index adjusted doppler flow measurement of pedal arteries in peripheral artery disease patients. J. Clin. Med. 2021, 10, x. https://doi.org/10.3390/xxxxx
43. Utsunomiya M, Nakamura M, Nagashima Y, et al. Predictive value of skin perfusion pressure after endovascular therapy for wound healing in critical limb ischemia. J Endovasc Ther 2014; 21: 662–670.
44. Boezeman RP, Becx BP, van den Heuvel D, et al. Monitoring of foot oxygenation with near-infrared spectroscopy in patients with critical limb ischemia undergoing percutaneous transluminal angioplasty: a pilot study. Eur J Vasc Endovasc Surg 2016; 52: 650–656.
45. Chiang N, Jain JK, Sleigh J, et al. Evaluation of hyper- spectral imaging technology in patients with peripheral vascular disease. J Vasc Surg 2017; 66: 1192–1201.
46. Guven G, Dijkstra A, Kuijper TM, et al. Comparison of laser speckle contrast imaging with laser Doppler perfusion imaging for tissue perfusion measurement. Microcirculation. 2023;30:e12795. https://doi.org/10.1111/micc.12795
47. Venermo M, Settembre N, Alback A, et al. Pilot assessment of the repeatability of indocyanine green fluores- cence imaging and correlation with traditional foot perfusion assessments. Eur J Vasc Endovasc Surg 2016; 52: 527–533.
48. Pantoja JL, Ali F, Baril DT, et al. Arterial spin labeling magnetic resonance imaging quantifies tissue perfusion around foot ulcers. J Vasc Surg Cases Innov Tech. 2022;3;8(4):817-824. doi: 10.1016/j.jvscit.2022.09.015.
49. Stacy MR, Zhou W, Sinusas AJ. Radiotracer imaging of peripheral vascular disease. J Nucl Med Technol 2015; 43: 185–192.
50. Alexandrescu VA, Neville RF, Kerzmann A, et al. Applicability of intentional topographic revascularization following the angiosome model in patients with chronic limb-threatening ischemia: from theory, to current clinical challenges. Clin Surg. 2024;9: 3701. DOI: https://dx.doi.org/10.25107/cis-v9-id3701
51. Diehm N. Commentary: Intra-arterial subtraction angiography: what you see is not always what you get. J Endovasc Ther 22: 252-253.
52. Lyssenko V, Vaag A. Genetics of diabetes‐associated microvascular complications. Diabetologia (2023) 66:1601–1613. https://doi.org/10.1007/s00125-023-05964-x
53. Katsui S, Inoue Y, Yamamoto Y et al. In patients with severe peripheral arterial disease, revascularization-induced improvement in lower extremity ischemia can be detected by laser speckle contrast imaging of the fluctuation in blood perfusion after local heating. Ann Vasc Surg. 2018; 48: 67-74. doi: 10.1016/j.avsg.2017.09.022.
54. Montero-Baker MF, Au-Yeung KY, Wisniewski NA, et al. The First-in-Man "Si Se Puede" Study for the use of micro-oxygen sensors (MOXYs) to determine dynamic relative oxygen indices in the feet of patients with limb-threatening ischemia during endovascular therapy. J Vasc Surg. 2015; 61(6):1501-9.e1.doi: 10.1016/j.jvs.2014.12.060.
55. Ahmed Z, Ochoa-Prieto M, Bhalla A, Strosberg DS, Dardik A, Altin SE. How much flow is enough: the use of fractional flow reserve in chronic limb-threatening ischemia in a series of patients with isolated occlusive tibial disease. J Vasc Surg Cases Innov Tech. 2023; 9:101017. https://doi.org/10.1016/j.jvscit.2022.08.022