COMPREHENSIVE REVIEW OF CHRONIC LIMB-THREATENING ISCHEMIA: FROM PATHOPHYSIOLOGY TO INNOVATIVE TREATMENT APPROACHES

Keywords: Chronic Limb-Threatening Ischemia, Peripheral Artery Disease, Revascularization, Angiogenesis, Atherosclerosis, Vascular Surgery

Abstract

Introduction: Chronic Limb-Threatening Ischemia (CLTI) represents the most advanced stage of peripheral artery disease (PAD) and is associated with a high risk of major amputation and mortality. Characterized by rest pain, non-healing ulcers, or gangrene, CLTI reflects severe systemic atherosclerosis with widespread cardiovascular involvement. The disease burden is increasing globally, particularly in aging populations with diabetes or hypertension.

Methods: A literature review of PubMed, Scopus, and Google Scholar summarized current evidence on the definition, pathophysiology, classification, diagnostic strategies, and management of CLTI. It also highlights emerging research directions, including novel endovascular and surgical revascularization techniques, biologic and cell-based therapies, and evolving approaches to patient-centered care.

Results: Advances in imaging modalities and revascularization strategies particularly endovascular, surgical, and hybrid techniques  have significantly improved limb salvage and survival rates. Recent studies emphasize the importance of individualized therapy and multidisciplinary management. Concurrently, innovative therapies focusing on angiogenesis, gene therapy, and regenerative medicine show promise for “no-option” patients, although further randomized trials are needed to validate long-term efficacy and safety.

Conclusions: CLTI remains a complex and life-threatening condition requiring early diagnosis, comprehensive risk factor control, and personalized treatment planning. The integration of precision medicine, advanced imaging, and regenerative approaches holds the potential to redefine therapeutic strategies and improve patient outcomes. Future research should focus on optimizing patient selection, expanding access to limb-salvage interventions, and reducing global disease burden through preventive care.

References

Wunnava, S. S. J., Ravulapalli, K., El-Sayed, T., Sivaharan, A., Sillito, S., Witham, M., & Nandhra, S. (2025). Impact of Age Differences in Chronic Limb-Threatening Ischemia Outcomes in Octogenarians. Annals of vascular surgery, 111, 212–224. https://doi.org/10.1016/j.avsg.2024.11.010

Mohamedali, A., Kiwan, G., Kim, T., Zhang, Y., Zhuo, H., Tonnessen, B., Dardik, A., & Chaar, C. I. O. (2022). Reinterventions in Patients with Claudication and Chronic Limb Threatening Ischemia. Annals of vascular surgery, 79, 56–64. https://doi.org/10.1016/j.avsg.2021.07.050

Kobayashi, T., Mukai, K., Katayama, Y., Ide, T., Tochigi, S., Okazaki, T., Okusako, R., Hamamoto, M., Hasegawa, M., Fujii, H., & Takahashi, S. (2025). Clinical Outcomes in Patients with Chronic Limb-Threatening Ischemia with or Without Hyperpolypharmacy After Revascularization. Annals of vascular surgery, 121, 568–577. https://doi.org/10.1016/j.avsg.2025.08.035

Ferreira, J., Carneiro, A., Vila, I., Silva, C., Cunha, C., Longatto-Filho, A., Mesquita, A., Cotter, J., Mansilha, A., Correia-Neves, M., & Cunha, P. (2023). Inflammation and Loss of Skeletal Muscle Mass in Chronic Limb Threatening Ischemia. Annals of vascular surgery, 88, 164–173. https://doi.org/10.1016/j.avsg.2022.07.009

St Hilaire C. (2022). Medial Arterial Calcification: A Significant and Independent Contributor of Peripheral Artery Disease. Arteriosclerosis, thrombosis, and vascular biology, 42(3), 253–260.

Daher, G., Upadhyay, S., & Li, J. (2025). Chronic Limb-Threatening Ischemia: A Comprehensive Review Paper. Interventional cardiology clinics, 14(2), 257–272. https://doi.org/10.1016/j.iccl.2024.11.011

Cheun, T. J., Hart, J. P., & Davies, M. G. (2025). The Value of Restaging WIfI (Wound, Ischemia, and Foot Infection) After Initial Vascular and Podiatric Intervention. Annals of vascular surgery, 111, 319–330. https://doi.org/10.1016/j.avsg.2024.11.005

Morisaki, K., Matsuda, D., Guntani, A., Matsubara, Y., Kinoshita, G., Kawanami, S., Yamashita, S., Honma, K., Furuyama, T., Yamaoka, T., Mii, S., Komori, K., & Yoshizumi, T. (2023). Treatment outcomes between bypass surgery and endovascular therapy in patients with chronic limb-threatening ischemia classified as bypass-preferred category based on Global Vascular Guidelines. Journal of vascular surgery, 78(2), 475–482.e1. https://doi.org/10.1016/j.jvs.2023.04.006

Cieri, I. F., Rodriguez Alvarez, A. A., Patel, S., Boya, M., Nurko, A., Teeple, W., & Dua, A. (2025). Association of Chronic Limb Ischemia Rutherford Classification with Clinical Outcomes Following Lower Extremity Revascularization. Annals of vascular surgery, 113, 227–234. https://doi.org/10.1016/j.avsg.2025.01.020

Choi, J. C., Miranda, J., Greenleaf, E., Conte, M. S., Gerhard-Herman, M. D., Mills, J. L., Sr, & Barshes, N. R. (2023). Lower-extremity pressure, staging, and grading thresholds to identify chronic limb-threatening ischemia. Vascular medicine (London, England), 28(1), 45–53. https://doi.org/10.1177/1358863X221147945

Stanley, G. A., Scherer, M. D., Hajostek, M. M., Yammine, H., Briggs, C. S., CrespoSoto, H. O., Nussbaum, T., & Arko, F. R., 3rd (2023). Utilization of coronary computed tomography angiography and computed tomography-derived fractional flow reserve in a critical limb-threatening ischemia cohort. Journal of vascular surgery cases and innovative techniques, 10(2), 101272. https://doi.org/10.1016/j.jvscit.2023.101272

Conte, M. S., Bradbury, A. W., Kolh, P., White, J. V., Dick, F., Fitridge, R., Mills, J. L., Ricco, J. B., Suresh, K. R., Murad, M. H., Aboyans, V., Aksoy, M., Alexandrescu, V. A., Armstrong, D., Azuma, N., Belch, J., Bergoeing, M., Bjorck, M., Chakfé, N., Cheng, S., … GVG Writing Group for the Joint Guidelines of the Society for Vascular Surgery (SVS), European Society for Vascular Surgery (ESVS), and World Federation of Vascular Societies (WFVS) (2019). Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery, 58(1S), S1–S109.e33. https://doi.org/10.1016/j.ejvs.2019.05.006

Cook, I. O., & Chung, J. (2025). Contemporary Medical Management of Peripheral Arterial Disease. Cardiovascular drugs and therapy, 39(2), 357–371. https://doi.org/10.1007/s10557-023-07516-2

Srinivasan, A., Miranda, J., & Mills, J. L. (2024). Appropriate care in chronic limb threatening ischemia: A review of current evidence and outcomes. Seminars in vascular surgery, 37(2), 249–257. https://doi.org/10.1053/j.semvascsurg.2024.04.001

Mumtaz, A., Berlas, M. F. T., Malik, J., Bhojani, M. F., Moeed, A., Panhwar, W., Rehman, K. U., & Tanveer, H. (2025). Comparison of Bypass Surgery versus Endovascular Interventions for Peripheral Artery Disease through Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of vascular and interventional radiology : JVIR, 36(6), 933–949.e6. https://doi.org/10.1016/j.jvir.2025.02.005

Dayama, A., Tsilimparis, N., Kolakowski, S., Matolo, N. M., & Humphries, M. D. (2019). Clinical outcomes of bypass-first versus endovascular-first strategy in patients with chronic limb-threatening ischemia due to infrageniculate arterial disease. Journal of vascular surgery, 69(1), 156–163.e1. https://doi.org/10.1016/j.jvs.2018.05.244

Vacirca, A., Faggioli, G., Pini, A., Pini, R., Abualhin, M., Sonetto, A., Spath, P., & Gargiulo, M. (2023). Revascularisation of Chronic Limb Threatening Ischaemia in Patients with no Pedal Arteries Leads to Lower Midterm Limb Salvage. European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery, 65(6), 878–886. https://doi.org/10.1016/j.ejvs.2023.03.043

Farber, A., Menard, M. T., Conte, M. S., Kaufman, J. A., Powell, R. J., Choudhry, N. K., Hamza, T. H., Assmann, S. F., Creager, M. A., Cziraky, M. J., Dake, M. D., Jaff, M. R., Reid, D., Siami, F. S., Sopko, G., White, C. J., van Over, M., Strong, M. B., Villarreal, M. F., McKean, M., … BEST-CLI Investigators (2022). Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia. The New England journal of medicine, 387(25), 2305–2316. https://doi.org/10.1056/NEJMoa2207899

Gouëffic, Y., Brodmann, M., Deloose, K., Dubosq-Lebaz, M., & Nordanstig, J. (2024). Drug-eluting devices for lower limb peripheral arterial disease. EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology, 20(18), e1136–e1153. https://doi.org/10.4244/EIJ-D-23-01080

Beropoulis, E., Avranas, K., Rouvi, E., & Donas, K. P. (2025). Real-World 12-Month Outcomes with Sirolimus-Coated Balloon Angioplasty for Complex Femoropopliteal Disease. Journal of clinical medicine, 14(2), 483. https://doi.org/10.3390/jcm14020483

Lyden, S. P., Soukas, P. A., De, A., Tedder, B., Bowman, J., Mustapha, J. A., Armstrong, E. J., & DETOUR2 Trial Investigators (2024). DETOUR2 trial outcomes demonstrate clinical utility of percutaneous transmural bypass for the treatment of long segment, complex femoropopliteal disease. Journal of vascular surgery, 79(6), 1420–1427.e2. https://doi.org/10.1016/j.jvs.2024.02.004

Peeters, J. A. H. M., Schepers, A., Hamming, J. F., & Quax, P. H. A. (2024). Therapeutic angiogenesis for patients with chronic limb-threatening ischemia: promising or hoax?. Vascular biology (Bristol, England), 6(1), e240009. https://doi.org/10.1530/VB-24-0009

Setia, O., Lee, S. R., & Dardik, A. (2024). Modalities to Deliver Cell Therapy for Treatment of Chronic Limb Threatening Ischemia. Advances in wound care, 13(5), 253–279. https://doi.org/10.1089/wound.2022.0114

Mustapha, J. A., Jacob, R., Miller, L. E., Pena, C. S., AlMahameed, A., Dippel, E. J., Beasley, R. E., & Wiechmann, B. N. (2025). The CLTI Paradigm Shift: Implications for Clinical Trial Design and Endpoints in Endovascular Management of Infrapopliteal Disease. Journal of endovascular therapy : an official journal of the International Society of Endovascular Specialists, 15266028251363541. Advance online publication. https://doi.org/10.1177/15266028251363541

Published
2025-12-26
Citations
How to Cite
Bartosz Burda, Justyna Tasior, Michał Szalach, Rafał Gołacki, Paweł Szymonek, Mateusz Jasiński, Radosław Januszczak, & Julianna Cholewa. (2025). COMPREHENSIVE REVIEW OF CHRONIC LIMB-THREATENING ISCHEMIA: FROM PATHOPHYSIOLOGY TO INNOVATIVE TREATMENT APPROACHES. International Journal of Innovative Technologies in Social Science, (4(48). https://doi.org/10.31435/ijitss.4(48).2025.4499

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