Chronic Limb-threatening Ischemia Patients Research Articles

Bypass Surgery as a Viable Option for Chronic Limb-threatening Ischemia Patients With Chronic Kidney Disease

Bypass Surgery as a Viable Option for Chronic Limb-threatening Ischemia Patients With Chronic Kidney Disease

Intravascular Ultrasound Use is Associated with Improved Patency in Lower Extremity Peripheral Arterial Interventions

ObjectivesIntravascular ultrasound (IVUS) facilitates detailed visualization of endoluminal anatomy not adequately appreciated on conventional angiography. However, it is unclear if IVUS use improves clinical outcomes of peripheral vascular interventions (PVI) for peripheral arterial disease (PAD). This study aimed to evaluate the impact of IVUS on 1-year outcomes of PVI in the vascular quality initiative (VQI). MethodsThe VQI-PVI modules were reviewed (2016-2020). All patients with available one-year follow up after lower extremity PVI were included and grouped as IVUS-PVI or non-IVUS PVI based on use of IVUS. Propensity matching (1:1) was performed using demographics and comorbidities. One-year major amputation and patency rates were compared. A generalized estimating equation (GEE) model was used to identify predictors of 1-year outcomes. Subgroup analysis based on Trans-Atlantic Inter-Society Consensus (TASC) classification, treatment length and treatment modalities were performed using same modeling approaches. ResultsThere were 56,633 procedures (non-IVUS PVI=55,302 vs IVUS-PVI=1,331) in 44,042 patients. Propensity matching yielded a total cohort of 1,854 patients matched (1:1), with no baseline differences. LER for claudication was performed in 60.4%, while one-third (33.9%) had chronic limb threatening ischemia (CLTI). IVUS was more commonly used for lesions >15cm in length (46.6% vs 43.3%) and for aortoiliac disease (31.8% vs 27.2%). Rates of atherectomy and stenting were significantly higher with IVUS-PVI (21.1% vs 16.8%), while balloon angioplasty was less common (13.5% vs 24.4%). One-year patency was better with IVUS-PVI (97.7% vs 95.2%, p=0.004). On subgroup analysis, IVUS (OR 2.20, 95% CI 1.29- 3.75) was associated with improved patency in CLTI patients, TASC C or D lesions, and treatment length >15cm. Adjunctive IVUS use during PVI did not significantly impact 1-year amputation (OR 1.7, 95%CI 0.78-3.91). On multivariable regression, adjunctive use of IVUS (OR 2.46 95%CI 1.43-4.25) and aortoiliac interventions (OR 2.91, 95%CI 1.09-7.75) were independent predictors of patency. Treatment modalities such as atherectomy, stenting or balloon angioplasty did not significantly impact patency at 1-year. ConclusionIVUS during lower extremity PVI is associated with improved 1-year patency, when compared to angiography alone. Certain subgroups, such as CLTI patients, lesions>15cm, and TASC C or D lesions might benefit from adjunctive use of IVUS.

Loss of FAM210A in Satellite Cell Drives Mitochondrial Dysfunction and Muscle Weakness in Experimental Peripheral Artery Disease

Introduction: Peripheral artery disease (PAD) affects approximately 200 million people globally. Chronic limb-threatening ischemia (CLTI) represents the most advanced clinical phenotype of PAD. Mitochondrial metabolism defects are apparent in the satellite cells of CLTI patients, and the muscle regeneration process demands increased energy, with satellite cell mitochondrial metabolism and dynamics playing a crucial role. However, our current understanding of the role of satellite cells and muscle regeneration in PAD pathology is notably inadequate. Recent studies have shown that the absence of FAM210A, a newly identified mitochondrial protein, can trigger morphological and energetic abnormalities in mitochondria, resulting in muscle function deterioration and promoting muscle wasting. Given the impaired mitochondrial function in satellite cells in CLTI patients and the heightened energy demand regulated by mitochondrial dynamics during muscle regeneration in satellite cell, it is therefore essential to exploring the role of FAM210A in satellite cells in CLTI limb pathology. The objective of this study was to investigate the impact of the loss of FAM210A in satellite cells in mice with experimental PAD. Methods: Male and female conditional FAM210A satellite cell knock out (FAM210ASCKO) and FAM210A floxed (FAM210Afl/fl) mice (N=3-5) were used for this project. Femoral artery ligation surgery was performed to induce PAD. Tamoxifen was administered for 5 days intraperitoneally one week prior to the surgery. Mice were euthanized twenty-eight days after surgery. Outcome measures included limb perfusion assessment, muscle weight, muscle force production, and mitochondrial respiration. Results: FAM210ASCKO mice had significantly decreased muscle mass of the tibialis anterior and extensor digitorum longus ( p<0.0001 and p=0.0004 respectively). More importantly, maximal muscle force with in-situ contraction in tibialis anterior was significantly lower in FAM210ASCKO mice compared to FAM210Afl/fl mice (FAM210Afl/fl mice: 1085.16 ± 331.08 mN; FAM210ASCKO mice: 430.77 ± 467.91 mN; p=0.0139). Furthermore, analysis of mitochondrial oxidative phosphorylation (OXPHOS) revealed that FAM210ASCKO mice had a significant reduction compared to FAM210Afl/fl mice (48%) in skeletal muscle mitochondrial bioenergetic function at various levels of energy demand mimicking from resting to maximal exercise when carbohydrate was used to energize mitochondria ( p=0.034). Importantly, the analysis of mitochondrial membrane potential consistently reveals a substantial reduction in FAM210ASCKO mice compared to FAM210Afl/fl mice, which can partially explain the diminished mitochondrial bioenergetic function observed in ischemic FAM210ASCKO mice. Conclusion: The results of this study indicate that the loss of FAM210A in satellite cells exacerbates ischemic muscle pathology evidenced by muscle weakness and mitochondrial failure in FAM210ASCKO mice with PAD. Future work is needed to elucidate the mechanisms by which FAM210A regulate ischemic satellite cell function and the therapeutic potential of preventing ischemia-induced loss of FAM210A in PAD. This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (to Dr Ryan). Mr Thome was supported by NIH grant F31-DK128920. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ischemia-Guided Coronary Revascularization Following Lower-Extremity Revascularization Improves 5-Year Survival of Patients With Chronic Limb-Threatening Ischemia.

To determine whether diagnosis of asymptomatic (silent) coronary ischemia using coronary computed tomography (CT)-derived fractional flow reserve (FFRCT) together with targeted coronary revascularization of ischemia-producing coronary lesions following lower-extremity revascularization can reduce adverse cardiac events and improve long-term survival of patients with chronic limb-threatening ischemia (CLTI). Prospective cohort study of CLTI patients with no cardiac history or symptoms undergoing elective lower-extremity revascularization. Patients with pre-operative coronary computed tomography angiography (CTA) and FFRCT evaluation with selective post-operative coronary revascularization (FFRCT group) were compared with patients with standard pre-operative evaluation and no post-operative coronary revascularization (control group). Lesion-specific coronary ischemia was defined as FFRCT≤0.80 distal to a coronary stenosis with FFRCT≤0.75 indicating severe ischemia. Endpoints included all-cause death, cardiac death, myocardial infarction (MI) and major adverse cardiovascular (CV) events (MACE=CV death, MI, stroke, or unplanned coronary revascularization) during 5 year follow-up. In the FFRCT group (n=111), FFRCT analysis revealed asymptomatic (silent) coronary ischemia (FFRCT≤0.80) in 69% of patients, with severe ischemia (FFRCT≤0.75) in 58%, left main ischemia in 8%, and multivessel ischemia in 40% of patients. The status of coronary ischemia in the control group (n=120) was unknown. Following lower-extremity revascularization, 42% of patients in FFRCT had elective coronary revascularization with no elective revascularization in controls. Both groups received guideline-directed medical therapy. During 5 year follow-up, compared with control, the FFRCT group had fewer all-cause deaths (24% vs 47%, hazard ratio [HR]=0.43 [95% confidence interval [CI]=0.27-0.69], p<0.001), fewer cardiac deaths (5% vs 26%, HR=0.18 [95% CI=0.07-0.45], p<0.001), fewer MIs (7% vs 28%, HR=0.21 [95% CI=0.10-0.47], p<0.001), and fewer MACE events (14% vs 39%, HR=0.28 [95% CI=0.15-0.51], p<0.001). Ischemia-guided coronary revascularization of CLTI patients with asymptomatic (silent) coronary ischemia following lower-extremity revascularization resulted in more than 2-fold reduction in all-cause death, cardiac death, MI, and MACE with improved 5 year survival compared with patients with standard cardiac evaluation and care (76% vs 53%, p<0.001). Silent coronary ischemia in patients with chronic limb-threatening ischemia (CLTI) is common even in the absence of cardiac history or symptoms. FFRCT is a convenient tool to diagnose silent coronary ischemia perioperatively. Our data suggest that post-surgery elective FFRCT-guided coronary revascularization reduces adverse cardiac events and improves long-term survival in this very-high risk patient group. Randomized study is warranted to finally test this concept.

Narrative Review of Biological Markers in Chronic Limb-Threatening Ischemia.

Chronic limb-threatening ischemia (CLTI), the advanced stage of peripheral arterial disease, is diagnosed in the presence of ischemic rest pain, non-healing ulcers, or gangrene. Several studies have demonstrated that inflammation and endothelial dysfunction are some of the main substrates of CLTI. A narrative review was conducted and reported according to PRISMA guidelines. Three databases were searched-Web of Science, Medline, and EMBASE-for the studies assessing CLTI and the biological markers related to it. We included 22 studies, and all the markers identified (C-reactive protein, D-dimers, fibrinogen, cytokines, IL-6, TNF-α, ICAM-1 (Intracellular Adhesion Molecule-1), VCAM-1 (Vascular Cell Adhesion Molecule-1), neutrophile-to-lymphocytes ratio (NLR), IL-8, Pentraxin-3, neutrophil gelatinase-associated lipocalin (NGAL), calprotectin, E-selectin, P-selectin, neopterin, High-Mobility Group Box-1 protein (HGMB-1), Osteoprotegerin (OPG) and Sortilin) were positively associated with advanced CLTI, with major limb or major cardiovascular events in these patients. All the studied markers had increased values in patients with CLTI, especially when associated with diabetes mellitus, proving a very important association between diabetes and major limb or cardiovascular events in these patients. There is a need for more studies to validate these markers in terms of diagnosis or prognosis in CLTI patients and in trying to find new medical strategies that target inflammation or endothelial dysfunction in these patients.

“Evolution of Drug-Coated Devices for the Treatment of Chronic Limb Threatening Ischemia”

For patients with Chronic Limb Threatening Ischemia (CLTI), endovascular approaches to revascularization are often employed as a component of multimodality care aimed at limb preservation. However, patients with CLTI are also prone to treatment failure, particularly following balloon angioplasty alone. Drug-coated devices utilizing Paclitaxel were developed to decrease restenosis but have been primarily studied in patients presenting with claudication. In recent years, data have emerged which describe the efficacy of drug-coated devices in the treatment of patients with CLTI. Concurrently, there has been major controversy surrounding the use of drug-coated devices in peripheral arterial disease. A historical narrative of the development and use of drug-coated devices for peripheral arterial disease is presented, along with discussion of major trials. Evidence argues that paclitaxel-based therapies for peripheral arterial disease (PAD) do not increase mortality risk compared to nondrug-coated devices. In CLTI patients, paclitaxel-based balloons and stents provide superior patency and freedom reintervention compared to nondrug-coated devices when treating femoropopliteal disease. However, the use of Paclitaxel-based therapies for below-the-knee (BTK) interventions has not been shown to provide clinically meaningful outcomes compared to nondrug-based therapies. Newer generation antiproliferative agents (Sirolimus, Everolimus) and delivery systems (bioabsorbable scaffolds) hold promise for BTK interventions with early data suggesting decreased rates of major amputation or major adverse limb events.

Sex-Related Differences and Factors Associated With Peri-Procedural and 1-Year Mortality in Chronic Limb-Threatening Ischemia Patients From the CLIMATE Italian Registry

Sex-Related Differences and Factors Associated With Peri-Procedural and 1-Year Mortality in Chronic Limb-Threatening Ischemia Patients From the CLIMATE Italian Registry

Poor short-term outcomes for prognostic high-risk patients with chronic limb-threatening ischemia undergoing endovascular therapy

BackgroundThe prognosis of chronic limb-threatening ischemia (CLTI) is poor, with an expected life expectancy of 2 or more years, which significantly influences treatment decisions. However, death may occur at the early stages of treatment for wound healing, and aggressive treatment may limit the quality of life of such patients. In patients with CLTI undergoing endovascular therapy (EVT), the Wound, Ischemia, and foot Infection (WIfI) clinical stage, male sex, older age, non-ambulatory status, low body mass index, and dialysis have been reported as predictors of mortality risk. However, most studies have not fully investigated the WIFI clinical stage as a prognostic predictor of CLTI. This study aimed to evaluate short-term prognosis and wound healing rates using the prognostic predictors (PPs) indicated above in risk-stratified patients with CLTI who underwent EVT.MethodsThis retrospective single-center observational study included 61 CLTI patients undergoing EVT from April 2020 to October 2022. The patients were divided into a high-risk group (PPs ≥ 4, n = 20) and low-risk group (PPs ≤ 3, n = 41) according to the number of PPs. Survival and wound healing rates within one year were compared between these two groups.ResultsThe mean age of the patients was 74.7 ± 1.6 years, and 42 (68.9%) were male. Among these patients, the high-risk group compared with the low-risk group had a significantly worse survival rate within one year (46.4% vs. 84.7%, log-rank p < 0.001). Fifteen patients died within one year. Of these, seven deaths were cardiovascular deaths and six were deaths from infectious diseases. Cox proportional hazards analysis showed that WIfI clinical stage 4 (p = 0.043, hazard ratio [HR] = 4.85) and the male sex (p = 0.037, HR = 6.34) influenced the prognosis of this population. The high-risk group tended to have a worse wound healing rate within one year than that had by the low-risk group (55.4% vs. 83.0%, log-rank p = 0.086).ConclusionsThe assessment of short-term prognosis and wound healing rates using PPs may be useful. Discussing the results of short-term clinical outcome assessments with patients should be considered when determining their individualized treatment plans.

Negative Pressure Wound Therapy with Instillation and Dwell Time Using Antiseptic Solution in Chronic Limb-threatening Ischemia.

Chronic limb-threatening ischemia (CLTI) is a severe peripheral artery disease with rest pain and lower limb ulceration. After revascularization, limb ulceration treatment should be completed quickly before restenosis. We aimed to investigate the effect of negative pressure wound therapy with instillation and dwell (NPWTi-d) using an antiseptic solution (AS) versus a saline solution (SS) in CLTI. There is no research limited to CLTI on this topic. All patients underwent revascularization and surgical debridement. NPWTi-d was applied after surgical debridement. We evaluated wound tissue cultivation from pre- and post-NPWTi-d, length of NPWTi-d, and laboratory data pre- and post-NPWTi-d. All data are presented as the median, interquartile range. For univariate analysis, nonnormally distributed data were examined using the Wilcoxon rank sum test between the two groups of NPWTi-d (AS and SS group). A P value of less than 0.05 was considered statistically significant. Forty-eight CLTI patients participated. The SS group included 24 patients (19 men, five women, average age 68.8 years) and the AS group included 24 patients (16 men, eight women, average age 67.4 years). The comorbidities included 23 and 19 patients with diabetes mellitus and hemodialysis in the SS group, and 22 and 16 patients in the AS group, respectively. There were no adverse events in either group. Both groups reduced the number of bacteria. The AS group required shorter NPWTi-d time (P = 0.02). The AS group was able to shorten the treatment duration in CLTI.

Single-centre prospective cohort study investigating the associations and one-year trends of frailty, cognition, disability and quality of life pre- and post-intervention for chronic limb-threatening ischaemia

Abstract Background: Half of people with chronic limb-threatening ischaemia (CLTI) have frailty. This study aimed to describe the associations of frailty with cognition, disability and quality of life (QoL) among CLTI patients over 1 year following surgical or endovascular procedures. Methods: A single-centre prospective cohort study was undertaken. Patients undergoing a procedure for CLTI between May 2019 and May 2021 were eligible (minimum age &gt;65 initially; &gt;50 from November 2019). Participants underwent preoperative assessments for frailty, physical and cognitive function, disability, mood, disease-specific QoL (Vascular QoL questionnaire (VascuQoL)) and generic health-related QoL (EuroQoL EQ-5D-5L). Follow-up was at 3 months (clinic or telephone) and 12 months (telephone). Baseline frailty was assessed using both the Edmonton frail scale (EFS) and the clinical frailty scale (CFS). Frailty during follow-up was re-assessed at 3 and 12 months using the CFS as it can be performed via telephone. Associations of baseline frailty with disability, QoL and mood scores during follow-up were investigated using repeated measures mixed models. Results: Ninety-nine patients completed the baseline assessments. Forty-five (45%) were classified as frail by the EFS. Frailty was associated with a higher prevalence of cognitive impairment based on the Montreal cognitive assessment (52% vs 17%; p&lt;0.001). Eighty-seven patients were eligible for follow-up. Baseline frailty (EFS) was associated with worse QoL scores at all timepoints (VascuQoL p=0.001; EQ-5D-5L p&lt;0.001). Both those with and without frailty at baseline (EFS) had modest improvement in QoL scores at 12 months (VascuQoL p&lt;0.001; EQ-5D-5L p=0.001). Barthel index (disability) scores were lower for those with frailty at baseline (EFS) (p&lt;0.001) and decreased slightly over 12 months for both groups (p=0.007). Five patients (12%) transitioned from frailty to non-frailty at 12 months based on the CFS. However, 10 patients (23%) transitioned from non-frailty to frailty. Conclusions: CLTI patients with frailty have worse QoL and greater disability both pre- and post-intervention. However, they demonstrate similar QoL benefit to those without frailty at 1 year following intervention. Baseline frailty assessment is important to inform prognostic discussions, expectations and shared decision making in CLTI.

Sex Related Differences and Factors Associated With Peri-Procedural and One Year Mortality in Chronic Limb Threatening Ischaemia Patients

Sex Related Differences and Factors Associated With Peri-Procedural and One Year Mortality in Chronic Limb Threatening Ischaemia Patients

Clinical efficacy of cord blood platelet gel in chronic limb-threatening ischaemia patients: a case series

The cord blood platelet gel (CBPG), rich in growth factors and chemoattractans molecules, is a useful tool to treat lesions with tissue loss as it accelerates remission and ensures the functional recovery of the limb. The results obtained in a series of 10 patients treated at the “Fondazione IRCCS Casa Sollievo della Sofferenza” in San Giovanni Rotondo (Italy) with CBPG in the treatment of revascularized patients with chronic limb-threatening ischemia (CLTI) are presented here. In the period 2017-2021, they were treated with surgical toileting of the ulcers and application of CBPG. As a general scheme, CBPG was applied once every 21 days for 3 times; 8 out of 10 patients observed had diabetes mellitus, of these 4 were on insulin therapy. One patient underwent a major amputation; two patients died for non-infectious causes. Studies in the literature show that CBPG is safe for patients affected by CLTI and undergoing revascularization, promoting faster healing. Our results appear to overlap this data, also showing CBPG as an effective therapeutic option for the treatment of vascularized patients with foot lesions for CLTI, reducing the risk of major amputation. In perspective, multicenter randomized studies are needed to evaluate immediate and late results.

Factors Influencing Ulcer Healing in Chronic Limb Threatening Ischemia Patients after Endovascular Angioplasty at Cipto Mangunkusumo General Hospital

Introduction. Chronic limb–threatening ischemia (CLTI) can cause rest pain in the lower extremities and the formation of ulcers or gangrene. Revascularization, which can be done using open surgery or endovascular procedures, is the first line of treatment in CLTI management. CLTI patients at CMGH usually came with advanced conditions and high re–amputation rates even after revascularization. This study aimed to determine factors associated with the outcome of endovascular angioplasty, especially ulcer healing. Method. A cross–sectional study was conducted at CMGH, enrolling CLTI patients with Rutherford grades 5 and 6 who underwent angioplasty. Age, gender, history of smoking, hypertension, atrial fibrillation, heart failure, chronic kidney disease (CKD), and diabetes mellitus were the independent variables of interest in this study. The dependent variable was ulcer healing, a clinical assessment after angioplasty assessed as complete ulcer epithelialization within four months after the procedure. Results. In 133 study subjects, it was found that 60.9% of patients underwent complete epithelialization. Factors that affect ulcer healing in CLTI patients include gender, hypertension, atrial fibrillation, heart failure, chronic kidney disease, and diabetes mellitus. The factor with the strongest association with ulcer healing after endovascular angioplasty based on the logistic regression test is diabetes mellitus. Conclusion. Factors that have a significant association with ulcer healing in patients with CLTI include gender, smoking, hypertension, atrial fibrillation, heart failure, CKD, and diabetes. The factor that was considered to have the strongest association was diabetes mellitus.

HTATIP2 regulates arteriogenic activity in monocytes from patients with limb ischemia.

Use of autologous cells isolated from elderly patients with multiple comorbidities may account for the modest efficacy of cell therapy in patients with chronic limb threatening ischemia (CLTI). We aimed to determine whether proarteriogenic monocyte/macrophages (Mo/MΦs) from patients with CLTI were functionally impaired and to demonstrate the mechanisms related to any impairment. Proarteriogenic Mo/MΦs isolated from patients with CLTI were found to have an impaired capacity to promote neovascularization in vitro and in vivo compared with those isolated from healthy controls. This was associated with increased expression of human HIV-1 TAT interactive protein-2 (HTATIP2), a transcription factor known to suppress angiogenesis/arteriogenesis. Silencing HTATIP2 restored the functional capacity of CLTI Mo/MΦs, which was associated with increased expression of arteriogenic regulators Neuropilin-1 and Angiopoietin-1, and their ability to enhance angiogenic (endothelial tubule formation) and arteriogenic (smooth muscle proliferation) processes in vitro. In support of the translational relevance of our findings, silencing HTATIP2 in proarteriogenic Mo/MΦs isolated from patients with CLTI rescued their capacity to enhance limb perfusion in the ischemic hindlimb by effecting greater angiogenesis and arteriogenesis. Ex vivo modulation of HTATIP2 may offer a strategy for rescuing the functional impairment of pro-angio/arteriogenic Mo/MΦs prior to autologous delivery and increase the likelihood of clinical efficacy.

Chronic Limb-Threatening Ischemia does not Enclose a Homogenous Population: Time for a More Detailed Classification.

Objective Chronic limb-threatening ischemia (CLTI) is associated with high morbidity and mortality. Classification methods differentiate into patients with rest pain or with ischemic ulcers. No distinction is made between the presence or absence of rest pain in patients with ischemic ulcers. Our aim is to determine any differences in outcome between these subdivisions so we can improve preoperative counseling and risk assessment. Materials and Methods This multicenter retrospective cohort study included all patients revascularized for a first episode of CLTI between 2013 and 2018. The cohort was divided in three groups: patients with solely rest pain (RP), solely ischemic ulcers (IU), and patients with both rest pain and ischemic ulcers (RP + IU). Baseline characteristics, morbidity, and mortality were analyzed. Results A total of 624 limbs in 599 patients were included: 225 (36.1%) in the rest pain group, 169 (27.1%) in the ischemic ulcers group, and 230 (36.2%) in combined group. Amputation rates were higher in the combined group at 6 months. Mortality rates were significantly higher in the ischemic ulcers group and the combined group at 6 months and 1 year. Conclusion Patients with solely rest pain have significantly lower mortality rates in comparison to patients with ischemic ulcers. Rest pain did not affect mortality rates in patients with ulcers. There was a higher amputation rate in patients with combined rest pain and ischemic ulcers because the presence of rest pain CLTI patients had a significant negative effect on amputation risk. A separate subdivision for patients with combined ulcers and rest pain is indicated.

Comparison of endovascular therapies for chronic limb-threatening ischemia and claudication

ObjectiveAnalysis of regional data from the Vascular Quality Initiative (VQI) suggested improved survival for patients undergoing stent placement compared with balloon angioplasty and atherectomy. Using national data from the VQI linked to Medicare claims data through the Vascular Implant Surveillance and Interventional Outcomes Network program, this study aimed to compare the rates of mortality, reintervention, and amputation after endovascular interventions (atherectomy, stenting, and balloon angioplasty) for two separate cohorts: patients with chronic limb-threatening ischemia (CLTI) and patients with claudication. MethodsThis was a secondary data analysis of Society for Vascular Surgery National VQI data linked to Medicare claims, between October 2016 and December 2019. Patients aged ≥65 years with symptoms of claudication or CLTI and a diagnosis of occlusive disease were included. Urgent or emergent interventions or those with concurrent procedures (endarterectomy, bypass, or bilateral intervention) were excluded. Interventions were grouped into (1) balloon angioplasty only; (2) stent (with or without balloon angioplasty); or (3) atherectomy (alone, with or without stent, with or without balloon angioplasty). Propensity score-matched cohorts were constructed to conduct pairwise intervention comparisons of mortality, reintervention, and amputation rates. Multivariable logistic regression was used to derive propensity scores for each patient. Kaplan-Meier estimates and Cox proportional hazards ratios (HRs) (95% confidence interval [CI]) analyses were performed. ResultsA total of 9785 (2665 claudication, 7120 CLTI) eligible patients were identified. After propensity score matching for the CLTI group, 2826, 3608, and 2796 pairs of cases were used to compare balloon angioplasty vs atherectomy, balloon angioplasty vs stent, and stent vs atherectomy, respectively. No statistically significant difference in mortality was observed among all interventions. However, atherectomy was associated with a significant increase in reintervention rate compared with balloon angioplasty (HR, 1.22; 95% CI, 1.06-1.39; P = .01) and compared with stenting (HR, 1.27; 95% CI, 1.10-1.46; P < .01) within the first year after the index procedure. Of note, both atherectomy (HR, 0.82; 95% CI, 0.68-0.98; P < .05) and stenting (HR, 0.76; 95% CI, 0.64-0.90; P < .01) showed lower rates of major amputation when compared with balloon angioplasty within 1 year after the index procedure. In the claudication group, there were no significant differences observed among interventions for peripheral arterial disease for mortality, reintervention, or amputation rates. ConclusionsFurther studies are needed to identify appropriate indications for atherectomy, because there may be a subset of patients with CLTI who benefit from this therapy with respect to amputation rates. Until then, caution should be exercised when using atherectomy because it is also associated with higher reintervention rates.

Endovascular and Surgical Venous Arterialization for No-Option Patients With Chronic Limb-Threatening Ischemia: A Systematic Review and Meta-Analysis.

Chronic limb-threatening ischemia (CLTI) is known for its high rates of major amputation and mortality. Conventional revascularization techniques often fail in CLTI patients due to the heavily diseased arteries. Foot vein arterialization (FVA) has been proposed as an alternative technique to provide arterial blood to the foot by using the disease-free venous bed. This systematic review and meta-analysis aimed to determine outcomes of surgical FVA (sFVA) and percutaneous FVA (pFVA) at 6 and 12 months post-procedure. PubMed, Scopus, Web of Science, and the Cochrane Library databases were searched to identify papers reporting clinical outcomes of sFVA and pFVA published between January 1966 and March 2023. Databases were searched for eligible studies. A meta-analysis was performed to evaluate the limb salvage rate, overall survival rate, and wound healing rate at 6 and 12 months. A total of 27 studies were included, with 753 patients and 793 limbs. Of the included studies, 16 analyzed the sFVA technique and 11 the pFVA technique. Of the included patients, 86.3% were Rutherford 5/6 in the sFVA group versus 98.4% in the pFVA group. The pooled limb salvage rate at 6 and 12 months was 78.1% and 74.1% in the sFVA group and 81.7% and 78.6% in the pFVA group, respectively. Wound healing rates were not reported in the sFVA group. In the pFVA group, the pooled wound healing rates were 48.1% and 64.5% at 6 and 12 months, respectively. This study showed promising results after FVA among a large population of CLTI patients. In high-risk patients, pFVA is a feasible option with favorable limb salvage and wound healing rates.

Percutaneous Deep Venous Arterialization for Limb Salvage in No Option Patients with Chronic Limb-Threatening Ischemia

An endovascular approach is often considered the first line treatment option for lower limb chronic limb-threatening ischemia (CLTI), which is defined by the presence of ischemic rest pain and severe tissue loss, such as ulcers or gangrene. Although the technical success rate of endovascular revascularization is high, in specific patients with advanced infrapopliteal disease and the absence of run-off tibial vessels, the so-called ‘desert foot’, the chance of successful endovascular revascularization is minimal. In order to avoid primary amputation, several treatment options are currently being investigated, including gene therapy and deep venous arterialization. This review focuses on the percutaneous deep venous arterialization technique as a promising, minimally invasive treatment option for limb salvage in CLTI patients presenting with a ‘desert foot’.

Minor amputation after revascularization in chronic limb-threatening ischemia: What is the optimal timing?

Patients with chronic limb-threatening ischemia (CLTI) have a high risk of lower limb amputation and loss of walking independence. Minor amputations play a key role in ensuring walking independence and they represent a challenge in terms of timing and level for vascular surgeons. A major cause of re-amputation is a defect in wound healing and a possible predictor of re-amputation for non-healing wounds could be the incorrect timing of minor amputation after revascularization. The lack of evidence in the literature leads to a wide variability of choices in clinical practice. The purpose of this study was to try to find the optimal timing analysing the risk of re-amputation in CLTI patients who have undergone successful revascularization and minor amputation focussing on timing of minor amputation. We conducted a single centre retrospective analysis on a cohort of 151 patients consecutively admitted to our hospital for CLTI (Rutherford 5) between January 2014 and April 2022. All the enrolled patients underwent successful revascularization of lower limbs and a minor amputation for dry acral necrosis. The characteristics of the patients and the revascularization procedures were collected and analysed. Patients were divided into two groups based on the timing of minor amputation performed before (group 1) or after the day (group 2) that best predicts the risk of re-amputation according to a Receiver Operating Characteristic (ROC) curve analysis. The primary outcome of this study was the risk of re-amputation during the first 60days of follow-up after a primary minor amputation, with revascularization still effective. The impact of the timing of minor amputation after revascularization, the type of revascularization and the presence of risk factors known to prolong the wound healing process were evaluated in a uni- and multi-variable logistic regression model. Systemic hypertension, and type of revascularization (i.e. open vs endovascular) were independent predictors of the risk of re-amputation at 60days (HR 4.26, 95% CI 1.30-14.04, p = .017 and HR 2.35, 95% CI 1.16-4.78, p = .018, respectively). Moreover, time ≤14days between revascularization and first amputation was associate with a clear, albeit not statistically significant, trend toward increased risk of re-amputation (HR 2.09, 95% CI 0.97-4.51, p = .06). In a cohort of patients who underwent a successful revascularization for CLTI and a minor amputation for dry gangrene in the first 14 days after revascularization, a higher -although not significant-risk of re-amputation was reported. In this cohort of patients, a delayed demolitive procedure should be considered to allow better tissue perfusion and to reduce the risk of re-amputation.

Abstract 18426: Secreted Frizzled-Related Protein 1 Mediates Adipogenic Differentiation of Vascular Cell Adhesion Protein 1 Fibroadipogenic Progenitors in the Ischemic Limb

Introduction: Chronic limb threatening ischemia (CLTI) patients display a skeletal muscle myopathy that is hallmarked by fatty infiltration. The replacement of functional muscle fibers with adipocytes impairs ambulatory function and is associated with poor clinical outcomes. The cell type responsible for fatty infiltration is a mesenchymal stromal cellular population, term fibroadipogenic progenitors (FAPs). We previously demonstrated that Vcam1+ FAPs represent a sub-population with increased adipogenic potential. However, the molecular mechanisms which govern Vcam1+ FAP mediated adipogenesis remain unknown. Herein, we sought to identify the intracellular mechanisms that drive Vcam1+ FAPs into an adipogenic cellular fate. Methods: We used single cell and bulk RNA-sequencing to identify Sfrp1 as an enriched gene in Vcam1+ FAPs. Next, to determine the sufficiency and necessity of Sfrp1, we overexpress Sfrp1 with a recombinant protein and inhibit Sfrp1 with a siRNA and assess adipogenesis. To assess the clinical significance of this FAP subpopulation, we apply single-cell RNA sequencing to CLTI patients. Results: We show in a CLTI murine model that Vcam1+ FAPs are enriched in Sfrp1. Next, we demonstrate that Sfrp1 is both sufficient and necessary for the differentiation of Vcam1+ FAPs into adipocytes. Finally, we demonstrate that human CLTI patients also have a pathologic FAP population that is enriched in Vcam1 and Sfrp1Conclusions: Our results reveal a novel mechanism for fatty infiltration, a histologic hallmark of CLTI patients, in the ischemic limb. We also validate the clinical significance of Vcam1+ Sfrp1+ FAPs by demonstrating the presence of this population in human CLTI patients. This work lays the foundation for future studies aimed at inhibiting fatty infiltration and promoting skeletal muscle regeneration in CLTI patients.