Establishing a Critical Limb Ischemia Outpatient Center: Separating Facts from Myth.

Critical Limb Ischemia or chronic limb-threatening ischemia represents the end stage of peripheral artery disease where arterial flow is compromised to the lower extremities and risk of limb loss may become imminent. Revascularization of lower extremities is one of the cornerstones of limb salvage and amputation prevention. Establishing centers of high quality CLI therapy requires creating different foundational pillars in order to be successful. This article discusses critical limb ischemia center creation from the perspective of critical limb ischemia therapists working in an outpatient setting.

Validation of MRI assessment of foot perfusion for improving treatment of patients with peripheral artery disease.

INTRODUCTION: Information on tissue perfusion in the foot is important when treating patients with chronic limb-threatening ischemia. This study aims to test the reliability of different magnetic resonance sequences when measuring perfusion in the foot. METHODS: Sixteen healthy volunteers had their right foot scanned in a test/retest study with six different magnetic resonance sequences (BOLD, multi-echo gradient echo (mGRE), 2D and 3D pCASL, PASL FAIR, and DWI with intravoxel incoherent motion (IVIM) with quantitative measurements of perfusion. For five sequences, cuff-induced ischemia followed by a hyperactive response was measured. Images of the feet were segmented into angiosomes and perfusion data were extracted from the five angiosomes. RESULTS: BOLD, PASL FAIR, mGRE, and DWI with IVIM had low mean differences between the first and second scans, while the results of 2D and 3D pCASL had the highest differences. Based on a paired t-test, BOLD, and FAIR were able to distinguish between perfusion and no perfusion in all angiosomes with p-values below 0.01. This was not the case with 2D and 3D pCASL with p-values above 0.05 in all angiosomes. The mGRE could not distinguish between perfusion and no perfusion in the lateral side of the foot. CONCLUSION: BOLD, mGRE, pASL FAIR, and DWI with IVIM seem to give more robust results compared to 2D and 3D pCASL. Further studies on patients with peripheral artery disease should explore if the sequences can have clinical relevance when assessing tissue ischemia and results of revascularization. IMPLICATIONS FOR PRACTICE: This study provides knowledge that could be used to improve the diagnosis of patient with chronic limb-threatening ischemia to explore tissue perfusion.

Gold Nanorod-Loaded Nano-Contrast Agent with Composite Shell-Core Structure for Ultrasonic/Photothermal Imaging-Guided Therapy in Ischemic Muscle Disorders.

Purpose: This study aims to broaden the application of nano-contrast agents (NCAs) within the realm of the musculoskeletal system. It aims to introduce novel methods, strategies, and insights for the clinical management of ischemic muscle disorders, encompassing diagnosis, monitoring, evaluation, and therapeutic intervention. Methods: We developed a composite encapsulation technique employing O-carboxymethyl chitosan (OCMC) and liposome to encapsulate NCA-containing gold nanorods (GNRs) and perfluoropentane (PFP). This nanoscale contrast agent was thoroughly characterized for its basic physicochemical properties and performance. Its capabilities for in vivo and in vitro ultrasound imaging and photothermal imaging were authenticated, alongside a comprehensive biocompatibility assessment to ascertain its effects on microcirculatory perfusion in skeletal muscle using a murine model of hindlimb ischemia, and its potential to augment blood flow and facilitate recovery. Results: The engineered GNR@OCMC-liposome/PFP nanostructure exhibited an average size of 203.18±1.49 nm, characterized by size uniformity, regular morphology, and a good biocompatibility profile. In vitro assessments revealed NCA's potent photothermal response and its transformation into microbubbles (MBs) under near-infrared (NIR) irradiation, thereby enhancing ultrasonographic visibility. Animal studies demonstrated the nanostructure's efficacy in photothermal imaging at ischemic loci in mouse hindlimbs, where NIR irradiation induced rapid temperature increases and significantly increased blood circulation. Conclusion: The dual-modal ultrasound/photothermal NCA, encapsulating GNR and PFP within a composite shell-core architecture, was synthesized successfully. It demonstrated exceptional stability, biocompatibility, and phase transition efficiency. Importantly, it facilitates the encapsulation of PFP, enabling both enhanced ultrasound imaging and photothermal imaging following NIR light exposure. This advancement provides a critical step towards the integrated diagnosis and treatment of ischemic muscle diseases, signifying a pivotal development in nanomedicine for musculoskeletal therapeutics.

Efficacy and Durability of Percutaneous Deep Vein Arterialization: A Systematic Review.

BACKGROUND: Endovascular deep vein arteriaization (DVA) is a novel technique aimed at salvaging peripheral arterial disease unamenable to conventional surgical intervention. This study aims to review contemporary literature on the efficacy, safety, and durability of DVA on patients with no-option critical limb ischemia (NO-CLI). METHODS: The study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, using predefined search terms of "percutaneous deep vein arterialization" or "percutaneous deep venous arterialization" in PubMed, Web of Sciences, OvidSP, and Embase. Only studies with 5 or more patients were included, and studies involving open or hybrid DVA were excluded. The primary outcomes included technical success and primary amputation rates. Secondary outcomes included rates of wound healing, complication, reintervention, and all-cause mortality. RESULTS: Ten studies encompassing a total of 233 patients were included. Patients were primarily those deemed to have NO-CLI. The median follow-up period was 12 months (range 1-63 months). The technical success rate was 97% (95% confidence interval [CI] 96.2%-97.9%) and the major amputation rate was 21.8% (95% 21.1%-22.4%). The wound healing rate was 69.5% (95% CI 67.9-71.0%), complication rate was 13.8% (95% CI 11.7%-15.9%), reintervention rate was 37.4% (95% CI 34.9%-39.9%), and all-cause mortality rate was 15.7% (95% CI 14.1%-17.2%). CONCLUSIONS: Our study showed that endovascular DVA is safe for patients with NO-CLI. Nonetheless, studies were small with follow-up period of less than 1 year. There is currently lack of level 1 evidence to recommend routine use in patients with NO-CLI.

Popliteal-to-Distal Extreme Bypass in Endovascular Era.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) is characterized by rest pain and tissue loss, with an annual mortality rate of 20% and amputation rate of 40%, if not treated. Open bypass surgery is recommended in CLTI, depending on the availability of good quality venous material, outflow artery patency, and surgical expertise. The aim of the study is to analyze primary patency, limb salvage, and survival rate in patients undergoing popliteal-to-distal bypass. METHODS: All consecutive patients who underwent popliteal-to-distal bypass surgery between January 2016 and December 2021 were enrolled in the study. Primary outcomes were primary patency, limb salvage, and overall survival. Secondary outcomes included amputation-free survival and secondary patency. RESULTS: Forty-nine patients were included during the study. Technical success was achieved in 100% of cases. Target outflow artery was in 27% (n. 13) of cases the anterior tibial artery, in 27% (n. 13) the dorsalis pedis, in 2% (n. 1) the peroneal artery, in 30% (n. 15) the retromalleolar tibial artery, in 10% (n. 5) the medial plantar artery, and in 4% (n. 2) the tarsal artery. Two-year primary patency was 85% ± 5. Secondary patency rates were 86% ± 3 at 2 years. The overall survival was 81% ± 6 at 2 years, the amputation-free survival was 70% ± 9, and the limb salvage rate was 81% ± 6. CONCLUSIONS: Popliteal-to-distal bypass requires high technical expertise to be performed. When a good autologous vein and adequate outflow artery are present, they can be feasible with good patency rates and overall survival.

Power-Doppler Ultrasonic Imaging of Peripheral Perfusion in Diabetic Mice.

OBJECTIVE: We explored the capabilities of power-Doppler ultrasonic (PD-US) imaging without contrast enhancement for monitoring changes in muscle perfusion over time. METHODS: Ischemic recovery was observed in healthy and type II diabetic male and female mice with and without exercise. In separate studies, perfusion was measured during and after 5-min ischemic periods and during four-week recovery periods following irreversible femoral ligation. A goal was to assess how well PD-US estimates tracked the diabetic-related changes in endothelial function that influenced perfusion. RESULTS: The average perfusion recovery time following femoral ligation increased 47% in diabetic males and 74% in diabetic females compared with non-diabetic mice. Flow-mediated dilation in conduit arteries and the reactive hyperemia index in resistive vessels each declined by one half in sedentary diabetic mice compared with sedentary non-diabetic mice. We found that exercise reduced the loss of endothelial function from diabetes in both sexes. The reproducibility of perfusion measurements was limited primarily by our ability to select the same region in muscle and to effectively filter tissue clutter. CONCLUSIONS/SIGNIFICANCE: PD-US measurements can precisely follow site-specific changes in skeletal muscle perfusion related to diabetes over time, which fills the need for techniques capable of regularly monitoring atherosclerotic changes leading to ischemic vascular pathologies.

Poor Limb Prognosis of Patients with Chronic Limb-Threatening Ischemia on Hemodialysis: A Retrospective Observational Study Based on the Global Limb Anatomic Staging System.

BACKGROUND: The Global Limb Anatomic Staging System (GLASS) has been widely used to evaluate patients with chronic limb-threatening ischemia (CLTI). As end-stage kidney disease (ESKD) is a well-known CLTI risk factor, we aimed to determine whether patients on hemodialysis (HD) have a worse limb prognosis than those without ESKD, considering the same GLASS background. METHODS: The data of 445 patients who underwent surgical and/or endovascular revascularization procedures for lower extremity ischemia were retrospectively collected in our division between 2005 and 2018. The major amputation rate and amputation-free survival (AFS) were compared between HD and non-HD patients. RESULTS: Among the 215 (48%) patients receiving HD, 58 limbs required major amputation (27% limb loss rate). Among the non-HD group, the limb loss rate was 13% (P < 0.0001). The overall AFS was significantly worse in patients receiving HD than those not (P < 0.0001). The AFS was significantly worse in HD patients when comparing GLASS-standardized subgroups. CONCLUSIONS: Patients with CLTI who were receiving HD had a worse limb prognosis than those not receiving, even when considering the same GLASS classification. Furthermore, there is a need for an ideal guideline focused on ESKD-directed peripheral artery disease.

Evaluation of short-term mortality in patients with Medicare undergoing endovascular interventions for chronic limb-threatening ischemia.

INTRODUCTION: Patients with chronic limb-threatening ischemia (CLTI) have high mortality rates after revascularization. Risk stratification for short-term outcomes is challenging. We aimed to develop machine-learning models to rank predictive variables for 30-day and 90-day all-cause mortality after peripheral vascular intervention (PVI). METHODS: Patients undergoing PVI for CLTI in the Medicare-linked Vascular Quality Initiative were included. Sixty-six preprocedural variables were included. Random survival forest (RSF) models were constructed for 30-day and 90-day all-cause mortality in the training sample and evaluated in the testing sample. Predictive variables were ranked based on the frequency that they caused branch splitting nearest the root node by importance-weighted relative importance plots. Model performance was assessed by the Brier score, continuous ranked probability score, out-of-bag error rate, and Harrell's C-index. RESULTS: A total of 10,114 patients were included. The crude mortality rate was 4.4% at 30 days and 10.6% at 90 days. RSF models commonly identified stage 5 chronic kidney disease (CKD), dementia, congestive heart failure (CHF), age, urgent procedures, and need for assisted care as the most predictive variables. For both models, eight of the top 10 variables were either medical comorbidities or functional status variables. Models showed good discrimination (C-statistic 0.72 and 0.73) and calibration (Brier score 0.03 and 0.10). CONCLUSION: RSF models for 30-day and 90-day all-cause mortality commonly identified CKD, dementia, CHF, need for assisted care at home, urgent procedures, and age as the most predictive variables as critical factors in CLTI. Results may help guide individualized risk-benefit treatment conversations regarding PVI.

Insulin Requirement and Infrainguinal Bypass Outcomes in Patients with Peripheral Arterial Disease.

BACKGROUND: Diabetes mellitus (DM) is a major risk factor for peripheral artery disease. The association of DM with major adverse limb events (MALE) after lower extremity revascularization remains controversial, as patients with diabetes are typically analyzed as a single, homogenous group. Using a large national database, this study examines the impact of insulin use and glycemic control on the outcomes following infrainguinal bypass. The hypothesis is that prevalent insulin therapy and elevated hemoglobin A1c (HbA1c) are associated with an increased risk of MALEs after infrainguinal bypass in patients with DM and could therefore be used for risk stratification. METHODS: The Vascular Quality Initiative database files for infrainguinal bypass (2007-2021) were retrospectively reviewed. Patients with DM undergoing bypass for peripheral artery disease were included. Patients on dialysis or with prior kidney transplantation were excluded. The characteristics and outcomes of patients with insulin-requiring diabetes mellitus (IRDM) were compared to those of patients not requiring insulin (noninsulin-requiring diabetes mellitus [NIRDM]) prior to the bypass procedure. RESULTS: A total of 9,686 patients with DM (56% IRDM) underwent bypass. Patients with IRDM were significantly younger than patients with NIRDM, more likely to be female (P < 0.01), African American (P < 0.01), and Hispanic (P = 0.031), and more likely to have comorbidities and be categorized into American Society of Anesthesiologist classes IV-V. They were more likely to be treated for chronic limb-threatening ischemia (P < 0.001). Patients with IRDM had significantly higher perioperative complications with no difference in perioperative mortality between the 2 groups. Beyond the perioperative period, with a mean follow-up of 427 days, patients with IRDM had significantly lower crude rates of primary patency and higher crude rates of major amputation, MALE, and mortality compared to patients with NIRDM. Regression analyses demonstrated that insulin requirement, but not HbA1c, was independently associated with a higher risk of MALE (hazard ratio = 1.17 [1.06-1.29]) and mortality (hazard ratio = 1.28 [1.16-1.43]). CONCLUSIONS: Insulin requirement, but not HbA1c, is significantly associated with MALEs and survival after infrainguinal bypass in the Vascular Quality Initiative. Stratification of patients with DM based on their prevalent insulin use prior to infrainguinal bypass surgery could improve the prediction of outcomes of peripheral arterial bypass surgery in patients with diabetes.

Proximal Arterial Inflow Revascularization Improves Pedal Arch Quality and Its Impact on Ischemic Diabetic Foot Ulcer Healing.

BACKGROUND: Arterial perfusion is a key factor in diabetic foot ulcer (DFU) healing. Although it is associated with pedal arch patency, not all patients are amenable to pedal artery angioplasty. This study aims to determine the impact of angiographic improvement of the pedal arch quality after proximal arterial inflow revascularization (PAIR) and its association with wound healing. METHODS: One hundred and fifty diabetic patients with tissue loss in 163 limbs who had digital subtraction angiography were studied. Cox regression analysis was used to determine independent predictors of wound healing. Wound healing rates in association with pedal arch patency were calculated by Kaplan-Meier analysis. RESULTS: End-stage renal disease, minor amputation, and complete pedal arch patency were significant independent predictors of wound healing following PAIR with hazard ratios for failure: 3.02 (P = 0.008), 0.54 (P = 0.023), and 0.40 (P = 0.039), respectively. The prevalence of complete pedal arches increased by 24.1% with successful intervention (P < 0.001). The overall rates of wound healing at 6, 12, and 24 months were 36%, 64%, and 72%, respectively. The wound healing rate at 1 year in patients with a complete pedal arch was 73% compared to 45% in those with an absent pedal arch (P = 0.017). CONCLUSIONS: PAIR increases complete pedal arch patency, a significant predictor of wound healing in DFU.

Below-the-Knee Endovascular Revascularization: A Position Statement.

Patients with chronic limb-threatening ischemia, the terminal stage of peripheral artery disease, are frequently afflicted by below-the-knee disease. Although all patients should receive guideline-directed medical therapy, restoration of inline flow is oftentimes necessary to avoid limb loss. Proper patient selection and proficiency in endovascular techniques for below-the-knee revascularization are intended to prevent major amputation and promote wound healing. This review, a consensus among an international panel of experienced operators, provides guidance on these challenges from an endovascular perspective and offers techniques to navigate this complex disease process.

Percutaneous Management of Dialysis Access Steal Syndrome: Interventions and Outcomes from a Single Institution's 20-Year Experience.

PURPOSE: To determine safety and effectiveness of percutaneous interventions performed by interventional radiologists at a single institution over 2 decades in patients with dialysis access steal syndrome (DASS). MATERIALS AND METHODS: A retrospective review of fistulograms from 2001 to 2021 (N = 11,658) was performed. In total, 286 fistulograms in 212 patients with surgically created dialysis accesses met inclusion criterion of fistulography for suspected DASS. Chart review collected data regarding patient demographics, comorbidities, access characteristics, fistulography findings, intervention(s) performed, and outcomes. Procedures with and without DASS intervention were compared. Odds ratios (ORs), adjusted for age, sex, comorbidities, access characteristics, and multiple within-patient events, were calculated using logistic regression to determine associations between steal intervention status and outcome variables: (a) major adverse events, (b) access preservation, and (c) follow-up surgery. A percutaneously treatable cause of DASS was present in 128 cases (45%). Treatment of DASS lesions was performed in 118 cases. Fifteen embolizations were also performed in patients without DASS lesions. RESULTS: Technical success of DASS interventions, defined by the Society of Interventional Radiology (SIR) reporting standards, was 94%; 54% of interventions resulted in DASS symptom improvement at a median follow-up of 15 days. Patients with steal intervention had 60% lower odds of follow-up surgery (OR, 0.4; P = .007). There was no difference in major adverse events (P = .98) or access preservation (P = .13) between groups. CONCLUSIONS: In this retrospective cohort study, approximately half of DASS fistulograms revealed a percutaneously treatable cause of steal. Over half of DASS interventions resulted in symptomatic relief. Percutaneous intervention was associated with lower odds of follow-up surgery without compromising access preservation.

Evaluation of intestinal necrosis with laser Doppler in experimental mesenteric ischemia model.

BACKGROUND: Acute mesenteric ischemia (AMI) is responsible for one in a thousand emergency hospital admissions in America and Europe and is associated with high morbidity and mortality rates. Current diagnostic and treatment methods fall short of desired outcomes, often resulting in delayed diagnoses and difficulties in detecting ischemic bowel tissue during treatment. This study evaluates the diagnostic value of commonly used biochemical markers in clinical practice-creatine kinase, C-reactive protein (CRP), and lactate dehydrogenase (LDH)-alongside blood flow measurements using laser Doppler in a rat model of experimental mesenteric ischemia. We also compare these markers with pathological ischemia scoring. METHODS: Rats were divided into five groups: control, 1 hour, 2 hours, 3 hours, and 4 hours. Mesenteric ischemia was induced for the respective durations in each group. After these periods, we measured blood flow using laser Doppler. We also collected blood samples and intestinal biopsies for biochemical parameter analysis. These values were assessed in relation to intestinal viability using the Chiu ischemia scoring system. RESULTS: Blood flow measurement with laser Doppler correlated with both the duration and severity of bowel ischemia. No significant relationship was found between CRP levels and the duration of ischemia. However, creatine kinase and lactate dehydrogenase (LDH) levels were significantly higher in ischemia lasting into the third and fourth hours. CONCLUSION: Creatine kinase and lactate dehydrogenase (LDH) levels may be useful biomarkers in patients with suspected acute mesenteric ischemia (AMI). Blood flow measurements using laser Doppler can accurately identify intestinal loops for resection during surgery.

Study of ischemic progression in different intestinal tissue layers during acute intestinal ischemia using swept-source optical coherence tomography angiography.

In acute intestinal ischemia, the progression of ischemia varies across different layers of intestinal tissue. We established a mouse model and used swept-source optical coherence tomography (OCT) to observe the intestinal ischemic process longitudinally in different tissue layers. Employing a method that combines asymmetric gradient filtering with adaptive weighting, we eliminated the vessel trailing phenomenon in OCT angiograms, reducing the confounding effects of superficial vessels on the imaging of deeper vasculature. We quantitatively assessed changes in vascular perfusion density (VPD), vessel length, and vessel average diameter across various intestinal layers. Our results showed a significant reduction in VPD in all layers during ischemia. The mucosa layer experienced the most significant impact, primarily due to disrupted capillary blood flow, followed by the submucosa layer, where vascular constriction or decreased velocity was the primary factor.

Longitudinal Changes in Iron and Myelination Within Ischemic Lesions Associate With Neurological Outcomes: A Pilot Study.

BACKGROUND: Combined quantitative susceptibility mapping and R2* relaxometry can distinguish iron and myelin components in ischemic lesions. We aimed to investigate whether longitudinal changes in magnetic susceptibility and R2* values within ischemic lesions were associated with neurological outcomes. METHODS: In this single-center prospective study, we included patients, 20 to 90 years of age, who were consecutively admitted to the stroke care unit between August 2020 and March 2022 due to acute ischemic stroke. The participants underwent 2 instances of quantitative susceptibility mapping and R2* relaxometry scanning before and after stroke rehabilitation. We compared the changes in these quantitative measures across different subtypes of acute ischemic stroke. Multiple linear regression models were used to investigate the associations between the National Institutes of Health Stroke Scale scores and the mean magnetic susceptibility and R2* values in ischemic lesions. RESULTS: Among a total of 112 patients with acute ischemic stroke, 32 participants (aged 73.3±9.4 years; 20 men and 12 women) were evaluated. The median time from stroke onset to the first imaging was 5 days and that to the second imaging was 102 days. The changes in magnetic susceptibility values of branch atheromatous disease were higher than those of cardioembolism (mean difference, 0.018 [95% CI, 0.009-0.027] ppm; P<0.001) and lacunar (mean difference, 0.013 [95% CI, 0.005-0.020] ppm; P=0.004). Across all patients, the changes in National Institutes of Health Stroke Scale scores were associated with those of magnetic susceptibility values (coefficient, 0.311 [95% CI, 0.098-0.520]; P=0.017) but not with R2* values (coefficient, 0.114 [95% CI, -0.127 to 0.345]; P=0.291). CONCLUSIONS: The longitudinal changes in the magnetic susceptibility values within ischemic lesions were associated with neurological outcomes during the restorative stages poststroke in patients experiencing acute ischemic stroke. REGISTRATION: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000050719.