2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Wharton's jelly mesenchymal stem cells transplantation for critical limb ischemia in patients with type 2 diabetes mellitus: a preliminary report of phase I clinical trial.

Peripheral artery disease (PAD) affects more than 230 million people worldwide, with approximately 11% of patients presenting with advanced-stage PAD or critical limb ischemia (CLI). To avoid or delay amputation, particularly in no-option CLI patients with infeasible or ineffective revascularization, new treatment strategies such as regenerative therapies should be developed. Mesenchymal stem cells (MSCs) are the most popular cell source in regenerative therapies. They possess significant characteristics such as angiogenic, anti-inflammatory, and immunomodulatory activities, which encourage their application in different diseases. This phase I clinical trial reports the safety, feasibility, and probable efficacy of the intramuscular administration of allogeneic Wharton's jelly-derived MSCs (WJ-MSCs) in type 2 diabetes patients with CLI. Out of six screened patients with CLI, five patients were administered WJ-MSCs into the gastrocnemius, soleus, and the proximal part of the tibialis anterior muscles of the ischemic lower limb. The safety of WJ-MSCs injection was considered a primary outcome. Secondary endpoints included wound healing, the presence of pulse at the disease site, the absence of amputation, and improvement in visual analogue scale (VAS), pain-free walking time, and foot and ankle disability index (FADI). No patient experienced adverse events and foot or even toe amputation during the 6-month follow-up. Six months after the intervention, there were a significantly lower VAS score and significantly higher pain-free walking time and FADI score than the baseline, but no statistically significant difference was seen between other time points. In conclusion, allogeneic WJ-MSC transplantation in patients with CLI seems to be safe and effective.

Sex-specific analysis of intravascular lithotripsy for peripheral artery disease from the Disrupt PAD III observational study.

OBJECTIVE: Endovascular therapy of lower extremity peripheral artery disease (PAD) is associated with higher complication rates and worse outcomes in women vs men. Although intravascular lithotripsy (IVL) has shown similarly favorable outcomes in men and women in calcified coronary arteries, there is no published safety and effectiveness data of peripheral IVL differentiated by sex. This study aims to evaluate sex-specific acute procedural safety and effectiveness following IVL treatment of calcified PAD. METHODS: We performed a secondary analysis of the multicenter Disrupt PAD III Observational Study, which assessed short-term procedural outcomes of patients undergoing treatment of symptomatic calcified lower extremity PAD with the Shockwave peripheral IVL system. Adjudicated acute safety and efficacy outcomes were compared by sex using univariate analysis performed with the χ2 test or Fisher exact test, as appropriate. RESULTS: A total of 1262 patients (29.9% women) were included, with >85% having moderate to severe lesion calcification. Women were older (74 vs 71 years; P < .001), had lower ankle-brachial index (0.7 vs 0.8; P = .003), smaller reference vessel size (5.3 vs 5.6 mm; P = .009), and more severe stenosis at baseline vs men (82.3% vs 79.8%; P = .012). Rates of diabetes, renal insufficiency, chronic limb-threatening ischemia, lesion length, and atherectomy use were similar in both groups. Residual stenosis after IVL alone was significantly reduced in both groups. Final residual stenosis was 21.9% in women and 24.7% in men (P = .001). Serious angiographic complications were infrequent and similar in both groups (1.4% vs 0.6%; P = .21), with no abrupt vessel closure, distal embolization, or thrombotic events during any procedure. CONCLUSIONS: The use of IVL to treat calcified PAD in this observational registry demonstrated favorable acute safety and effectiveness in both women and men.

Comparison of outcomes of percutaneous deep venous arterialization in multiple practice settings.

OBJECTIVE: We compared the efficacy of percutaneous deep venous arterialization (pDVA) in patients with no-option chronic limb-threatening ischemia in the hospital vs in office-based laboratory (OBL) settings. METHODS: A retrospective chart review was performed of all patients who underwent pDVA using off-the-shelf devices from January 2018 to March 2023 in a hospital and an OBL. We identified 73 eligible patients, 41 from a hospital setting (59% male; median age, 72 years; interquartile range, 18 years) and 32 from an OBL setting (59% males; 67 years; interquartile range, 16 years). All eligible patients were deemed to have no-option critical limb ischemia, had at least one patent proximal tibial artery available for the creation of an arteriovenous anastomosis, and were classified as having Rutherford classification IV or higher peripheral arterial disease. Patients were ineligible if classified as Rutherford classification III or lower, had active infection, did not have at least one appropriate venous target, and/or had rapidly progressing wounds requiring immediate major amputation. The primary outcome was major amputation-free survival (AFS). Secondary outcomes included technical success, limb salvage, survival, primary patency, reintervention rate, adverse events, and partial and complete wound healing. Outcomes were evaluated using Kaplan-Meier method, log-rank, and two-stage procedure tests. RESULTS: Technical success was achieved in 70 patients (96%) with 1 hospital (2.4%) and 2 OBL (6.3%) patients lost to follow-up. Major AFS estimates at 6 months, 1 year, and 2 years were 51.4%, 40.4%, and 30.2% in the hospital group and 69.4%, 54.0%, and 49.5% in the OBL group, respectively. Partial wound healing estimates at 6 months, 1 year, and 2 years were 27.5%, 71.7%, and 81.2% in the hospital group and 62.7% at all time points in the OBL group. Complete wound healing estimates at 6 months, 1 year, and 2 years were 6.7%, 33.3%, and 33.3% in the hospital group and 5.3%, 37.7%, and 41.6% in the OBL group, respectively. There was no significant difference in major AFS (P = .13), limb salvage (P = .07), survival (P = .69), primary patency (P = .53), partial (P = .08), or complete wound healing (P = .79) between groups. Reintervention was performed in 8 hospital (20.5%) and 14 OBL (45.2%) patients. CONCLUSIONS: pDVA is a feasible and safe procedure for no-option critical limb ischemia in the hospital and OBL setting without significant differences in outcomes at ≤2 years.

Association between tissue loss type and amputation risk among Medicare patients with concomitant diabetes and peripheral arterial disease.

OBJECTIVE: Prior studies have described risk factors associated with amputation in patients with concomitant diabetes and peripheral arterial disease (DM/PAD). However, the association between the severity and extent of tissue loss type and amputation risk remains less well-described. We aimed to quantify the role of different tissue loss types in amputation risk among patients with DM/PAD, in the context of demographic, preventive, and socioeconomic factors. METHODS: Applying International Classification of Diseases (ICD)-9 and ICD-10 codes to Medicare claims data (2007-2019), we identified all patients with continuous fee-for-service Medicare coverage diagnosed with DM/PAD. Eight tissue loss categories were established using ICD-9 and ICD-10 diagnosis codes, ranging from lymphadenitis (least severe) to gangrene (most severe). We created a Cox proportional hazards model to quantify associations between tissue loss type and 1- and 5-year amputation risk, adjusting for age, race/ethnicity, sex, rurality, income, comorbidities, and preventive factors. Regional variation in DM/PAD rates and risk-adjusted amputation rates was examined at the hospital referral region level. RESULTS: We identified 12,257,174 patients with DM/PAD (48% male, 76% White, 10% prior myocardial infarction, 30% chronic kidney disease). Although 2.2 million patients (18%) had some form of tissue loss, 10.0 million patients (82%) did not. The 1-year crude amputation rate (major and minor) was 6.4% in patients with tissue loss, and 0.4% in patients without tissue loss. Among patients with tissue loss, the 1-year any amputation rate varied from 0.89% for patients with lymphadenitis to 26% for patients with gangrene. The 1-year amputation risk varied from two-fold for patients with lymphadenitis (adjusted hazard ratio, 1.96; 95% confidence interval, 1.43-2.69) to 29-fold for patients with gangrene (adjusted hazard ratio, 28.7; 95% confidence interval, 28.1-29.3), compared with patients without tissue loss. No other demographic variable including age, sex, race, or region incurred a hazard ratio for 1- or 5-year amputation risk higher than the least severe tissue loss category. Results were similar across minor and major amputation, and 1- and 5-year amputation outcomes. At a regional level, higher DM/PAD rates were inversely correlated with risk-adjusted 5-year amputation rates (R2 = 0.43). CONCLUSIONS: Among 12 million patients with DM/PAD, the most significant predictor of amputation was the presence and extent of tissue loss, with an association greater in effect size than any other factor studied. Tissue loss could be used in awareness campaigns as a simple marker of high-risk patients. Patients with any type of tissue loss require expedited wound care, revascularization as appropriate, and infection management to avoid amputation. Establishing systems of care to provide these interventions in regions with high amputation rates may prove beneficial for these populations.

Secondary interventions following open vs endovascular revascularization for chronic limb threatening ischemia in the BEST-CLI trial.

OBJECTIVES: Patients undergoing revascularization for chronic limb-threatening ischemia experience a high burden of target limb reinterventions. We analyzed data from the Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) randomized trial comparing initial open bypass (OPEN) and endovascular (ENDO) treatment strategies, with a focus on reintervention-related study endpoints. METHODS: In a planned secondary analysis, we examined the rates of major reintervention, any reintervention, and the composite of any reintervention, amputation, or death by intention-to-treat assignment in both trial cohorts (cohort 1 with suitable single-segment great saphenous vein [SSGSV], n = 1434; cohort 2 lacking suitable SSGSV, n = 396). We also compared the cumulative number of major and all index limb reinterventions over time. Comparisons between treatment arms within each cohort were made using univariable and multivariable Cox regression models. RESULTS: In cohort 1, assignment to OPEN was associated with a significantly reduced hazard of a major limb reintervention (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.28-0.49; P < .001), any reintervention (HR, 0.63; 95% CI, 0.53-0.75; P < .001), or any reintervention, amputation, or death (HR, 0.68; 95% CI, 0.60-0.78; P < .001). Findings were similar in cohort 2 for major reintervention (HR, 0.53; 95% CI, 0.33-0.84; P = .007) or any reintervention (HR, 0.71; 95% CI, 0.52-0.98; P = .04). In both cohorts, early (30-day) limb reinterventions were notably higher for patients assigned to ENDO as compared with OPEN (14.7% vs 4.5% of cohort 1 subjects; 16.6% vs 5.6% of cohort 2 subjects). The mean number of major (mean events per subject ratio [MR], 0.45; 95% CI, 0.34-0.58; P < .001) or any target limb reinterventions (MR, 0.67; 95% CI, 0.57-0.80; P < .001) per year was significantly less in the OPEN arm of cohort 1. The mean number of reinterventions per limb salvaged per year was lower in the OPEN arm of cohort 1 (MR, 0.45; 95% CI, 0.35-0.57; P < .001 and MR, 0.66; 95% CI, 0.55-0.79; P < .001 for major and all, respectively). The majority of index limb reinterventions occurred during the first year following randomization, but events continued to accumulate over the duration of follow-up in the trial. CONCLUSIONS: Reintervention is common following revascularization for chronic limb-threatening ischemia. Among patients deemed suitable for either approach, initial treatment with open bypass, particularly in patients with available SSGSV conduit, is associated with a significantly lower number of major and minor target limb reinterventions.

Tips and Tricks for Simple and Complex Below-the-Ankle Punctures.

CLINICAL IMPACT: When the standard endovascular crossing maneuvers have failed during CLTI recanalization procedures and the distal below-the-knee or proximal below-the-ankle retrograde access is not possible due to chronic occlusion of the vessels, mastering the more distal and complex retrograde BTA punctures may be advantageous.There are scanty reports regarding the retrograde puncture of the mid and forefoot vessels. The aim of this article is to review different tips and tricks related to these techniques to help operators to apply them in specific scenarios to eventually improve procedural success rate.

Subcutaneous injection of lidocaine around ischemic ankle provides safe and effective foot analgesia in patients with critical limb ischemia.

OBJECTIVE: It is often difficult to alleviate foot pain associated with critical limb ischemia (CLI) using common analgesics. Neuraxial block is contraindicated in anticoagulant therapy. This study was designed to determine the response to subcutaneous injection of lidocaine around the network of peripheral nerves around the ankle in patients with CLI pain on anticoagulants and antiplatelets. METHODS: Sixteen patients with CLI pain in the foot were enrolled in this double-blind placebo-controlled crossover study. Patients were randomized to receive either 2% lidocaine or saline via catheters inserted into the subcutaneous area around the ankle. After recurrence of pain, the patients were crossed over to receive the alternative treatment. Pain was assessed with a numerical rating scale (NRS) before and 15 min after injection. Patients used a descriptive scale to grade pain control and were asked to determine the duration of analgesia in each arm of the study. RESULTS: No serious complications including protracted bleeding occurred. Lidocaine significantly decreased the NRS on movement from 10 (6, 10) [median (range)] to 2 (0, 10) (p < .001), and the differences in the Δ change in NRS between lidocaine and placebo were significant (p = .009). Of the 16 patients, 14 patients were very satisfied after lidocaine but only one described the same after saline. The effect of lidocaine and placebo lasted 11 (0, 28) and 1 (0, 22) h, respectively. CONCLUSION: Subcutaneous injection of lidocaine around the ischemic ankle affectively alleviated pain in patients with CLI without serious adverse effects under anticoagulant therapy.

Success of transmetatarsal amputation for limb salvage in patients with peripheral artery disease.

Limb salvage is a difficult path for patients to travel as there is no guarantee of the outcome, often the major factor is perfusion. For patients who underwent transmetatarsal amputation (TMA), success rate is crucial as the next option is most likely a major amputation. We performed a 10 years (2010-2020) retrospective review of patients that underwent a TMA and had an angiogram or computed tomography angiography (CTA) perioperatively at the Dallas VA Medical Center. Failure after TMA was defined as a patient requiring a proximal amputation within 1 year. There were 125 TMAs performed between 2010 and 2020 at the institution. Forty-four (35.2%) patients had an angiogram/CTA peri-operative and met the inclusion criteria. Seventeen subjects (38.6%) had a higher level of amputation. Of the 17 failures, 2 (11.8%) patients had no patent vessel runoff to the foot, 9 (52.9%) had one vessel, 4 (23.5%) had two vessels, and 2 (11.8%) had three vessels runoff. One vessel runoff to the foot yielded a high rate of poor outcomes (56.3%) defined as a higher level of amputation. Two or more vessels runoff to the foot had over 75% success of limb salvage with a TMA.

Limb salvage in octogenarians with critical limb ischemia after lower extremity bypass surgery.

OBJECTIVES: Peripheral artery disease is a worldwide epidemic that affects millions of patients, especially the elderly. It has a prevalence of 20% in individuals >80 years old. Although peripheral artery disease affects >20% of octogenarians, information about limb salvage rates in this patient population is limited. Therefore, this study aims to understand the impact of bypass surgery on limb salvage in patients aged >80 years with critical limb ischemia. METHODS: We conducted a retrospective analysis by querying the electronic medical records at a single institution from 2016 through 2022 to identify the population of interest and analyzed their outcomes after lower extremity bypass. The primary outcomes were limb salvage and primary patency, with hospital length of stay and 1-year mortality as secondary outcomes. RESULTS: We identified 137 patients who met the inclusion criteria. The lower extremity bypass population was divided into two cohorts: <80 years old (n = 111) with a mean age of 66 or ≥80 years old (n = 26) with a mean age of 84 years. The gender distribution was similar (P = .163). No significant difference was found in the two cohorts when it came to coronary artery disease, chronic kidney disease, or diabetes mellitus. However, when current and former smokers were grouped together, they were significantly more common in the younger cohort when compared with nonsmokers (P = .028). The primary end point of limb salvage was not significantly different between the two cohorts. Hospital length of stay was not significantly different between the two cohorts with 4.13 days vs 4.17 days in the younger vs octogenarian cohorts, respectively (P = .95). The 30-day all-cause readmissions were also not found to be significantly different between the two groups. The primary patency at 1 year was 75% and 77% (P = .16) for the <80-year-old and ≥80-year-old cohorts, respectively. Mortality was low in both cohorts, with two and three for the younger and octogenarian populations, respectively; thus, no analysis was performed. CONCLUSIONS: Our study shows that octogenarians who undergo the same preoperative risk assessment as younger populations have similar outcomes when it comes to primary patency, hospital length of stay, and limb salvage when comorbidities were considered. Further studies need to be done to determine the statistical impact on mortality in this population with a larger cohort.

A systematic review and meta-analysis of primary bypass surgery compared with bypass surgery after endovascular treatment in peripheral artery disease patients.

OBJECTIVE: Both bypass surgery and endovascular treatment are well-recognized interventions for the treatment of peripheral artery disease; however, the effect of failed endovascular treatment on subsequent surgeries remains controversial. A systematic review was conducted to compare the outcomes of primary bypass and bypass surgery after endovascular treatment. METHODS: Three academic databases (Embase, PubMed, and Scopus) were searched from their inception to August 2022. Two independent investigators searched for studies that reported the outcomes of primary bypass surgery and bypass surgery after endovascular treatment in patients with peripheral artery disease. Abstracts and full-text studies were screened independently using duplicate data abstraction. Dichotomous outcome measures were reported using a random-effects model to generate a summary odds ratio (OR) and 95% confidence interval (CI). The risk of bias was assessed using the Newcastle-Ottawa Scale. RESULTS: Seventeen retrospective observational studies were selected from 3911 articles and included 8064 patients, 6252 of whom underwent primary bypass surgery and 1812 underwent bypass surgery after endovascular treatment. The mean age was 69.0 years and 61.2% (n = 4938) were male. For perioperative outcomes, the 30-day results showed no difference in mortality (OR, 0.76; 95% CI, 0.53-1.10), or amputation (OR, 0.89; 95% CI, 0.67-1.20). For short- to mid-term outcomes, primary patency did not differ at 6 months (OR, 0.98; 95% CI, 0.81-1.19), 1 year (OR, 1.12; 95% CI, 0.97-1.30), or 2 years (OR, 1.17; 95% CI, 0.85-1.61) follow-up. Amputation-free survival did not differ at 6 months (OR, 1.03; 95% CI, 0.82-1.30), 1 year (OR, 1.09; 95% CI, 0.89-1.32), 2 years (OR, 1.18; 95% CI, 0.93-1.50), or 3 years (OR, 1.09; 95% CI, 0.84-1.40) of follow-up. No significant difference was found in overall survival or second patency. CONCLUSIONS: This meta-analysis of retrospective, nonrandomized, observational studies suggests that prior endovascular treatment of lower extremity arterial disease does not result in worse perioperative, short-term, or mid-term clinical outcomes of subsequent infrainguinal bypass surgery compared with patients without prior endovascular treatment.

Baseline modern medical management in the BEST-CLI trial.

OBJECTIVES: The use of optimal medical therapy (OMT) in patients with chronic limb-threatening ischemia (CLTI) has not been well-studied. The Best Endovascular vs Best Surgical Therapy in Patients with CLTI study (BEST-CLI) is a multicenter, randomized, controlled trial sponsored by the National Institutes of Health comparing revascularization strategies in patients with CLTI. We evaluated the use of guideline-based OMT among patients with CLTI at the time of their enrollment into the trial. METHODS: A multidisciplinary committee defined OMT criteria related to blood pressure and diabetic management, lipid-lowering and antiplatelet medication use, and smoking status for patients enrolled in BEST-CLI. Status reports indicating adherence to OMT were provided to participating sites at regular intervals. Baseline demographic characteristics, comorbid medical conditions, and use of OMT at trial entry were evaluated for all randomized patients. A linear regression model was used to identify the relationship of predictors to the use of OMT. RESULTS: At the time of randomization (n = 1830 total enrolled), 87% of patients in BEST-CLI had hypertension, 69% had diabetes, 73% had hyperlipidemia, and 35% were currently smoking. Adherence to four OMT components (controlled blood pressure, not currently smoking, use of one lipid-lowering medication, and use of an antiplatelet agent) was modest. Only 25% of patients met all four OMT criteria; 38% met three, 24% met two, 11% met only one, and 2% met none. Age ≥80 years, coronary artery disease, diabetes, and Hispanic ethnicity were positively associated, whereas Black race was negatively associated, with the use of OMT. CONCLUSIONS: A significant proportion of patients in BEST-CLI did not meet OMT guideline-based recommendations at time of entry. These data suggest a persistent major gap in the medical management of patients with advanced peripheral atherosclerosis and CLTI. Changes in OMT adherence over the course of the trial and their impact on clinical outcomes and quality of life will be assessed in future analyses.

Potential metabolic biomarkers of critical limb ischemia in people with type 2 diabetes mellitus.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a significant risk factor for the development of critical limb ischemia (CLI), the most advanced stage of peripheral arterial disease. The concurrent existence of T2DM and CLI often leads to adverse outcomes, namely limb amputation. OBJECTIVE: To identify biomarkers for improving the screening of CLI in high-risk people with T2DM. METHODS: We investigated metabolome profiles in serum samples of 113 T2DM people with CLI (n = 23, G2) and without CLI (n = 45, G0: no lower limb stenosis (LLS) and n = 45, G1: LLS < 50%), using hydrogen nuclear magnetic resonance (1H NMR) approach. Principle component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were used to analyze 1H NMR data. RESULTS: Twenty potential metabolites that could discriminate people with T2DM and CLI (G2) from non-CLI patients without LLS (G0) were determined in serum samples. The correct percent of classification for the PLS-DA model for the test set samples was 85% (n = 20) and 100% (n = 5) for G0 and G2 groups, respectively. Non-CLI patients with LLS < 50% (G1) were projected on the PCA abstract space built using 20 discriminatory metabolites. Eleven people with T2DM and LLS < 50% were prospectively followed, and their ankle-brachial index (ABI) was measured after 4 years. A promising agreement existed between the PCA model's predictions and those obtained by ABI values. CONCLUSION: The findings suggest that confirmation of blood potential metabolic biomarkers as a complement to ABI for screening of CLI in a large group of high-risk people with T2DM is needed.

Delayed rupture of peroneal artery pseudoaneurysm following endovascular treatment in a patient with chronic limb-threatening ischemia: A case report.

Below-the-knee (BTK) pseudoaneurysms that occur after endovascular therapy (EVT) and result in delayed rupture have rarely been reported. In this report, we present a rare case of an 86-year-old man with chronic limb-threatening ischemia who developed delayed rupture of an idiopathic pseudoaneurysm of the peroneal artery (PA) following EVT. The PA chronic total occlusion (CTO) was successfully crossed using a guidewire via an antegrade approach, however, subintimal crossing was confirmed by intravascular ultrasound. Balloon angioplasty was then performed using an appropriately sized balloon, resulting in successful recanalization of the PA CTO with minor dissection and no complications. Postoperatively, the patient's condition was stable until he suddenly complained of right calf pain 10 days after EVT. Computed tomography revealed a rupture of the PA pseudoaneurysm. Urgent angiography revealed two pseudoaneurysms, one saccular and the other spindle-shaped. The ruptured saccular aneurysm was successfully excluded through coil embolization and stent graft placement. To the best of our knowledge, this is the first reported case of delayed rupture of a BTK pseudoaneurysm following EVT. Balloon angioplasty in the subintimal space can lead to the formation of a pseudoaneurysm and its delayed rupture.

Skeletal Muscle Bioenergetics in Critical Limb Ischemia and Diabetes.

INTRODUCTION: Mitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus (T2DM) is a major risk factor for PAD development and progression to CLI and may also independently be related to mitochondrial dysfunction. We set out to determine the effect of T2DM in the relationship between CLI and muscle mitochondrial respiratory capacity and coupling control. METHODS: We studied CLI patients undergoing revascularization procedures or amputation, and non-CLI patients with or without T2DM of similar age. Mitochondrial respiratory capacity and function were determined in lower limb permeabilized myofibers by high-resolution respirometry. RESULTS: Fourteen CLI patients (65 ± 10y) were stratified into CLI patients with (n = 8) or without (n = 6) T2DM and were compared to non-CLI patients with (n = 18; 69 ± 5y) or without (n = 19; 71 ± 6y) T2DM. Presence of CLI but not T2DM had a marked impact on all mitochondrial respiratory states in skeletal muscle, adjusted for the effects of sex. Leak respiration (State 2, P < 0.025 and State 4o, P < 0.01), phosphorylating respiration (P < 0.001), and maximal respiration in the uncoupled state (P < 0.001), were all suppressed in CLI patients, independent of T2DM. T2DM had no significant effect on mitochondrial respiratory capacity and function in adults without CLI. CONCLUSIONS: Skeletal muscle mitochondrial respiratory capacity was blunted by ∼35% in patients with CLI. T2DM was not associated with muscle oxidative capacity and did not moderate the relationship between muscle mitochondrial respiratory capacity and CLI.

Twenty-Four Month Results of Tack-Optimized Balloon Angioplasty Using the Tack Endovascular System in Below-the-Knee Arteries.

PURPOSE: To report 24 month safety and efficacy of the Tack Endovascular System for treatment of post-percutaneous transluminal angioplasty (PTA) infrapopliteal dissections in patients with critical limb-threatening ischemia (CLTI). MATERIALS AND METHODS: The Tack-Optimized Balloon Angioplasty (TOBA) II below-the-knee (BTK) study was a prospective, multicenter, single-arm evaluation of the Tack Endovascular system for post-PTA infrapopliteal dissection repair. Patients with Rutherford Clinical Category (RC) 3 to 5 and a post-PTA dissection(s) of the BTK arteries were enrolled. The 30 day primary safety endpoint was a composite of major adverse limb events (MALE) and all-cause perioperative death (POD). The primary effectiveness endpoint was a composite of MALE at 6 months and 30 day POD. Outcomes were assessed as observational endpoints at 24 months. RESULTS: Tack-Optimized Balloon Angioplasty II BTK enrolled 233 patients; all patients had a post-PTA dissection(s) and received ≥1 Tack implant (range, 1-16). Mean age was 74.4±10.0 years and 67.4% were men. Most patients had CLTI (RC 3: 16.3%; RC 4/5: 83.7%). Mean target lesion length was 80±49 mm. Moderate to severe calcium was present in 89 (35.8%) lesions and total occlusions were present in 118 (47.6%) lesions. Kaplan-Meier freedom from MALE at 24 months + POD at 30 days was 92.2% and 24 month freedom from clinically-driven target lesions revascularization was 73.6%. Kaplan-Meier target limb salvage was 95.7% and amputation-free survival was 75.4%. Improvements in functional status and quality of life were observed through 24 months. CONCLUSION: The TOBA II BTK study demonstrated sustained safety and efficacy through 24 months in patients treated for post-PTA dissection(s) of BTK lesions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02942966.

Safety and Effectiveness of Excimer Laser Ablation Combined With Drug-Coated Balloon for Atherosclerotic Obliterans in the Lower Extremity.

PURPOSE: To evaluate the safety and effectiveness of excimer laser ablation (ELA) combined with drug-coated balloon (DCB) for atherosclerotic obliterans (ASO) of the lower extremities. MATERIALS AND METHODS: From June 2019 to December 2020, all eligible patients were enrolled. Demographics, characteristics of lesions, complications, and follow-up information were collected and analyzed. The primary endpoint was major amputation-free survival (MAFS). Secondary endpoints included technical success, primary patency, bailout stent, distal embolization, target lesion reintervention (TLR), and ulcer healing rate. Major amputation-free survival and primary patency were calculated by Kaplan-Meier analysis. RESULTS: A total of 71 patients were enrolled. Forty-eight (81.7%) patients presented critical limb ischemia (CLI) and 48.6% of them was calcification class 4 according to Peripheral Arterial Calcium Scoring System (PACSS). Chronic totally occluded (CTO) disease was the most common lesion in 66.0% of them and superficial femoral artery (SFA) was the most common segment in 59.6%. Technical success rate was 93.0%. One-year follow-up was finished in 25 (35.2%) patients. The primary patency and MAFS were 92.0%±27.6% and 96.0%±20.0% at 12 months, respectively. During the mean follow-up of 9.4±4.3 months, clinically-driven TLR occurred in 2 (2.8%) patients, and major and minor amputation occurred in 2 (2.8%) and 1 (1.4%) patient, respectively. CONCLUSION: The early results demonstrated that ELA was an effective treatment in de novo, in-stent restenosis (ISR) and CTO lesions. Meanwhile, ELA could prepare the lumen for the use of DCB and reduce the implantation of stents, especially in segments unsuitable for stenting. Mid-term and long-term results need to be awaited.

Novel Therapeutic Concepts for Complex Femoropopliteal Lesions Using the Jetstream Atherectomy System.

INTRODUCTION: The presence of severe arterial calcification is associated with less favorable outcomes in terms of procedural and clinical success as well as higher rates of major adverse limb events. Recent studies incorporating rotational atherectomy for effective preparation of severely calcified lesions demonstrate beneficial procedural outcomes by obtaining maximal luminal gain and improved long-term outcomes. METHODS: This prospective single-center, observational study includes patients with severely calcified femoropopliteal lesions with chronic limb ischemia Rutherford 1-5 between January 2017 and July 2019, who underwent atherectomy using the Jetstream Atherectomy system, followed by drug-coated balloon angioplasty. Lesion calcification was categorized by the Peripheral Arterial Calcium Scoring System (PACSS), whereas lesion complexity was classified by the Transatlantic Inter-Society Consensus (TASC). Safety and efficacy aspects in terms of vessel injury, thromboembolism, and clinical success were systematically analyzed up to 12 months of follow-up (FU). RESULTS: In 162 consecutive patients, 210 non-stented and 22 stented lesions were treated. Twelve (7.4%) patients received bail-out stenting. Mean lesion length was 24.2±4.8 cm; 51% were chronic total occlusions (mean occlusion length 18.2±5.1 cm). TASC C lesions were present in 38 patients (23.5%) and TASC D lesions in 124 patients (76.5%). The mean PACCS score was 3.3±0.9. Device success was achieved in 88%; procedural success was noted in 99% of the lesions. Embolic protection device was used in 11.7%. Perforation or dissection occurred in none of the cases. Asymptomatic peripheral embolization was noted in 10 patients (6.2%). Clinical FU at 12 months was available in 157 of 162 patients (96.9%). At 12 month FU, (1) mean Rutherford classification at baseline of 3.7±0.6 significantly dropped to 1.0±0.9 (p<0.05), (2) baseline mean anke-brachial index (ABI) of 0.4±0.1 significantly increased to 0.8±0.2 (p<0.05), (3) 92.6% were free from target lesion revascularization (TLR), (4) 95.1% were free from target vessel revascularization (TVR), and (5) binary restenosis measured by duplex occurred in 22 patients (13.6%). Multivariate analyses showed lesion length as predictive of stent placement (p=0.02), whereas both lesion length (p=0.006) and PACCS score (p=0.02) are predictive of clinical success. CONCLUSION: Rotational atherectomy in combination with drug-coated balloon (DCB) can be safely performed in long, calcified (non-) occlusive lesions with a relatively low rate of bail-out stenting and favorable clinical mid-term results. CLINICAL IMPACT: In this prospective, single arm study we demonstrated that combination treatment using rotational atherectomy and DCB is safe and effective in complex and calcified TASC C/D femoropopliteal lesions in patients with claudication or CLTI in a real-world clinical setting. Despite mean lesion length of >20cm and a relatively high rate of chronic total occlusions, the rate of bail-out stenting was surprisingly low (7.4%), whereas the rates of freedom from TLR and TVR were surprisingly high. Thus, our study may encourage vascular specialists to choose an endovascular -first approach even in such complex and calcified femoropopliteal lesions and occlusions in daily clinical practice.

Clinical Implications of Diabetic Peripheral Neuropathy in Primary Infrapopliteal Angioplasty Approach for Neuro-Ischemic Foot Wounds.

BACKGROUND: To assess the clinical effects of diabetic peripheral neuropathy (DPN) in patients with chronic limb-threatening ischemia (CLTI) treated by primary infrapopliteal angioplasty for neuro-ischemic Rutherford 5, foot wounds. MATERIALS AND METHODS: Over a 10-year period (2009-2019), a series of 304 diabetic ischemic limbs adding or not evincible neuropathic affectation were treated by primary infrapopliteal angioplasty and their files were retrospectively reviewed. Mean length of treated arterial lesions was 6.1 cm (range 1-22 cm). Inferior limb vibration perception threshold diagnostic was performed for comparing and scoring detectable DPN in all studied diabetic patients (classed from 0 to 10 points). There were 19% limbs with normal (0-1 points) perception (group 1), 55% others with "mild" and "moderate" (2-6 points) neuropathic impairment (group 2), and 26% limbs showing "severe" (7-10 points) DPN (group 3). RESULTS: Primary infrapopliteal angioplasty succeeded in 89% cases in group 1, in 82% in group 2, and in 68% of limbs in group 3. This latest group assembled the heaviest neuropathic affectation and arterial calcifications and proved the lowest clinical benefit at 36 months: 35% (95% confidence interval [CI]=22% to 48%) of primary patency, 36% (95% CI=22% to 50%) wound healing, and 54% (95% CI=39% to 69%) limb preservation rates. A comparison between groups 1 vs 3 and 2 vs 3 of primary patency (p=0.014 and p=0.043), tissue healing (p=0.049 and p=0.01), and limb salvage (p=0.006 and p=0.023) proved significant, yet without statistical weight for group 1 vs 2 (p>0.05). Overall survival was not significantly affected between groups (p=0.34). CONCLUSION: The presence of severe DPN may jeopardize the results of infrapopliteal angioplasty in terms of patency, tissue cicatrization, and limb preservation, yet without significance on survival of these patients. When present, DPN requires appropriate stratification as specific indicator in CLTI treatment.

Predictors of Revascularization in Lower-Extremity Peripheral Artery Disease: Insights From the PORTRAIT Study.

BACKGROUND: Peripheral artery disease (PAD) guidelines recommend revascularization only for patients with lifestyle-limiting claudication that is refractory to goal-directed medical therapy (class IIA, level of evidence A). However, real-world invasive treatment patterns and predictors of revascularization in patients with symptomatic lower-extremity PAD are still largely unknown. AIM: We aimed to examine rates, patient-level predictors, and site variability of early revascularization in patients with new or worsening PAD symptoms. METHODS: Among patients with new-onset or recent exacerbation of PAD in the 10-center Patient-centered Outcomes Related to TReatment practices in peripheral Arterial disease: Investigating Trajectories (PORTRAIT) study enrolled between June 2011 and September 2015, we classified early revascularization (endovascular or surgical) as procedures being performed within 3 months of presentation. Hierarchical logistic regression was used to identify patient characteristics associated with early revascularization. Variability across sites was estimated using the median odds ratio (OR). RESULTS: Among 797 participants, early revascularization procedures were performed in 224 (28.1%). Rutherford class 3 (vs Rutherford class 1; OR=1.86, 95% confidence interval [CI] 1.04-3.33) and having lesions in both iliofemoral and below-the-knee arterial segments (vs below the knee only; OR=1.75, 95% CI: 1.15-2.67) were associated with a higher odds of revascularization. Longer PAD duration >12 months (vs 1-6 months; OR=0.50, 95% CI: 0.32-0.77), higher ankle-brachial index scores (per 0.1 unit increase; OR=0.86, 95% CI: 0.78-0.96), and higher Peripheral Artery Questionnaire Summary scores (per 10 unit increase; OR=0.89, 95% CI: 0.80-0.99) were associated with a lower odds of revascularization. The raw rates for revascularization in different sites ranged from 6.25% to 66.28%, and the median OR was 1.88, 95% CI: 1.38-3.57. CONCLUSIONS: About 1 in 3 patients with symptomatic PAD received early revascularization. A more extensive disease and symptom burden were the main predictors of receiving early revascularization in PAD. There was significant site variability in revascularization patterns, and further studies will better understand the source of this variability and optimal selection criteria for early revascularization. CLINICAL IMPACT: Real world patterns and predictors of early revascularization in peripheral artery disease are not well understood. In this retrospective analysis of the POTRAIT study, about 1 out of 3 patients with PAD symptoms received early revascularization, with significant site variability. A more extensive disease and symptom burden were the main predictors of receiving early revascularization in PAD.