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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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) presents a significant clinical challenge, leading to tissue ischemia and potentially resulting in limb necrosis or amputation. Cell‐based regenerative therapies offer promise for improving outcomes in CLI, but their effectiveness is often limited by poor cell survival and engraftment. This study hypothesized that a thermo‐responsive polymer, poly(polyethylene glycol citrate‐co‐N‐isopropylacrylamide) (PPCN), combined with pro‐survival bioactive peptides, can create a protective microenvironment to improve endothelial cell survival and function after their delivery. Through in vitro and in vivo experiments, laminin‐derived peptide A5G81 and vascular endothelial growth factor (VEGF)‐derived peptide QK are identified as effective in promoting endothelial cell spreading, proliferation, and prolonged survival. PPCN's viscoelastic properties protected against shear stress during injection, while the peptides supported endothelial cell behavior through distinct molecular pathways. Importantly, delivery of endothelial cells with PPCN‐A5G81 and PPCN‐QK in a murine hindlimb ischemia model resulted in significant improvements in limb perfusion, tissue preservation, and functional outcomes compared to controls. Additionally, this approach enhanced skeletal muscle remodeling following ischemic injury. This innovative biomaterial platform represents a versatile solution for addressing cell survival challenges and advancing regenerative therapies in CLI and other ischemic conditions. [ABSTRACT FROM AUTHOR]

Chronic Limb Threatening Ischemia (CLTI) is a challenging clinical problem associated with high morbidity and mortality. Endovascular interventions have been the cornerstone of treatment whenever possible. It is estimated that CLTI represents < 10% of all Peripheral Artery Disease patients, yet 50% of the patients end up either with a major amputation of the lower limbs or die of cardiovascular causes within one year period, especially in those with unsuccessful revascularization or “no-option” CLTI. Cell-based therapeutics, especially bone marrow-derived mesenchymal stromal cells have emerged as a potential, promising, and novel alternate therapeutic modality in the management of CLTI, bolstered with positive results in numerous research, including randomized and nonrandomized trials. REGENACIP® is one such BM-MSC therapy approved by Central Drugs Standard Control Organization in India for the management of “no-option” Atherosclerotic Peripheral Arterial disease / Buerger’s disease patients with established critical limb ischemia in Rutherford Grade III-5 or III-6, not eligible for or have failed traditional revascularization treatment, with rest pain and / or ulcers in the affected limb. The current review aims to deliberate upon the various aspects of CLTI and clinical benefits of REGENACIP® therein. [ABSTRACT FROM AUTHOR]

Recent trends indicate a rise in the incidence of critical limb ischemia (CLI) among younger adults. This study examines trends in CLI hospitalization and outcomes among young adults with peripheral arterial disease (PAD) in the United States. Adult hospitalizations (18–40 years) for PAD/CLI were analyzed from the 2016–2020 nationwide inpatient sample database using ICD-10 codes. Rates were reported per 1000 PAD or 100,000 cardiovascular disease admissions. Outcomes included trends in mortality, major amputations, revascularization, length of hospital stay (LOS), and hospital costs (THC). We used the Jonckheere–Terpstra tests for trend analysis and adjusted costs to the 2020 dollar using the consumer price index. Approximately 63,045 PAD and 20,455 CLI admissions were analyzed. The mean age of the CLI cohort was 32.7 ± 3 years. The majority (12,907; 63.1 %) were female and white (11,843; 57.9 %). Annual CLI rates showed an uptrend with 3265 hospitalizations (227 per 1000 PAD hospitalizations, 22.7 %) in 2016 to 4474 (252 per 1000 PAD hospitalizations, 25.2 %) in 2020 (Ptrend<0.001), along with an increase in PAD admissions from 14,405 (188 per 100,000, 0.19 %) in 2016 to 17,745 (232 per 100,000, 0.23 %%) in 2020 (Ptrend<0.0001). Annual in-hospital mortality increased from 570 (2.8 %) in 2016 to 803 (3.9 %) in 2020 (Ptrend = 0.001) while amputations increased from 1084 (33.2 %) in 2016 to 1995 (44.6 %) in 2020 (Ptrend<0.001). Mean LOS increased from 5.1 (SD 2.7) days in 2016 to 6.5 (SD 0.9) days in 2020 (Ptrend = 0.002). The mean THC for CLI increased from $50,873 to $69,262 in 2020 (Ptrend<0.001). The endovascular revascularization rates decreased from 11.5 % (525 cases) in 2016 to 10.7 % (635 cases) in 2020 (Ptrend = 0.025). Surgical revascularization rates also increased from 4.9 % (225 cases) in 2016 to 10.4 % (600 cases) in 2020 (Ptrend = 0.041). Hospitalization and outcomes for CLI worsened among young adults during the study period. There is an urgent need to enhance surveillance for risk factors of PAD in this age group. • Most young adults hospitalized for CLI are female and white. • There has been an unexpected increase in CLI cases among 18–40-year-olds in the U.S. • 2016–2020 data reveals higher mortality and amputation rates in young CLI patients. • The average length of hospital stay and costs for CLI treatment have significantly risen over five years. [ABSTRACT FROM AUTHOR]

The evaluation of hemodynamic conditions in critical limb-threatening ischemia (CLTI) patients is inevitable in endovascular interventions. In this study, the performance of color-coded digital subtraction angiography (ccDSA) and the recently developed color-coded digital variance angiography (ccDVA) was compared in the assessment of key time parameters in lower extremity interventions. The observational study included 19 CLTI patients who underwent peripheral vascular intervention at our institution in 2020. Pre- and post-dilatational images were retrospectively processed and analyzed by a commercially available ccDSA software (Kinepict Medical Imaging Tool 6.0.3; Kinepict Health Ltd., Budapest, Hungary) and by the recently developed ccDVA technology. Two protocols were applied using both a 4 and 7.5 frames per second acquisition rate. Time-to-peak (TTP) parameters were determined in four pre- and poststenotic regions of interest (ROI), and ccDVA values were compared to ccDSA read-outs. The ccDVA technology provided practically the same TTP values as ccDSA (r = 0.99, R2 = 0.98, p < 0.0001). The correlation was extremely high independently of the applied protocol or the position of ROI; the r value was 0.99 (R2 = 0.98, p < 0.0001) in all groups. A similar correlation was observed in the change in passage time (r = 0.98, R2 = 0.96, p < 0.0001). The color-coded DVA technology can reproduce the same hemodynamic data as a commercially available DSA-based software; therefore, it has the potential to be an alternative decision-supporting tool in catheter labs. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is associated with systemic cardiovascular and non-cardiovascular diseases. Treatments primarily targeting limb-related outcomes may not improve overall life prognosis. We aimed to describe in-hospital mortality and the underlying etiologies in Japanese patients with CLI. We analyzed the Diagnosis Procedure Combination (DPC) database from approximately 1200 Japanese acute-care hospitals between April 2018 and March 2020. The definition of patients with CLI was based on the diagnostic codes listed as the most resource-intensive diagnosis and information regarding invasive procedures (endovascular treatment, bypass, or amputation). The DPC database provides information on whether in-hospital death was caused by the most resource-intensive diagnosis. Among 15,228 distinct patients with CLI, we identified 18,970 records, including 5,378 amputations. In-hospital death occurred in 1238 (6.5%) patients. Among them, 811 (65.5%) were due to causes unrelated to CLI. In patients who underwent amputation (n = 5378), causes unrelated to CLI accounted for 70.0% of in-hospital deaths, whereas among patients who did not undergo amputation (n = 13,592), this proportion was 60.1%. When compared to patients who died due to causes related to CLI, the prevalence of male patients was higher (62.6% vs 52.7%, p = 0.001), and amputation was more frequently performed (58.0% vs 47.1%, p < 0.001) in those who died due to causes unrelated to CLI. The majority of in-hospital deaths among patients with CLI necessitating endovascular treatment, bypass, or amputation were attributable to factors unrelated to the primary condition of CLI. Managing systemic cardiovascular and non-cardiovascular diseases beyond the affected limb is crucial to improve the prognosis of these patients. [ABSTRACT FROM AUTHOR]

Introduction: Studies exploring the relationship between peripheral arterial disease (PAD), critical limb ischemia (CLI), and chronic kidney disease (CKD) and its effect on in-hospital outcomes are limited. We aimed to analyze the outcomes of patients with CKD and PAD who are admitted for CLI. Methods: We utilized the National Inpatient Sample (NIS) to capture hospitalizations for CLI from 2012 to 2020 and then identified cases with concomitant CKD. The primary outcome was mortality, and secondary outcomes were cerebrovascular accident, major bleeding, vasopressor requirement, percutaneous coronary intervention, cardiac arrest, acute respiratory failure, transfusion, length of stay, and total hospital charges. Multivariable logistic regression was performed to adjust for covariates. Results: A total of 441,245 patients with CLI were identified, of which 122,370 (27.7%) reported concomitant CKD. Patients with CKD had higher in-patient mortality (odds ratio [OR] 1.68, 95% confidence interval [CI], 1.17–1.68, p < 0.001), vascular complications (OR 1.31, 95% CI, 1.17–1.48, p < 0.001), acute kidney injury requiring hemodialysis (OR 3.17, 95% CI, 2.64–3.80, p < 0.001), and major bleeding (OR 1.12, 95% CI, 1.05–1.19, p < 0.001). Patients with CKD underwent minimally invasive endovascular therapy (31.08% vs. 36.73%, p < 0.0001) and invasive procedures (14.73% vs. 23.55%, p < 0.0001) less often. PAD-CLI with CKD was associated with major (20.54% vs. 16.17%, OR 1.04; p < 0.0001) and minor (26.87% vs. 19.53%, OR 1.2, p < 0.0001) amputations more often. Conclusion: Patients admitted for PAD-CLI with concomitant CKD have significantly higher in-hospital mortality as compared to patients without CKD. Moreover, patients with CKD and PAD-CLI are less likely to receive revascularization and more likely to undergo amputation. [ABSTRACT FROM AUTHOR]

Chronic limb-threatening ischemia (CLTI) represents the advanced stages of peripheral arterial disease (PAD) and is caused by atherosclerotic damage in the lower limbs, having a greater risk of major amputation. The aim of this study was to analyze the impact of systemic immune index (SII), systemic inflammation response index (SIRI), and the aggregate index of systemic inflammation (AISI) on the clinical severity and long-term risk of amputation among patients with CLTI after percutaneous transluminal angioplasty (PTA). This is a retrospective observational study involving 104 patients diagnosed with CLTI and treated with PTA. Based on clinical severity, the cohort was divided into two groups: stage III Leriche-Fontaine and stage IV Leriche-Fontaine. We observed higher levels of SII (p = 0.027), SIRI (p = 0.0008), and AISI (p = 0.0024) in patients with trophic lesions. Kaplan–Meier analysis showed that patients with values of SII (p = 0.008), SIRI (p = 0.022), and AISI (p = 0.006) above the median at the time of admission are at a higher risk of major amputation in the long term following PTA. At the multivariate regression analysis, high baseline values of SIRI (odds ratio (OR) = 2.28; p = 0.017) and AISI (OR = 2.32; p = 0.043) were associated with stage IV Leriche-Fontaine, but not SII (OR = 1.71; p = 0.055). Additionally, in the Cox regression analysis, we found that SII (hazard ratio (HR) = 1.56; p = 0.010), SIRI (HR = 1.63; p = 0.009), and AISI (HR = 1.55; p = 0.016) are predictive factors for long-term risk of major amputation after endovascular treatment. Elevated levels of SIRI and AISI have been found to be linked with the severity of clinical symptoms and an increased risk of long-term major amputation in patients with CLTI following PTA. Additionally, higher baseline values for SII were associated with a greater risk of major amputation, but not with clinical severity in the same group of patients. [ABSTRACT FROM AUTHOR]

Background/Aim: Chronic lower limb ischaemia is a peripheral arterial disease (PAD) which is typically instigated by atherosclerotic plaques in the peripheral vasculature. This article reports on a unique case of chronic ischaemia in the lower limb, presenting in a distinctive manner as a fungal toenail infection. Case Report: An 82-year-old frail woman with multimorbidity presented with toenail symptoms in her right foot. While initial examination had shown onychomycosis, further investigation was unexpectedly consistent with chronic ischaemia in the lower limb. We explored the clinical presentation, diagnostic challenges encountered, and the subsequent management of this unique manifestation in the context of the patient’s multimorbidity. Conclusion: This case report highlights the need to consider chronic limb ischemia as a differential diagnosis in toenail infections when no alternative causes or predisposing factors are identified. [ABSTRACT FROM AUTHOR]

A bidirectional approach is necessary for treating critical limb ischemia with complex, multiple lesions. We report an ultrasound-guided bidirectional puncture through an occluded vessel to treat an obstruction extending from the anterior tibial artery to the dorsal foot artery in a patient with toe gangrene and rest pain. This technique effectively restored arterial patency and is a promising approach for managing challenging critical limb ischemia occlusions.

Abstract Chronic Limb Threatening Ischemia (CLTI) is a challenging clinical problem associated with high morbidity and mortality. Endovascular interventions have been the cornerstone of treatment whenever possible. It is estimated that CLTI represents

Purpose: To compare the efficacy and safety of percutaneous mechanical debulking (PMD) using mechanical rotational atherectomy combined with paclitaxel drug-coated balloon (DCB) versus using paclitaxel DCB alone in the treatment of in-stent restenosis. Material and Methods: This is a multicentric retrospective observational study conducted over a period of 2 years from 2020 to 2022. The study included 49 patients presented with chronic limb-threatening ischemia (CLTI) associated with in-stent restenosis, either acute (3 months). The enrolled patients underwent endovascular revascularization using either PMD combined with paclitaxel DCB or paclitaxel DCB only. They were followed up for 6 months after the intervention clinically and by duplex evaluation. Results: The lesion length was about 14.2 mm in the group treated by PMD+ DCB and 9.3 mm in the group treated by DCB alone. The technical success rate was the same between the two groups. However, the follow-up after 6 months showed that patencies for PMD + DCB and DCB alone were 15 (68.2%) patients and 15 (55.6%) patients, respectively (significant p value = 0.028). Procedural-related complications for PMD + DCB are distal embolization (9%) of cases and no vessel perforation. Regarding the candidates who were treated by DCB alone, there were minor groin hematomas (11.1%), distal arterial thrombosis (11.1%) and contrast-induced nephropathy (CIN) (11.1%) cases. Conclusion: The endovascular management of in-stent restenosis using percutaneous mechanical debulking (PMD) in conjunction with paclitaxel drug-coated balloon (DCB) showed that PMD combined with DCB is a safe and effective modality for achieving recanalization. It gives a satisfactory outcome in terms of technical success, freedom from clinically driven target lesion revascularization rate (CD-TLR) and mortality. Despite these promising results, further research with a large enrolled population may be required to determine the cost/benefit.

Background: Endovascular interventions are a standard treatment approach for patients suffering chronic limb threatening ischemia. This approach however can be complicated in some cases owing to difficult anatomy of the lesion that hinders successful crossing and recanalization of the diseased artery. Hence retrograde access and recanalization technique was described and used. Aims and Objectives: The aim of this study was to assess the procedural success, periprocedural complications and evaluate the safety of retrograde popliteal access for SFA and iliac lesions and tibial and pedal access for difficult tibial lesions. Materials and Methods: This is a case series of 60 patients who underwent percutaneous retrograde access (SFA, popliteal, tibial, pedal) for the recanalization of difficult lesions (aorto-iliac, SFA, tibial) between November 2018 to December 2022. We analyzed the technical success and number of periprocedural complications following successful revascularization through a prospective, nonrandomized, single–center, observational study conducted at Jain Institute of Vascular Sciences, Bengaluru, Karnataka, India. We have also analyzed safety of retrograde access and hemodynamic success (based on post-operative ABI improvement) following revascularization. Results: Of the 60 cases, retrograde access was successfully performed in all 60 patients, SFA in 3.3% (n=2), popliteal in 30% (n=18) (3 were primary PA retrograde access and remaining 15 were secondary), ATA was utilized in 35% (n=21), PTA in 20% (n=12), DPA in 6.7% (n=4) and peroneal in 5% (n=3). Technical success was achieved in 92% (n=55). Hemodynamic success was achieved in 75% (n=45). The recorded complication rate was 8.3% which included perforation of artery in 3% (n=2), iatrogenic AV fistula in 1.7% (n=1), arterial thrombosis in 1.7% (n=1) and peri-operative death in 1.7% (n=1). Conclusions: Hence, we recommend that retrograde access angioplasty is a safe and effective approach for revascularization when antegrade access fails and should be considered after proper anatomic evaluation, under US or fluoroscopic guidance.

Overproduction of reactive oxygen species accompanied by hypoxia and inflammation in critical limb ischemia contributes to aggravated limb gangrene and loss. However, the existing drug and surgical treatments are not satisfactory. Nanoenzymes that catalyze endogenous H2O2 into O2 to reshape the hostile oxidative microenvironment are a promising strategy for increasing limb salvage rates. Here, Ti2C-(OH)2-MXene nanosheets were prepared and used for the treatment of limb ischemia. The biological activity and therapeutic effects of the nanosheets were verified in vitro using HUVECs and 3T3 cells, and in vivo using a C57BL/6 mouse model of femoral arteriovenous resection. Results showed that the nanosheets catalyze H2O2 into O2 in a gentle and sustainable manner. Notably, they exhibit a strong protective effect on cell viability and motility and regulate the intracellular levels of ROS and O2 under inflammatory conditions. More importantly, when delivered to ischemic hindlimbs in mice, the nanosheets inhibited in vivo ROS accumulation, promoted macrophage polarization from M1 to M2 to reduce inflammation, and upregulated the expression of myogenic regulatory factors (MyoG and MyoD) to protect skeletal muscle from necrosis. Over a 21-day monitoring period, significantly enhanced angiogenesis and limb salvage were observed. Together, our results indicate that Ti2C-(OH)2 nanosheets are a type of nanoenzyme that may effectively treat critical limb ischemia. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is a state of severe peripheral artery disease, with no effective treatment. Cell therapy has been investigated as a therapeutic tool for CLI, and pericytes are promising therapeutic candidates based on their angiogenic properties. We firstly generated highly proliferative and immunosuppressive pericyte-like cells from embryonic stem (ES) cells. In order to enhance the angiogenic potential, we transduced the basic fibroblast growth factor (bFGF) gene into the pericyte-like cells and found a significant enhancement of angiogenesis in a Matrigel plug assay. Furthermore, we evaluated the bFGF-expressing pericyte-like cells in the previously established chronic hindlimb ischemia model in which bone marrow–derived MSCs were not effective. As a result, bFGF-expressing pericyte-like cells significantly improved blood flow in both laser Doppler perfusion imaging (LDPI) and dynamic contrast-enhanced MRI (DCE-MRI). These findings suggest that bFGF-expressing pericyte-like cells differentiated from ES cells may be a therapeutic candidate for CLI. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study is to describe a bailout technical strategy to prevent below-the-knee (BTK) distal embolization during procedures with increased inherent risk using universally-available "off-the-shelf" devices. Technique: A conventional retrograde access is obtained of the BTK target vessel where embolization protection is sought. Before starting any potential proximal maneuver with an associated significant risk of distal embolization (eg, atherectomy and mechanical thrombectomy), a low-profile balloon is inserted and inflated through the distal retrograde access, so that any debris resulting from the recanalization procedure is blocked by the stagnant column of blood generated by the inflated balloon. Once the revascularization procedure has been completed, a 4F curved catheter is antegradely advanced down to the distally-inflated balloon, and in case of distal embolization the debris is aspirated in a standard fashion way. Conclusion: A retrograde balloon-assisted "off-the-shelf" embolic protection approach may be considered for BTK revascularization procedures where there is an inherent increased risk of distal trash, especially in the presence of distal single-vessel runoff. Clinical Impact: Distal embolization following endovascular procedures can have devastating consequences and there is a general recommendation for selective use of EPDs in high-risk-scenarios. The increased cost and low availability of the current EPD devices for BTK/BTA arteries have prohibited their widespread use. The retrograde balloon-assisted "off-the-shelf" EPD prevents distal embolization during procedures with increased risk of distal trash using inexpensive, nonspecific equipment available in any basic endovascular suite. [ABSTRACT FROM AUTHOR]

The risk of coronary artery disease in peripheral arterial disease (PAD) is high, life prognosis is poor, and lipid-lowering treatment with statins has been reported to improve prognosis. In clinical practice, however, hypolipidemia is more common in patients with severe PAD and statin prescription rates appear to be low, but specific data are scarce in Japan. Therefore, we conducted this cross-sectional study in collaboration with other centers of vascular surgery to determine the rate of statin prescriptions for PAD patients in real-world practice, the rate of achievement of low-density lipoprotein (LDL) cholesterol control targets, and whether statin non-use is a determinant factor of critical limb ischemia (CLI). A total of 246 PAD patients (97 with CLI) from 5 sites were included in this study. Medical history and blood test data were obtained from medical records and interviews with patients, and were compared between CLI and non-CLI patients. Statin prescription rate was only 34 %. The overall LDL cholesterol control target rate was 46 % of CLI cases and 51 % of non-CLI cases, according to the lipid management criteria of the Japanese Society for Atherosclerosis 2022 guidelines. Patients in the CLI group had a lower mean body mass index and lower LDL cholesterol levels than those in the non-CLI group, suggesting that these factors were responsible for the lower statin prescription rate. However, multivariate analysis revealed that statin non-use was one of the determinants of CLI. Statin prescription rates for PAD patients were low in real-world practice settings in the field of vascular surgery. Since statin non-use is a determinant of CLI, there is a need to educate physicians engaged in treatment regarding lipid-lowering treatment with statins. [Display omitted] • Statin prescription rates for peripheral arterial disease (PAD) patients were only 34% in real-world practice settings • LDL cholesterol control target rate was 46% of critical limb ischemia (CLI) cases and 51% of non-CLI cases • Patients in the CLI group had lower LDL-cholesterol levels than those in the non-CLI group • Multivariate analysis revealed that statin non-use was one of the determinants of CLI • Lipid-lowering therapy should be provided in patients with PAD, regardless of their lipid levels [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the relationship between bacteriological findings and wound healing after minor amputation in the treatment of chronic limb-threatening ischemia (CLTI) with infection. Methods: This single-center retrospective study analyzed 135 consecutive limbs with tissue loss and infection from 120 patients who underwent endovascular therapy (EVT) and minor forefoot amputation for CLTI with wound infection between November 2017 and August 2021. The Kaplan-Meier method was used to assess the rate of wound healing after the procedure. The Cox proportional-hazards model was used to examine the impact of bacteriological findings and baseline characteristics on wound healing. Results: The wound healing rate at 6 months was 72.6%. In a multivariate analysis, in addition to hemodialysis (hazard ratio [HR]=1.73; p=0.009) and amputation above the metatarsophalangeal (MP) joint (HR=1.81; p=0.006), antimicrobial-resistant bacterial infection (HR=1.80, p=0.004) and polymicrobial infection (H=1.51; p=0.049) were predictors of delayed wound healing. Conclusion: Antimicrobial-resistant bacterial infection, polymicrobial infection, hemodialysis, and amputation above the MP joint were independent predictors of delayed wound healing after EVT and minor forefoot amputation in patients with CLTI and bacterial wound infection. Clinical Impact: In this single-center retrospective study, we analyzed 136 consecutive limbs with tissue loss and infection from 120 patients who underwent endovascular therapy and minor forefoot amputation for chronic limb-threatening ischemia (CLTI) with wound infection between November 2017 and August 2021. Our main findings were that antimicrobial-resistant bacterial infection, polymicrobial infection, hemodialysis, and amputation above the metatarsophalangeal joint were independent predictors of delayed wound healing after minor amputation. This is the first report of the association between bacteriological studies and wound healing in CLTI with infection, and will be of great help in the future clinical practice. [ABSTRACT FROM AUTHOR]

Purpose: Chronic limb-threatening ischemia (CLTI) represents the clinical end stage of lower extremity peripheral arterial disease (PAD). Although conventional open and endovascular revascularization options are available, some CLTI patients do not respond to these treatments, generally due to small vessel occlusive disease, with only limited or no clinical improvement achieved. This article aims to provide insights related to pertinent venous anatomy of the leg and below the ankle and a technical review of percutaneous deep venous arterialization (pDVA) creation using commonly-available devices. Technique: For patients with "no-option" CLTI, the risk of major amputation and mortality remains high. Although arterial revascularization remains the optimal treatment of CLTI, some patients with severely-diseased or gracile distal arteries have poor outcome. Deep venous arterialization (DVA), in a subset of patients with tibial anatomy amenable to DVA creation, represents the last-ditch attempt before these patients are deemed to have "no-hope" at limb salvage, and major amputation becomes necessary. Refinement in technique and advancement in device development have been shown to allow pDVA to be created with respectable outcomes for the "no-option" CLTI patient population. Conclusion: The pDVA has garnered increasing interest among endovascular specialists to further understand the anatomical and technical key points of this procedure, and it may yet prove to be a useful addition in the armamentarium in our battle against CLTI. Clinical Impact: Percutaneous deep venous arterialisation provides another option in the treatment of challenging "no-option" CLTI patients, and off-the-shelf devices will allow this procedure to be performed in centers where dedicated devices are not available. [ABSTRACT FROM AUTHOR]

Objective To investigate the mid-term efficacy and patency rate of TurboHawk peripheral plaque excision system in the treatment of femoral popliteal artery lesions with different Global Limb Anatomic Staging System (GLASS) grades. Methods The clinical data of 141 patients with femoral popliteal arteriosclerosis obliterans who were treated with TurboHawk from January 2018 to July 2022 in our institution were retrospectively analyzed. There were 109 male patients and 32 female patients. Recordings were made of the patient’s symptoms of limb ischemia, technical success rate, primary patency rate of target vessels, ankle brachial index (ABI), GLASS grades, postoperative complications, and a statistical analysis with the patient’s preoperative treatment was conducted. Results All patients had improved limb ischemia symptoms to varying degrees after surgery, with a technical success rate of 100% (femoral artery puncture and superficial femoral artery recanalization) without bleeding, hematoma, pseudoaneurysm, arteriovenous fistula or other complications. The follow-up period was 1-24 months, during which the severity of claudication, resting pain, and toe ulcers significantly improved. The primary patency rate of the target vessel was 98.58% (139/141), and the ABI significantly increased on the second day, three months, and six months after surgery compared to before surgery. No major adverse events were found during follow-up. The patency rates at 1, 6, 12 and 24 months after intervention were 100%, 80%, 75% and 60% respectively. Conclusion The mid-term efficacy and patency rate of TurboHawk in the treatment of femoral popliteal artery lesions with GLASS I patients have the best mid-term prognosis, the highest mid-term survival rate, and the highest vascular patency. The plaque removal system has proven to be an effective treatment for individual localized chronic total occlusion lesions. Additionally, the TurboHawk system provides a safe and minimally invasive treatment alternative for superficial femoral artery conditions, achieving significant therapeutic results within a brief period.

CONTEXT: NL003 is a plasmid engineered to simultaneously express two isoforms of hepatocyte growth factor. The Phase II clinical trial shows that intramuscular injection of NL003 in the affected limb of patients with critical limb ischemia (CLI) is safe and could alleviate pain and promote ulcer healing. The purpose of this study was to evaluate the long-term safety and efficacy of NL003. METHODS: A total of 108 participants were evaluated: 32 in the placebo group and 76 in the NL003 group. The primary endpoint was 5-year amputation-free survival and the secondary endpoints were pain, ulcer, and adverse reactions. RESULTS: During a mean follow-up period of 10.4 years, the 5-year amputation-free survival rate was 67.1% (51/76) in the NL003 group and 37.5% (12/32) in the placebo group (P < 0.05). The median amputation-free survival was 9.53 years in the NL003 group and 4.51 years in the placebo group. There was no significant difference in the rates of major amputation between the two groups (21.1% vs. 21.9%). Pain relief and ulcer healing tended to favor the NL003 group. No serious adverse reactions such as gene integration and tumor were found during the follow-up. CONCLUSIONS: NL003 has a favorable long-term safety profile and may provide long-term benefit for patients with CLI.

Critical limb ischemia (CLI) is a devastating disease characterized by the progressive blockage of blood vessels. Although the paracrine effect of growth factors in stem cell therapy made it a promising angiogenic therapy for CLI, poor cell survival in the harsh ischemic microenvironment limited its efficacy. Thus, an imperative need exists for a stem-cell delivery method that enhances cell survival. Here, a collagen microgel (CMG) cell-delivery scaffold (40 × 20 μm) was fabricated via micro-fragmentation from collagen–hyaluronic acid polyionic complex to improve transplantation efficiency. Culturing human adipose-derived stem cells (hASCs) with CMG enabled integrin receptors to interact with CMG to form injectable 3-dimensional constructs (CMG-hASCs) with a microporous microarchitecture and enhanced mass transfer. CMG-hASCs exhibited higher cell survival (p

Anders Møller,1,2 Nikolaj Eldrup,3– 5 Jørn Wetterslev,6 Dorthe Hellemann,1,5 Henning Bay Nielsen,7,8 Klaus Rostgaard,9,10 Henrik Hjalgrim,5,9– 11,&ast; Ole Birger Pedersen5,10,12,&ast; 1Department of Anesthesia and Intensive Care, Næstved-Slagelse-Ringsted, Slagelse Hospital, Slagelse, Denmark; 2Department of Anaesthesia and Intensive Care, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark; 3Department of Vascular Surgery, Rigshospitalet, Copenhagen, Denmark; 4Danish Vascular Registry, Aarhus, Denmark; 5Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 6Private Office, Tuborg Sundpark, Hellerup, 2900, Denmark; 7Department of Anesthesia and Intensive Care, Zealand University Hospital Roskilde, Roskilde, Denmark; 8Department of Nutrition, Exercise and Sport, Faculty of Science, University of Copenhagen, Copenhagen, Denmark; 9Danish Cancer Institute, Danish Cancer Society, Copenhagen, Denmark; 10Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 11Department of Hematology, Copenhagen University Hospital, Copenhagen, Denmark; 12Department of Clinical Immunology, Zealand University Hospital, Køge, Denmark&ast;These authors contributed equally to this workCorrespondence: Anders Møller, Department of Anesthesia and Intensive Care, Næstved-Slagelse-Ringsted Hospital, Fælledvej 11, Slagelse, DK-4200, Denmark, Tel +45 58 55 92 02, Email dr.andersm@gmail.comBackground: The prevalence of occlusive lower extremity artery disease (LEAD) is rising worldwide while European epidemiology data are scarce. We report incidence and mortality of LEAD repair in Denmark from 1996 through 2018, stratified on open aorto-iliac, open peripheral, and endovascular repair.Methods: A nationwide cohort study of prospective data from population-based Danish registers covering 1996 to 2018. Comorbidity was assessed by Charlson’s Comorbidity Index (CCI). Incidence rate (IR) ratios and mortality rate ratios (MRR) were estimated by multivariable Poisson and Cox regression, respectively.Results: We identified 41,438 unique patients undergoing 46,236 incident first-time LEAD repairs by either aorto-iliac- (n=5213), peripheral surgery (n=18,665) or percutaneous transluminal angioplasty (PTA, n=22,358). From 1996 to 2018, the age- and sex-standardized IR for primary revascularization declined from 71.8 to 50.2 per 100,000 person-years (IRR, 0.70; 95% CI, 0.66– 0.75). Following a 2.5-fold IR increase of PTA from 1996 to 2010, all three repair techniques showed a declining trend after 2010. The declining IR was driven by decreasing LEAD repair due to claudication, and by persons aged below 80 years, while the IR increased in persons aged above 80 years (p interaction< 0.001). LEAD repair was more frequent in men (IRRfemale vs male, 0.78; 95% CI, 0.77– 0.80), which was consistent over calendar time (p interaction=0.41). Crude mortality decreased following open/surgical repair, and increased following PTA, but all three techniques trended towards lower adjusted mortality comparing the start and the end of the study period (MRRaorto-iliac, 0.71; 95% CI, 0.54– 0.93 vs MRRperipheral, 0.76; 95% CI, 0.69– 0.83 vs MRRPTA, 0.96; 95% CI, 0.86– 1.07). Increasing age and CCI, male sex, smoking, and care dependency associated with increased mortality.Conclusion: The incidence rate of LEAD repair decreased in Denmark from 1996 to 2018, especially in persons younger than 80 years, and primarily due to reduced revascularization for claudication. Adjusted mortality rates decreased following open surgery, but seemed unaltered following PTA.Keywords: vascular surgery, critical limb ischemia, claudication, Danish Vascular Registry, Danish National Patient Registry, registers

Current assessment standards for peripheral arterial disease (PAD), such as the ankle brachial index, are limited in their utility and portability. Near-infrared spectroscopy (NIRS) has shown some promise in diagnosing PAD when used in conjunction with a provocative maneuver. The purpose of this study was to assess the viability of NIRS in conjunction with a transient leg elevation provocative maneuver for detecting severe PAD. This retrospective observational cross-sectional study assessed 57 limbs in 34 patients receiving routine vascular screening for PAD at Madigan Army Medical Center. The patient limbs were stratified into normal (n = 17), mild (n = 9), moderate (n = 16), and severe (n = 15) PAD groups based on the clinician assessments. Additionally, the patients were assessed with NIRS measurements taken with the patient in the supine position at rest and using a provocative leg raise maneuver of transient leg elevation of 45° for 60 seconds. The resting tissue oxygen saturation (StO2) and the change in StO2 (ΔStO2) from rest to elevation were recorded and compared between the PAD severity groups via independent measures analysis of variance with the Tukey honest significant difference post hoc test. The supine resting StO2 was not different between the normal (77.5% ± 7.7%), mild (72.5% ± 7.4%), moderate (72.0% ± 10.3%), and severe (74.2% ± 5.4%) PAD groups (P = .23). However, the ΔStO2 with transient leg elevation was significantly greater in the severe PAD group (−17.2% ± 6.0%) compared with the normal (−3.9% ± 4.8%), mild (−6.9% ± 4.7%), and moderate (−9.7% ± 5.2%) PAD groups (P < .002 for all). Similar results were observed in the changes in oxyhemoglobin and deoxyhemoglobin. The leg elevation protocol was also used for two patients before and after lower limb revascularization, which demonstrated that the ΔStO2 corresponded with the clinical assessment of PAD severity. Resting supine NIRS images were unable to detect any differences among normal and limbs with different PAD severity. However, NIRS imaging with 45° leg elevation for 60 seconds showed a significant difference between severe PAD compared healthy patients and those with mild to moderate PAD in a fast, precise, and accurate manner. These preliminary data support the use of NIRS and transient leg elevation as a tool to diagnose severe PAD but do not support the use of NIRS alone as a screening test for PAD. NIRS measurements with leg elevation might be a viable noninvasive, noncontact, and portable method of assessing severe PAD for home monitoring, in rural communities, and/or in standard clinical practice.

Background: Critical limb ischemia (CLI) patients take too many medications because they are elderly and frail patients with multiple comorbidities. Polypharmacy is associated with frailty, although its prognostic significance in CLI patients is unknown. In this study, we aimed to determine the prevalence of hyperpolypharmacy among adults with CLI and its effect on 1-year amputation and mortality. Methods: A total of 200 patients with CLI who underwent endovascular therapy (EVT) for below-knee (CTC) lesions were included in this study. Hyperpolypharmacy was defined as using ≥10 drugs. Patients were divided into two groups according to the presence of hyperpolypharmacy Results: We detected hyperpolypharmacy in 66 patients. The incidence of 1-year amputation [24 (36.4) versus 12 (9), p <.001] and mortality [28 (42.4) versus 12 (9), p <.001] were higher in patients with hyperpolypharmacy. Univariate and multivariate cox regression analyses were used to determine the independent predictors of amputation and mortality. In the receiver operating characteristic curve analysis, the cut-off value was defined as 10 or more drug use was able to detect the presence of 1-year mortality with 67.5% sensitivity and 79.4% specificity. The Kaplan–Meier method showed a significant difference (rank p <.001 between log groups), and hyperpolypharmacy was associated with 1-year amputation and mortality. Conclusion: Hyperpolypharmacy was significantly associated with 1-year mortality and major amputation in CLI patients. Hyperpolypharmacy can be a valuable aid in patient risk assessment in the CLI. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is associated with high rates of readmission following endovascular interventions and contributes to a significant hospital readmission burden. Quality metrics like hospital readmissions affect hospital performance, but must adjust to local trends. Our primary goal was to evaluate risk factors and readmission rates post-percutaneous peripheral intervention in a US-Mexico border city, at a single tertiary university hospital. We performed a retrospective review of patients with PAD undergoing first time peripheral intervention from July 2015 to June 2020. Among 212 patients, 58% were readmitted with median 235-day follow-up (inter-quartile range (IQR) 42–924); 35.3% of readmissions occurred within 30 days, and 30.2% of those were within 7 days. Median time to readmission was 62 days. Active smokers had 84% higher risk of readmission (hazard ratio (HR) 1.84, 95% CI 1.23–2.74, P <.01). Other significant factors noted were insurance status—Medicaid or uninsured (HR 1.94, 95% CI 1.22–3.09), prior amputation (HR 1.69, 95% CI 1.13–2.54), heart failure, both preserved (HR 4.35, 95% CI 2.07–9.16) and reduced ejection fraction (HR 1.88, 95% CI 1.14–3.10). Below the knee, interventions were less likely to be readmitted (adjusted HR.64, 95% CI 0.42–.96). Readmission rates were unrelated to medication adherence. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is the advanced stage of peripheral arterial disease, which impairs blood flow to the extremities due to occlusion of arteries, in which patients suffer from ischemic pain at rest and gangrene or ulcers. It is frequently accompanied by major adverse cardiac events, resulting in exceedingly high mortality from a cardiac or cerebrovascular event in this population. Although there have been considerable amounts of novel and costly revascularization and wound dressing technology, mortality is still high. Therefore, the risk factors for such high mortality need to be addressed. This review aimed to summarize the potential risk factors for mortality in patients with CLI of the lower extremities. There are several such risk factors, including modifiable and nonmodifiable risk factors. This review further discusses some highlighted major modified risk factors, including renal failure, cardiovascular, and diabetes. The strategy of regular surveillance and modification of such risk factors in any patients with CLI should be developed. [ABSTRACT FROM AUTHOR]

BackgroundPeripheral artery disease (PAD) is on the rise worldwide, ranking as the third leading cause of atherosclerosis-related morbidity; much less is known about its trends in hospitalizations among methamphetamine and cocaine users.ObjectivesWe aim to evaluate the overall trend in the prevalence of hospital admission for PAD with or without the use of stimulant abuse (methamphetamine and cocaine) across the United States. Additionally, we evaluated the PAD-related hospitalizations trend stratified by age, race, sex, and geographic location.MethodsWe used the National Inpatient Sample (NIS) database from 2008 to 2020. The Cochran Armitage trend test was used to compare the trend between groups. Multivariate logistic regression was used to examine adjusted odds for PAD and CLI hospitalizations among methamphetamine and cocaine users.ResultsBetween 2008 and 2020, PAD-related hospitalizations showed an increasing trend in Hispanics, African Americans, and western states, while a decreasing trend in southern and Midwestern states (p-trend 64 years, southern and western states (p-trend 64 years, and CLI-related amputations declined for women, White patient population, age group >40, and all regions (p-trend

Background Peripheral arterial disease and related lower extremity wounds are prominent causes of amputation. Revascularization may reduce amputation rates or the amputation margin more distally in patients with peripheral arterial disease who have wounds resulting from critical limb ischemia. This study examined the association of risk factors and intervention types with amputation rates in patients with critical lower extremity arterial disease. Methods A total of 211 patients who underwent peripheral intervention because of foot wound were followed up for 12 months after the intervention. All patients had lower extremity wounds resulting from peripheral arterial disease. The effects of treatment approaches were compared in patients who underwent and did not undergo amputation. Results Revascularization of the anterior tibial artery reduced the amputation rate by 6.52 times compared with occlusion. Posterior tibial artery revascularization reduced the amputation rate by 49.95 times. Conclusion In this study of percutaneous intervention methods for prevention of amputation, the most effective option was revascularization of the posterior tibial artery and anterior tibial artery. Considering these results, treatment of critical peripheral arterial disease can be cost-effective and efficient and may shorten procedure time.

Abstract Background and objectives Limb ischemia or compartment syndrome, requiring surgery, are some of the frequent cannula-related complications in patients supported with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). The purpose of this exploratory study is to depict and evaluate the dynamic changes in the lower limb muscles with ultrasound shear wave elastography as marker for early lower limb ischemia. Methods Eleven patients with VA-ECMO after cardiac arrest were included in this study. Seven patients received distal perfusion cannula (DPC) after implantation of the VA-ECMO, whereas 4 had no DPC after VA-ECMO. Compartment syndrome was clinically excluded in all patients. Both lower limbs, e.g., with and without arterial cannula, were monitored with near-infrared spectroscopy (NIRS) for the oxygen saturation of the local tissue. We performed ultrasound shear wave elastrography (SWE) to assess dynamic changes of the medial gastrocnemius muscle at maximum passive muscle stretch (exercise) of both legs. Color-coded duplexsonography was conducted to examine the blood flow velocity of the popliteal artery of the lower limb. Results We found no difference between DPC and no DPC (p = 0.115) during use of VA-ECMO. However, we detected marked lower limb muscle perfusion deficits of cannulated (58.9 ± 13.5 kPa) vs. cannula-free limb (95.7 ± 27.9 kPa: p

Abstract Background The BYCROSS™ device is a novel device intended for use in atherectomy of the peripheral arterial disease (PAD). With the BYCROSS™ atherectomy system, also prolonged calcifying lesions can be treated in a minimally invasive manner, which was previously reserved for bypass surgery. The aim of this study is to collect additional clinical data on safety and performance of the BYCROSS™ from patients undergoing revascularization of severely stenotic or occluded peripheral arterial vessels with the BYCROSS™. Methods and design This is an investigator-initiated national prospective multicenter observational study in patients with PAD. Sixty patients (20 per center) with PAD with stenosis higher than 80% or complete occlusion (de novo or recurrent stenosis) of vessels below the aortic bifurcation (min 3 mm vessel diameter) will be recruited. Three vascular surgery centers are participating in the study. The primary efficacy endpoint is procedural success, defined as passage of the occlusion through the BYCROSS device, and safety outcomes, explicated as freedom from device-related serious adverse events (SADEs). Secondary endpoints include primary and secondary patency rates, change in Rutherford classification, and freedom from amputation at 3 and 12 months. Discussion The BYCROSS atherectomy system may be a novel device for the minimally invasive treatment of prolonged calcified lesions previously reserved for bypass surgery. This national prospective multicenter observational study could represent another step in demonstrating the efficancy and safety of this device for treatment of PAD. Trial registration #DRKS00029947 (who.int). Protocol approval id #22–0047(Ethics Committee at Ludwig-Maximilians-University Munich).

The evaluation of hemodynamic conditions in critical limb-threatening ischemia (CLTI) patients is inevitable in endovascular interventions. In this study, the performance of color-coded digital subtraction angiography (ccDSA) and the recently developed color-coded digital variance angiography (ccDVA) was compared in the assessment of key time parameters in lower extremity interventions. The observational study included 19 CLTI patients who underwent peripheral vascular intervention at our institution in 2020. Pre- and post-dilatational images were retrospectively processed and analyzed by a commercially available ccDSA software (Kinepict Medical Imaging Tool 6.0.3; Kinepict Health Ltd., Budapest, Hungary) and by the recently developed ccDVA technology. Two protocols were applied using both a 4 and 7.5 frames per second acquisition rate. Time-to-peak (TTP) parameters were determined in four pre- and poststenotic regions of interest (ROI), and ccDVA values were compared to ccDSA read-outs. The ccDVA technology provided practically the same TTP values as ccDSA (r = 0.99, R2 = 0.98, p < 0.0001). The correlation was extremely high independently of the applied protocol or the position of ROI; the r value was 0.99 (R2 = 0.98, p < 0.0001) in all groups. A similar correlation was observed in the change in passage time (r = 0.98, R2 = 0.96, p < 0.0001). The color-coded DVA technology can reproduce the same hemodynamic data as a commercially available DSA-based software; therefore, it has the potential to be an alternative decision-supporting tool in catheter labs.

Heparan sulphate (HS) can act as a co-receptor on the cell surface and alterations in this process underpin many pathological conditions. We have previously described the usefulness of mimics of HS (glycomimetics) in protection against β-glycerophosphate-induced vascular calcification and in the restoration of the functional capacity of diabetic endothelial colony-forming cells in vitro. This study aims to investigate whether our novel glycomimetic compounds can attenuate glycated low-density lipoprotein (g-LDL)-induced calcification by inhibiting RAGE signalling within the context of critical limb ischemia (CLI). We used an established osteogenic in vitro vascular smooth muscle cell (VSMC) model. Osteoprotegerin (OPG), sclerostin and glycation levels were all significantly increased in CLI serum compared to healthy controls, while the vascular calcification marker osteocalcin (OCN) was down-regulated in CLI patients vs. controls. Incubation with both CLI serum and g-LDL (10 µg/mL) significantly increased VSMC calcification vs. controls after 21 days, with CLI serum-induced calcification apparent after only 10 days. Glycomimetics (C2 and C3) significantly inhibited g-LDL and CLI serum-induced mineralisation, as shown by a reduction in alizarin red (AR) staining and alkaline phosphatase (ALP) activity. Furthermore, secretion of the osteogenic marker OCN was significantly reduced in VSMCs incubated with CLI serum in the presence of glycomimetics. Phosphorylation of cyclic AMP response element-binding protein (CREB) was significantly increased in g-LDL-treated cells vs. untreated controls, which was attenuated with glycomimetics. Blocking CREB activation with a pharmacological inhibitor 666-15 replicated the protective effects of glycomimetics, evidenced by elevated AR staining. In silico molecular docking simulations revealed the binding affinity of the glycomimetics C2 and C3 with the V domain of RAGE. In conclusion, these findings demonstrate that novel glycomimetics, C2 and C3 have potent anti-calcification properties in vitro, inhibiting both g-LDL and CLI serum-induced VSMC mineralisation via the inhibition of LDLR, RAGE, CREB and subsequent expression of the downstream osteogenic markers, ALP and OCN. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. The use of IVL to treat calcified PAD in this observational registry demonstrated favorable acute safety and effectiveness in both women and men. [ABSTRACT FROM AUTHOR]

OBJECTIVES: Peripheral venoarterial extracorporeal membrane oxygenation (ECMO) with femoral access is obtained through unilateral or bilateral groin cannulation. Whether one cannulation strategy is associated with a lower risk for limb ischemia remains unknown. We aim to assess if one strategy is preferable. DESIGN: A retrospective cohort study based on the Extracorporeal Life Support Organization registry. SETTING: ECMO centers worldwide included in the Extracorporeal Life Support Organization registry. PATIENTS: All adult patients (≥ 18 yr) who received peripheral venoarterial ECMO with femoral access and were included from 2014 to 2020. INTERVENTIONS: Unilateral or bilateral femoral cannulation. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the occurrence of limb ischemia defined as a composite endpoint including the need for a distal perfusion cannula (DPC) after 6 hours from implantation, compartment syndrome/fasciotomy, amputation, revascularization, and thrombectomy. Secondary endpoints included bleeding at the peripheral cannulation site, need for vessel repair, vessel repair after decannulation, and in-hospital death. Propensity score matching was performed to account for confounders. Overall, 19,093 patients underwent peripheral venoarterial ECMO through unilateral (n = 11,965) or bilateral (n = 7,128) femoral cannulation. Limb ischemia requiring any intervention was not different between both groups (bilateral vs unilateral: odds ratio [OR], 0.92; 95% CI, 0.82–1.02). However, there was a lower rate of compartment syndrome/fasciotomy in the bilateral group (bilateral vs unilateral: OR, 0.80; 95% CI, 0.66–0.97). Bilateral cannulation was also associated with lower odds of cannulation site bleeding (bilateral vs unilateral: OR, 0.87; 95% CI, 0.76–0.99), vessel repair (bilateral vs unilateral: OR, 0.55; 95% CI, 0.38–0.79), and in-hospital mortality (bilateral vs unilateral: OR, 0.85; 95% CI, 0.81–0.91) compared with unilateral cannulation. These findings were unchanged after propensity matching. CONCLUSIONS: This study showed no risk reduction for overall limb ischemia-related events requiring DPC after 6 hours when comparing bilateral to unilateral femoral cannulation in peripheral venoarterial ECMO. However, bilateral cannulation was associated with a reduced risk for compartment syndrome/fasciotomy, lower rates of bleeding and vessel repair during ECMO, and lower in-hospital mortality. [ABSTRACT FROM AUTHOR]

Approximately 6% of adults worldwide suffer from peripheral artery disease (PAD), primarily caused by atherosclerosis of lower limb arteries. Despite optimal medical care and revascularization, many PAD patients remain symptomatic and progress to critical limb ischemia (CLI) and risk major amputation. Delivery of pro-angiogenic factors as proteins or DNA, stem, or progenitor cells confers vascular regeneration and functional recovery in animal models of CLI, but the effects are not well replicated in patients and no pro-angiogenic biopharmacological procedures are approved in the US, EU, or China. The reasons are unclear, but animal models that do not represent clinical PAD/CLI are implicated. Consequently, it is unclear whether the obstacles to clinical success lie in the toxic biochemical milieu of human CLI, or in procedures that were optimized on inappropriate models. The question is significant because the former case requires abandonment of current strategies, while the latter encourages continued optimization. These issues are discussed in the context of relevant preclinical and clinical data, and it is concluded that preclinical mouse models that include age and atherosclerosis as the only comorbidities that are consistently present and active in clinical trial patients are necessary to predict clinical success. Of the reviewed materials, no biopharmacological procedure that failed in clinical trials had been tested in animal models that included advanced age and atherosclerosis relevant to PAD/CLI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Adipose-derived stem cells (ASCs) have been used as a therapeutic intervention for peripheral artery disease (PAD) in clinical trials. To further explore the therapeutic mechanism of these mesenchymal multipotent stromal/stem cells in PAD, this study was designed to test the effect of xenogeneic ASCs extracted from human adipose tissue on hypoxic endothelial cells (ECs) and terminal unfolded protein response (UPR) in vitro and in an atherosclerosis-prone apolipoprotein E-deficient mice (ApoE−/− mice) hindlimb ischemia model in vivo. ASCs were added to Cobalt (II) chloride-treated ECs; then, metabolic activity, cell migration, and tube formation were evaluated. Fluorescence-based sensors were used to assess dynamic changes in Ca2+ levels in the cytosolic- and endoplasmic reticulum (ER) as well as changes in reactive oxygen species. Western blotting was used to observe the UPR pathway. To simulate an acute-on-chronic model of PAD, ApoE−/− mice were subjected to a double ligation of the femoral artery (DLFA). An assessment of functional recovery after DFLA was conducted, as well as histology of gastrocnemius. Hypoxia caused ER stress in ECs, but ASCs reduced it, thereby promoting cell survival. Treatment with ASCs ameliorated the effects of ischemia on muscle tissue in the ApoE−/− mice hindlimb ischemia model. Animals showed less muscle necrosis, less inflammation, and lower levels of muscle enzymes after ASC injection. In vitro and in vivo results revealed that all ER stress sensors (BIP, ATF6, CHOP, and XBP1) were activated. We also observed that the expression of these proteins was reduced in the ASCs treatment group. ASCs effectively alleviated endothelial dysfunction under hypoxic conditions by strengthening ATF6 and initiating a transcriptional program to restore ER homeostasis. In general, our data suggest that ASCs may be a meaningful treatment option for patients with PAD who do not have traditional revascularization options. [ABSTRACT FROM AUTHOR]

Background and objectives: Limb ischemia or compartment syndrome, requiring surgery, are some of the frequent cannula-related complications in patients supported with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). The purpose of this exploratory study is to depict and evaluate the dynamic changes in the lower limb muscles with ultrasound shear wave elastography as marker for early lower limb ischemia. Methods: Eleven patients with VA-ECMO after cardiac arrest were included in this study. Seven patients received distal perfusion cannula (DPC) after implantation of the VA-ECMO, whereas 4 had no DPC after VA-ECMO. Compartment syndrome was clinically excluded in all patients. Both lower limbs, e.g., with and without arterial cannula, were monitored with near-infrared spectroscopy (NIRS) for the oxygen saturation of the local tissue. We performed ultrasound shear wave elastrography (SWE) to assess dynamic changes of the medial gastrocnemius muscle at maximum passive muscle stretch (exercise) of both legs. Color-coded duplexsonography was conducted to examine the blood flow velocity of the popliteal artery of the lower limb. Results: We found no difference between DPC and no DPC (p = 0.115) during use of VA-ECMO. However, we detected marked lower limb muscle perfusion deficits of cannulated (58.9 ± 13.5 kPa) vs. cannula-free limb (95.7 ± 27.9 kPa: p < 0.001), applying SWE. No relationship was detected between NIRS measurements and SWE values (kPa) of both lower limbs. The mean peak systolic velocity of the popliteal artery at the cannulated side (30.0 ± 11.7 cm/s) was reduced compared to the non-cannulated side (39.3 ± 18.6 cm/s; p = 0.054). Conclusions: Regardless of DPC after implantation of VA-ECMO, the gastrocnemius muscles seem to lose function due to cannula-related microcirculatory deficits. Muscle function analysis via SWE combined with NIRS might offer a sensitive indicator for early onset leg ischemia during VA-ECMO-related arterial cannulation. [ABSTRACT FROM AUTHOR]

Background: The BYCROSS™ device is a novel device intended for use in atherectomy of the peripheral arterial disease (PAD). With the BYCROSS™ atherectomy system, also prolonged calcifying lesions can be treated in a minimally invasive manner, which was previously reserved for bypass surgery. The aim of this study is to collect additional clinical data on safety and performance of the BYCROSS™ from patients undergoing revascularization of severely stenotic or occluded peripheral arterial vessels with the BYCROSS™. Methods and design: This is an investigator-initiated national prospective multicenter observational study in patients with PAD. Sixty patients (20 per center) with PAD with stenosis higher than 80% or complete occlusion (de novo or recurrent stenosis) of vessels below the aortic bifurcation (min 3 mm vessel diameter) will be recruited. Three vascular surgery centers are participating in the study. The primary efficacy endpoint is procedural success, defined as passage of the occlusion through the BYCROSS device, and safety outcomes, explicated as freedom from device-related serious adverse events (SADEs). Secondary endpoints include primary and secondary patency rates, change in Rutherford classification, and freedom from amputation at 3 and 12 months. Discussion: The BYCROSS atherectomy system may be a novel device for the minimally invasive treatment of prolonged calcified lesions previously reserved for bypass surgery. This national prospective multicenter observational study could represent another step in demonstrating the efficancy and safety of this device for treatment of PAD. Trial registration: #DRKS00029947 (who.int). Protocol approval id: #22–0047(Ethics Committee at Ludwig-Maximilians-University Munich). [ABSTRACT FROM AUTHOR]

Critical limb ischemia incidence and prevalence have increased over the years. However, there are no successful treatments to improve quality of life and to reduce the risk of cardiovascular and limb events in these patients. Advanced regenerative therapies have focused their interest on the generation of new blood vessels to repair tissue damage through the use of stem cells. One of the most promising sources of stem cells with high potential in cell-based therapy is adipose-derived stem cells (ASCs). ASCs are adult mesenchymal stem cells that are relatively abundant and ubiquitous and are characterized by a multilineage capacity and low immunogenicity. The proangiogenic benefits of ASCs may be ascribed to: (a) paracrine secretion of proangiogenic molecules that may stimulate angiogenesis; (b) secretion of microvesicles/exosomes that are also considered as a novel therapeutic prospect for treating ischemic diseases; and (c) their differentiation capability toward endothelial cells (ECs). Although we know the proangiogenic effects of ASCs, the therapeutic efficacy of ASCs after transplantation in peripheral artery diseases patients is still relatively low. In this review, we evidence the potential therapeutic use of ASCs in ischemic regenerative medicine. We also highlight the main challenges in the differentiation of these cells into functional ECs. However, significant efforts are still needed to ascertain relevant transcription factors, intracellular signaling and interlinking pathways in endothelial differentiation. [ABSTRACT FROM AUTHOR]

Objective: The optimal management for revascularization after critical limb ischemia (CLI) is controversial due to limited studies comparing long-term results of endovascular and open techniques. This study compares long-term outcomes after initial management of CLI via lower extremity bypass (LEB) and percutaneous vascular intervention (PVI). Methods: This retrospective cohort study investigates outcomes of patients who underwent endovascular or open surgical management for CLI at a single institution from 2013–2018. All patients with diagnosis of CLI were included and separated based on initial therapy of PVI or LEB. Demographic, procedural, and follow-up data were assessed. Primary endpoints included major adverse limb events (MALE), specifically the need for major amputation and reintervention. Secondary endpoints included mortality at 30 days and one year. A multivariable Cox Proportional Hazard regression model was used to assess the relationship between Surgery group and time to MALE/death while controlling for confounding variables. Results: This study identified 338 patients with an initial diagnosis of CLI who underwent either LEB (n = 108, 32%) or PVI (n = 230, 68%). The average age was 71.4, 54.4% were male, 30% were African American, 53.6% were diabetic, and 93.2% had hypertension. Patients who underwent LEB were more predominantly smokers (p =.003) and less predominantly on dialysis at time of surgery (p =.01). Re-intervention rates in the bypass group (11%) were not significantly different than the PVI group (9%; p =.95). In the bypass group, 20 (19%) patients had a major amputation with a median time of 189.5 days compared to 23 (10%) patients at a median time of 113 days in the PVI group; however, this difference was not significant (p =.16). There was no significant difference in 1-year mortality between the LEB (2%) and PVI group (4%; p =.2). The cumulative incidence of MALE/death at 30 days was 4.0% in the bypass group and 3.7% in the PVI group (p =.2). Incidences of MALE/death were 21.1% and 48.5% in the bypass group and 19.7 and 45.9% in the PVI group at one and 2 years, respectively. Intervention type was not found to be significantly associated with MALE/death after controlling for possible confounders (HR = 0.82, p =.43). Conclusions: In the initial management of CLI, there is no significant difference in long-term outcomes in terms of major amputation, need for reintervention, limb-salvage, and 1-year mortality. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is a common complication of diabetes mellitus that typically occurs in the later stages of the disease. Vascularization is indeed an important physiological process involving the formation of new blood vessels from existing ones. It occurs in response to various normal and pathophysiological conditions, and one of its critical roles is to compensate for inadequate oxygen supply, which is often seen in situations like chronic limb ischemia (CLI). Histidine triad nucleotide-binding protein 1 (Hint1) is a member of the Hint family that has been shown to attenuate cardiac hypertrophy, but its role in vascularization still needs to be clarified. In this study, we investigated the role of Hint1 in CLI. We found that Hint1 is significantly reduced in the muscle tissue of STZ-induced diabetic mice and high-glucose (HG)-treated endothelial cells (ECs). Hint1 deletion impaired blood flow recovery and vascularization, whereas Hint1 overexpression promoted these processes. In addition, our in vitro study showed that Hint1 deficiency aggravated mitochondrial dysfunction in ECs, as evidenced by impaired mitochondrial respiration, decreased mitochondrial membrane potential, and increased reactive oxygen species. Our findings suggest that Hint1 deficiency impairs blood perfusion by damaging mitochondrial function and that Hint1 may represent a potential therapeutic target for treating CLI. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Patients with peripheral arterial disease (PAD) have a significant risk of myocardial infarction and death secondary to concomitant coronary artery disease (CAD). This is particularly true in patients with critical limb-threatening ischemia (CLTI) who exceed a 20% mortality rate at 6 months despite standard treatment with risk factor modification. Although systematic preoperative coronary testing is not recommended for patients with PAD without cardiac symptoms, the clinical manifestations of CAD are often muted in patients with CLTI due to poor mobility and activity intolerance. Thus, the true incidence and impact of “silent” CAD in a CLTI cohort is unknown. This study aims to determine the prevalence of ischemia-producing coronary artery stenosis in a CLTI cohort using coronary computed tomography angiography (cCTA) and computed tomography (CT)-derived fractional flow reserve (FFRCT), a noninvasive imaging modality that has shown significant correlation to cardiac catheterization in the detection of clinically relevant coronary ischemia. Methods: Patients presenting with newly diagnosed CLTI at our institution from May 2020 to April 2021 were screened for underlying CAD. Included subjects had no known history of CAD, no cardiac symptoms, and no anginal equivalent complaints at presentation. Patients underwent cCTA and FFRCT evaluation and were classified by the anatomic location and severity of CAD. Significant coronary ischemia was defined as FFRCT ≤0.80 distal to a >30% coronary stenosis, and severe coronary ischemia was documented at FFRCT ≤0.75, consistent with established guidelines. Results: A total of 170 patients with CLTI were screened; 65 patients (38.2%) had no coronary symptoms and met all inclusion/exclusion criteria. Twenty-four patients (31.2%) completed cCTA and FFRCT evaluation. Forty-one patients have yet to complete testing secondary to socioeconomic factors (insurance denial, transportation inaccessibility, testing availability, etc). The mean age of included subjects was 65.4 ± 7.0 years, and 15 (62.5%) were male. Patients presented with ischemic rest pain (n = 7; 29.1%), minor tissue loss (n = 14; 58.3%) or major tissue loss (n = 3; 12.5%). Significant (≥50%) coronary artery stenosis was noted on cCTA in 19 of 24 patients (79%). Significant left main coronary artery stenosis was identified in two patients (10%). When analyzed with FFRCT, 17 patients (71%) had hemodynamically significant coronary ischemia (FFRCT ≤0.8), and 54% (n = 13) had lesion-specific severe coronary ischemia (FFRCT ≤0.75). The mean FFRCT in patients with coronary ischemia was 0.70 ± 0.07. Multi-vessel disease pattern was present in 53% (n = 9) of patients with significant coronary stenosis. Conclusions: The use of cCTA-derived fractional flow reserve demonstrates a significant percentage of patients with CLTI have silent (asymptomatic) coronary ischemia. More than one-half of these patients have lesion-specific severe ischemia, which may be associated with increased mortality when treated solely with risk factor modification. cCTA and FFRCT diagnosis of significant coronary ischemia has the potential to improve cardiac care, perioperative morbidity, and long-term survival curves of patients with CLTI. Systemic improvements in access to care will be needed to allow for broad application of these imaging assessments should they prove universally valuable. Additional study is required to determine the benefit of selective coronary revascularization in patients with CLTI.