Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

A single center's 15-year experience with palliative limb care for chronic limb threatening ischemia in frail patients.

OBJECTIVE: Our institution's multidisciplinary Prevention of Amputation in Veterans Everywhere (PAVE) program allocates veterans with critical limb threatening ischemia (CLTI) to immediate revascularization, conservative care, primary amputation, or palliative limb care according to previously reported criteria. These four groups align with the approaches outlined by the global guidelines for the management of CLTI. In the present study, we have delineated the natural history of the palliative limb care group of patients and quantified the procedural risks and outcomes. METHODS: Veterans prospectively enrolled into the palliative limb cohort of our PAVE program from January 2005 to January 2020 were analyzed. The primary outcome was mortality. The secondary outcomes included overall and limb-related readmissions, limb loss, and wound healing. The clinical frailty scale (CFS) score was calculated, and the 5-year expected mortality was estimated using the Veterans Affairs Quality Enhancement Research Initiative tool. Regression analysis was performed to establish associations among the following variables: mortality, wound, ischemia, and foot infection (WIfI) score, CFS score, overall admissions, and limb-related admissions. RESULTS: The PAVE program enrolled 1158 limbs during 15 years. Of the 1158 limbs, 157 (13.5%) in 145 patients were allocated to the palliative limb care group. The overall mortality of the group was 88.2% (median interval, 3.5 months; range, 0-91 months). Of the 128 patients who had died, 64 (50%) had died within 3 months of enrollment. The predicted 5-year mortality for the group was 66%. The average CFS score for the group was 6.2, denoting persons moderately to severely frail. Using the CFS score, 106 patients were considered frail and 39 were considered not frail. No differences were found in mortality between the frail and nonfrail patients. However, a statistically significant difference was found in early (<3 months) mortality (56.2% vs 37.5%; P = .032). The 30-day limb-related readmission rate was 4.7%. Eventual major amputation was necessary for 18 limbs (11.5%). Wound healing occurred in 30 patients (20.6%). Regression analysis demonstrated no association between the CFS score and mortality (r = 0.55; P = .159) or between the WIfI score and mortality (r = 0.0165; P = .98). However, a significant association was found between the WIfI score and limb-related admissions (r = 0.97; P < .001). CONCLUSIONS: Frail patients with CLTI had high early mortality and a low risk of limb-related complications. They also had a low incidence of deferred primary amputation or limb-related readmissions. In our cohort, the vast majority of patients had died within a few months of enrollment without requiring an amputation. A comprehensive approach to the treatment of CLTI patients should include a palliative limb care option because a significant proportion of these patients will have limited survival and can potentially avoid unnecessary surgery and major amputation.

Hydrogel Loaded with VEGF/TFEB-Engineered Extracellular Vesicles for Rescuing Critical Limb Ischemia by a Dual-Pathway Activation Strategy.

Critical limb ischemia (CLI) is the most severe clinical manifestation of peripheral arterial disease, which causes many amputations and deaths. Conventional treatment strategies for CLI (e.g., stent implantation and vascular surgery) bring surgical risk, which are not suitable for each patient. Extracellular vesicles (EVs) can be a potential solution for CLI. Herein, vascular endothelial growth factor (VEGF; i.e., a crucial molecule related to angiogenesis) and transcription factor EB (TFEB; i.e., a pivotal regulator of autophagy) are chosen as the target gene to improve the bioactivity of EVs derived from endothelial cells. The VEGF/TFEB-engineered EVs (Engineered-EVs) are fabricated by genetically engineering the parent cells, and their versatile functions are confirmed using three cell models (human umbilical vein endothelial cells, myoblast, and monocytes). Injectable thermal-responsive hydrogel are then combined with Engineered-EVs to combat CLI. These results reveal that the hydrogel can enhance the stability of Engineered-EVs in vivo and release EVs at different temperatures. Moreover, the results of animal studies indicate that Engineered-EV/Hydrogel can significantly improve neovascularization, attenuate muscle injury, and recover limb function after CLI. Finally, mechanistic studies shed light on the therapeutic effect of Engineered-EV/Hydrogel due to the activated VEGF/VEGFR pathway and autophagy-lysosomal pathway.

Deep Venous Arterialization for Chronic Limb Threatening Ischemia in Atherosclerosis Patients - A Meta-Analysis.

BACKGROUND: Venous arterialization is an upcoming and novel alternative in chronic limb threatening ischemia (CLTI) patients in the absence of standard revascularization options. The aim of this study is to systematically review and analyze outcomes of venous arterialization. METHODS: A systematic literature search was performed in 5 databases using the PRISMA methodology. Inclusion criteria were English language original research papers on CLTI patients treated with venous arterialization. EXCLUSION CRITERIA: absence of CLTI due to atherosclerosis, duplicate study or reporting of patients, meeting abstract only. Quality and risk of bias were evaluated. Meta-analysis was performed using random effects model on articles that have a sample size of equal or greater than 10. RESULTS: Twelve studies included 442 patients that underwent treatment for 445 limbs (374 patients and 377 limbs underwent venous arterialization while remainder underwent traditional bypass and served as control subjects). Average age was 66 [18 studies, range 37 -91 years], 68% were male [271/366, 15 studies] and 67% diabetic [271/406, 16 studies]). Most limbs (88%, 352/398, 16 studies) had tissue loss. Pooled 30-day mortality was 3.7% (95%-confidence interval [CI] 0.8 -6.6%), 30-day morbidity was 15.5% (95%-CI 3.2 -27.8%), 30-day major adverse cardiovascular event was 5.2% (95%-CI 1.7 -8.6%) and 30-day major adverse limb event was 16.7% (95%-CI 1.5 -31.9%). Pooled 1-year limb-salvage rate was 79.0% (95%-CI 68.7 -90.7) and 1-year survival rate was 85.7% (95%-CI 76.2 -96.4). Studies quality varied significantly across studies. CONCLUSION: Venous arterialization has an acceptable a 1-year limb salvage rate of 79%, however, this is based on low levels of evidence. More randomized controlled trials or high-quality cohort studies are needed to further define the effectiveness of this procedure for CLTI.

Association Between CRP/Albumin Ratio and Long-Term Mortality in Patients With cHronIc Limb-Threatening Ischemia Undergoing EndovaScular Therapy Below The Knee: The ACHILES-BTK Registry.

BACKGROUND: Chronic limb-threatening ischemia (CLTI), which presents with ischemic rest pain, ulceration, or gangrene, is a complex form of peripheral artery disease that can cause mortality and amputation. C-reactive protein (CRP), an inflammatory marker, indicates vascular inflammation resulting from the cytokine-dependent inflammatory process in the arterial wall, and arterial atherosclerosis resulting from the inflammation. Lower albumin levels are also associated with peripheral artery disease. We investigated the association between CRP/Albumin ratio (CAR) and long-term mortality in patients with CLTI. METHODS: A total of 172 patients who underwent endovascular treatment (EVT) for below the knee (BTK) lesions were enrolled in this study. Patients with acute infection requiring antibiotic therapy, chronic inflammatory disease, end-stage liver disease, malignancy were excluded from the study. Besides, patients with pre-follow-up intervention to the same vascular bed were also excluded from the study. The primary endpoint of the study was all-cause mortality. Patients were divided into 2 groups according to mortality. RESULTS: A total of 70 patients (40.6%) died during 32 ± 21 months of follow-up in the present study. The major amputation rate was 21.5%. The mortality (+) group was older and had higher rates of congestive heart failure, chronic kidney disease, history of stroke, and CRP levels. Moreover, statin and ACE inhibitor/angiotensin receptor blocker (ACE/ARB) use, GFR, and albumin levels were lower in the mortality (+) group. CAR was significantly higher in the mortality (+) group when comparing both groups (3.25 [1.46 - 7.86] vs. 9.75 [4.5 - 17.71], P < 0.001). CAR, congestive heart failure, chronic kidney disease, history of stroke, ACE/ARB, or statin use were independent predictors of all-cause mortality in multivariable Cox regression analysis. CONCLUSIONS: CAR was associated with mortality in CLTI patients undergoing EVT for BTK lesions. CAR may be a simple method to help patient selection, assessment, and intervention strategy for EVT and may improve patient outcomes.

Contemporary outcomes of concomitant suprainguinal bypass with infrainguinal revascularization procedures in patients with chronic limb-threatening ischemia.

OBJECTIVE: Combined suprainguinal and infrainguinal revascularization is sometimes necessary in the treatment of patients with chronic limb-threatening ischemia (CLTI). However, data on outcomes of concomitant revascularization procedures are lacking. We studied the outcomes of patients with CLTI who underwent suprainguinal bypass (SIB) alone, SIB with concomitant infrainguinal bypass (IIB), and SIB with concomitant infrainguinal peripheral endovascular intervention (IIPVI). METHODS: We reviewed all patients in the Vascular Quality Initiative with CLTI who underwent SIB from January 2010 to June 2020. Logistic regression, Kaplan-Meier survival estimates, log-rank tests, and Cox regression were used to analyze outcomes. Outcomes were 30-day mortality, perioperative myocardial infarction, perioperative major amputation, 1-year amputation-free survival, and 5-year survival. RESULTS: Of 8037 patients included, 81.3% (n = 6537) underwent SIB alone, 9.7% (n = 783) underwent SIB+IIB, and 8.9% (n = 717) underwent SIB+IIPVI. The indication for surgery was rest pain in 5040 (62.5%) and tissue loss in 3031 (37.6%). There were no significant differences in 30-day mortality and perioperative myocardial infarction rates. However, there was 2.8-fold increased odds of perioperative major amputation in both SIB+IIPVI (odds ratio [OR], 2.76; 95% confidence interval [CI], 1.30-5.88; P = .008) and SIB+IIB (OR, 2.79; 95% CI, 1.38-5.54; P = .004) among patients with rest pain as compared with SIB alone. Comparing SIB+IIPVI with SIB alone, there were no significant differences in 1-year freedom from amputation and amputation-free survival. SIB+IIPVI was associated with a 27% increased risk of 5-year mortality (hazard ratio [HR], 1.27; 95% CI, 1.03-1.55; P = .035). Compared with SIB alone, SIB+IIB was associated with 97% increased risk of 1-year major amputation among patients with rest pain (HR, 1.97; 95% CI, 1.06-3.69; P = .033), but a 47% decreased risk of 1-year major amputation or death for patients with tissue loss (HR, 0.53; 95% CI, 0.37-0.78; P = .001). SIB+IIPVI, compared with SIB+IIB, was associated with a two-fold increased risk of 1-year major amputation or death (HR, 2.04; 95% CI, 1.04-2.23), P = .003) and a 52% increased risk of 5-year mortality (HR,1.52; 95% CI, 1.04-2.24; P = .032) among patients with tissue loss. CONCLUSIONS: This study shows that SIB with concomitant infrainguinal revascularization in patients with rest pain is associated with an increased risk of amputation, whereas SIB+IIB in patients with tissue loss is associated with decreased risk of amputation or death. SIB+IIB outperformed SIB+IIPVI in patients with tissue loss. SIB with infrainguinal revascularization should be limited in patients with rest pain in line with current guidelines, but SIB+IIB may be preferred in patients with tissue loss.

The Society for Vascular Surgery Objective Performance Goals for Critical Limb Ischemia are attainable in select patients with ischemic wounds managed with wound care alone.

BACKGROUND: To set therapeutic benchmarks, in 2009 the Society for Vascular Surgery defined objective performance goals (OPG) for treatment of patients with chronic limb threatening ischemia (CLTI) with either open surgical bypass or endovascular intervention. The goal of these OPGs are to set standards of care from a revascularization standpoint and to provide performance benchmarks for 1 year patency rates for new endovascular therapies. While OPGs are useful in this regard, a critical decision point in the treatment of patients with CLTI is determining when revascularization is necessary. There is little guidance in the comprehensive treatment of this patient population, especially in the nonoperative cohort. Guidelines are needed for the CLTI patient population as a whole and not just those revascularized, and our aim was to assess whether CLTI OPGs could be attained with nonoperative management alone. METHODS: Our cohort included patients with an incident diagnosis of CLTI (by hemodynamic and symptomatic criteria) at our institution from 2013-2017. The primary outcome measured was mortality. Secondary outcomes were limb loss and failure of amputation-free survival. Descriptive statistics were used to define the 2 groups - patients undergoing primary revascularization and patients undergoing primary wound management. The risk difference in outcomes between the 2 groups was estimated using collaborative-targeted maximum likelihood estimation. RESULTS: Our cohort included 349 incident CLTI patients; 60% male, 51% white, mean age 63 +/- 13 years, 20% Rutherford 4, and 80% Rutherford 5. Most patients (277, 79%) underwent primary revascularization, and 72 (21%) were treated with wound care alone. Demographics and presenting characteristics were similar between groups. Although the revascularized patients were more likely to have femoropopliteal disease (72% vs. 36%), both groups had a high rate of infrapopliteal disease (62% vs. 57%). Not surprisingly, the patients in the revascularization group were less likely to have congestive heart failure (34% vs. 42%), complicated diabetes (52% vs. 79%), obesity (19% vs. 33%), and end stage renal disease (14% vs. 28%). In the wound care group, 2-year outcomes were 65% survival, 51% amputation free survival, 19% major limb amputation, and 17% major adverse cardiac event. The wound care cohort had a 13% greater risk of death at 2 years; however, the risk of limb loss at 2 years was 12% less in the wound care cohort. CONCLUSIONS: A comprehensive set treatment goals and expected amputation free survival outcomes can guide revascularization, but also assure that appropriate outcomes are achieved for patients treated without revascularization. The 2-year outcomes achieved in this cohort provide an estimate of outcomes for nonrevascularized CLTI patients. Although multi-center or prospective studies are needed, we demonstrate that equal, even improved, limb salvage rates are possible.

Association of Frailty With Treatment Selection and Long-Term Outcomes Among Patients With Chronic Limb-Threatening Ischemia.

Background The optimal treatment strategy for patients with chronic limb-threatening ischemia (CLTI) is often unclear. Frailty has emerged as an important factor that can identify patients at greater risk of poor outcomes and guide treatment selection, but few studies have explored its utility among the CLTI population. We examine the association of a health record-based frailty measure with treatment choice and long-term outcomes among patients hospitalized with CLTI. Methods and Results We included patients aged >65 years hospitalized with CLTI in the Medicare Provider Analysis and Review data set between October 1, 2009 and September 30, 2015. The primary exposure was frailty, defined by the Claims-based Frailty Indicator. Baseline frailty status and revascularization choice were examined using logistic regression. Cox proportional hazards regression was used to determine the association between frailty and death or amputation, stratifying by treatment strategy. Of 85 060 patients, 35 484 (42%) were classified as frail. Frail patients had lower likelihood of revascularization (adjusted odds ratio [OR], 0.78; 95% CI, 0.75‒0.82). Among those revascularized, frailty was associated with lower likelihood of surgical versus endovascular treatment (adjusted OR, 0.76; CI, 0.72‒0.81). Frail patients experienced increased risk of amputation or death, regardless of revascularization status (revascularized: adjusted hazard ratio [HR], 1.34; CI, 1.30‒1.38; non-revascularized: adjusted HR, 1.22; CI, 1.17‒1.27). Among those revascularized, frailty was independently associated with amputation or death irrespective of revascularization strategy (surgical: adjusted HR, 1.36; CI, 1.31‒1.42; endovascular: aHR, 1.29; CI, 1.243‒1.35). Conclusions Among patients hospitalized with CLTI, frailty is an important independent predictor of revascularization strategy and longitudinal adverse outcomes.

Angiogenic effects of cell therapy within a biomaterial scaffold in a rat hind limb ischemia model.

Critical limb ischemia (CLI) is a life- and limb-threatening condition affecting 1-10% of humans worldwide with peripheral arterial disease. Cellular therapies, such as bone marrow-derived mesenchymal stem cells (MSCs) have been used for the treatment of CLI. However, little information is available regarding the angiogenic potency of MSCs and mast cells (MC) in angiogenesis. The aim of this study was to evaluate the ability of MCs and MSCs to induce angiogenesis in a rat model of ischemic hind limb injury on a background of a tissue engineered hydrogel scaffold. Thirty rats were randomly divided into six control and experimental groups as follows: (a) Control healthy (b) Ischemic positive control with right femoral artery transection, (c) ischemia with hydrogel scaffold, (d) ischemia with hydrogel plus MSC, (e) ischemia with hydrogel plus MC and (f) ischemia with hydrogel plus MSC and MCs. 106 of each cell type, isolated from bone marrow stroma, was injected into the transected artery used to induce hind limb ischemia. The other hind limb served as a non-ischemic control. After 14 days, capillary density, vascular diameter, histomorphometry and immunohistochemistry at the transected location and in gastrocnemius muscles were evaluated. Capillary density and number of blood vessels in the region of the femoral artery transection in animals receiving MSCs and MCs was increased compared to control groups (P < 0.05). Generally the effect of MCs and MSCs was similar although the combined MC/MSC therapy resulted in a reduced, rather than enhanced, effect. In the gastrocnemius muscle, immunohistochemical and histomorphometric observation showed a great ratio of capillaries to muscle fibers in all the cell-receiving groups (P < 0.05). The data indicates that the combination of hydrogel and cell therapy generates a greater angiogenic potential at the ischemic site than cell therapy or hydrogels alone.

Sex Differences in Trends and In-Hospital Outcomes Among Patients With Critical Limb Ischemia: A Nationwide Analysis.

Background Critical limb ischemia (CLI) represents the most severe form of peripheral artery disease and is associated with significant mortality and morbidity. Contemporary data comparing the sex differences in trends, revascularization strategies, and in-hospital outcomes among patients with CLI are scarce. Methods and Results Using the National Inpatient Sample database years 2002 to 2015, we identified hospitalizations for CLI. Temporal trends for hospitalizations for CLI were evaluated. The differences in demographics, revascularization, and in-hospital outcomes between both sexes were compared. Among 2 400 778 CLI hospitalizations, 43.6% were women. Women were older and had a higher prevalence of obesity, hypertension, heart failure, and prior stroke. Women were also less likely to receive any revascularization (34.7% versus 35.4%, P<0.001), but the trends of revascularization have been increasing among both sexes. Revascularization was associated with lower in-hospital mortality among women (adjusted odds ratio [OR], 0.76; 95% CI, 0.71-0.81) and men (adjusted OR, 0.69; 95% CI, 0.65-0.73). On multivariable analysis adjusting for patient- and hospital-related characteristics as well as revascularization, women had a higher incidence of in-hospital mortality, postoperative hemorrhage, need for blood transfusion, postoperative infection, ischemic stroke, and discharge to facilities compared with men. Conclusions In this nationwide contemporary analysis of CLI hospitalizations, women were older and less likely to undergo revascularization. Women had a higher incidence of in-hospital mortality and bleeding complications compared with men. Sex-specific studies and interventions are needed to minimize these gaps among this high-risk population.

Autologous cell therapy in diabetes­associated critical limb ischemia: From basic studies to clinical outcomes (Review).

Cell therapy is becoming an attractive alternative for the treatment of patients with no­option critical limb ischemia (CLI). The main benefits of cell therapy are the induction of therapeutic angiogenesis and neovascularization that lead to an increase in blood flow in the ischemic limb and tissue regeneration in non­healing cutaneous trophic lesions. In the present review, the current state of the art of strategies in the cell therapy field are summarized, focusing on intra­operative autologous cell concentrates in diabetic patients with CLI, examining different sources of cell concentrates and their mechanisms of action. The present study underlined the detrimental effects of the diabetic condition on different sources of autologous cells used in cell therapy, and also in delaying wound healing capacity. Moreover, relevant clinical trials and critical issues arising from cell therapy trials are discussed. Finally, the new concept of cell therapy as an adjuvant therapy to increase wound healing in revascularized diabetic patients is introduced.

Peripheral neural blockade for pain control in patients undergoing percutaneous angioplasty for complex infrapopliteal disease.

In recent years, percutaneous transluminal angioplasty has become the preferred revascularization option for chronic limb-threatening ischemia (CLTI) and infrapopliteal (IP) arterial disease. CLTI and IP disease require complex and lengthy procedures that necessitate multiple balloon inflations and frequent contrast injections. It will lead to severe discomfort if periprocedural pain control is inadequate. Conventional methods such as local anesthesia and systemic opioids are usually inadequate to provide pain control for complex IP arterial disease interventions. Ultrasound-guided peripheral nerve blockade (PNB) has been recently employed in peripheral procedures, with several small studies reporting favorable results in patients who underwent not complex interventions. In the present series, we report our experience of 4 patients who underwent PNB to relieve pain during endovascular treatment of complex IP disease, and in whom we have observed excellent periprocedural pain control that led to satisfactory postprocedural outcomes.

Comparison of Clinical Outcomes With Drug Coated Balloons Versus Plain Balloon Angioplasty In Chronic Limb-Threatening Ischemia.

OBJECTIVE: The use of drug coated balloon (DCB) for angioplasty has shown superior efficacy against plain balloons for treating complex infrainguinal arterial disease. We report and compare the clinical outcomes following application of DCB(Paclitaxel) and plain angioplasty (POBA) in our tertiary care centre. METHODS: A retrospective, single centre analysis of 301 patients with chronic limb-threatening ischemia involving the infrainguinal segment was conducted between September 2014 and September 2018, after approval from the Institutional review board. We analyzed clinical outcomes by measuring postoperative ABI improvement, restenosis requiring reintervention procedure, minor and major amputations at the end of 18 months. . To find the association between the group variables (POBA and DCB) and other risk variables, Chi-square test/Fisher's exact test was used. Multivariable logistic regression analysis was used. RESULTS: Patients who underwent treatment with plain balloon (POBA) and DCB(Paclitaxel) angioplasty were 246(81.7%) and 55(18.3%) respectively. Our study group was predominantly male (Male: Female = 6.7:1), most patients were more than 50 years of age (n = 251, 83.4%). Smoking (n = 199, 66.1%) and diabetes (n = 210, 69.8%) were the most common atherosclerotic risk factors. Postoperative Ankle Brachial Pressure Index (ABI) improvement were similar in both groups (POBA = 57.7%; DCB = 69.8%; p = 0.103). Minor and major amputations following POBA were 26% and 22%; and DCB were 12.7% and 16.4% respectively. Re-stenosis requiring a re-interventional procedure within 18 months was 15%, (n = 37) following POBA; and 12.7% (n = 7) following DCB (p = 0.661). CONCLUSIONS: This retrospective study shows similar clinical limb related outcomes following POBA and DCB at 18 months. However, our comparative analysis between the POBA and DCB groups was totally unadjusted and not adjusted for common confounders such as age and sex. Hence, for one to draw definitive conclusions leading to changes in clinical practice; a randomized, prospective study with a larger patient cohort is needed.

Clinical practice patterns and ascertainment bias for cardiovascular events in a randomized trial: A survey of investigators in the BEST-CLI trial.

Ascertainment bias is a well-recognized source of bias in research, but few studies have systematically analyzed sources of ascertainment bias in randomized trials in which blinding is not possible and endpoint assessment is not protocolized. In the current study, we sought to evaluate differences in the clinical practice patterns of trial investigators with respect to bias in the ascertainment of pre-revascularization patient risk and the incidence of secondary endpoints post-revascularization. We conducted a cross-sectional survey of active investigators (n = 936) from the Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) trial. The total survey response rate was 19.6% (183/936). Vascular surgeons were more likely than nonsurgical interventionalists to order tests for cardiac complications after both surgical bypass (p < 0.001) and endovascular revascularization (p = 0.038). Post-procedure, investigators were more likely to order additional testing for cardiac complications in open surgery versus endovascular cases (7% vs 16% never, 41% vs 65% rarely, 43% vs 17% sometimes, 9% vs 2% always, respectively; p < 0.0001). Significant variation in practice patterns exist in the pre- and post-procedure assessment of cardiac risk and events for patients with CLI undergoing revascularization. Variation in the ascertainment of risk and outcomes according to the type of revascularization procedure and physician specialty should be considered when interpreting the results of clinical studies, such as the BEST-CLI trial. ClinicalTrials.gov Identifier: NCT02060630.

Molecular basis of the effect of atorvastatin pretreatment on stem cell therapy in chronic ischemic diseases - critical limb ischemia.

Autologous stem cell therapy is the most promising alternative treatment in patients with chronic ischemic diseases, including ischemic heart disease and critical limb ischemia, which are characterized by poor prognosis related to serious impair of quality of life, high risk of cardiovascular events and mortality rates. However, one of the most serious shortcomings of stem cell transplantation are low survival after transplantation to the site of injury, as large number of stem cells are lost within 24 hours after delivery. Multiple studies suggest that combination of lipid-lowering drugs, statins, and stem cell transplantation might improve therapeutic efficacy in regenerative medicine. Statins are inhibitors of HMG-CoA reductase and belong to recommended therapy in all patients suffering from critical limb ischemia. Statins possess non-lipid effects which involve improvement of endothelial function, decrease of vascular inflammation and oxidative stress, anti-cancer and stem cell modulation capacities. These non-lipid effects are explained by inhibition of mevalonate synthesis via blocking isoprenoid intermediates synthesis, such as farnesylpyrophospate and geranylgeranylpyrophospate and result in modulation of the PI3K/Akt pathway. Moreover, statin-mediated microRNA regulation may contribute to the pleiotropic functions. MicroRNA interplay in gene regulatory network of IGF/Akt pathway may be of special significance for the treatment of critical limb ischemia. We assume further studies are needed for detailed analysis of statin interactions with microRNA at the molecular level and their link to PI3K/Akt and IGF/Akt pathway in stem cells, which are currently the most promising treatment strategy used in chronic ischemic diseases.

Safety and Efficacy of Placenta-Derived Mesenchymal Stem Cell Treatment for Diabetic Patients with Critical Limb Ischemia: A Pilot Study.

AIM: Diabetic foot has become the main cause of non-traumatic amputation. Stem cell therapy, especially mesenchymal stem cells (MSCs), holds a great promise as a therapy for diabetic foot with ischemia limb arterial disease. The aim of this pilot study is to evaluate the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment for diabetic patients with critical limb ischemia (CLI). METHODS: Four eligible diabetic patients with CLI were consecutively enrolled in this pilot study. On the base of the standard-of-care treatment, these patients accepted P-MSCs treatment by intramuscular injection for successive 3 times at an interval of 4 weeks, and the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment were evaluated. RESULTS: There were no serious adverse events during the period of P-MSCs injection and the 24-weeks follow-up period. The clinical ischemic features of patients were improved 24 weeks after P-MSCs treatment. The scores of resting pain and limb coldness significantly decreased, and pain-free walking distance significantly increased from baseline to 24 weeks after P-MSCs therapy. The resting ankle brachial index increased, but no statistically significant difference was found. The findings of magnetic resonance angiography showed the increase of collateral vessel formation in one patient, but there were no significant changes observed in the other patients. CONCLUSIONS: The data in this pilot study indicated that multiple intramuscular P-MSCs injections may be a safe and effective alternative therapy for diabetic patients with CLI, and larger, placebo-controlled, perspective studies are needed to prove these results.

Risk Stratification for 2-Year Mortality in Patients with Chronic Limb-Threatening Ischemia Undergoing Endovascular Therapy.

AIM: The latest Global Vascular Guidelines (GVG) recommend assessing the 2-year mortality risk in patients with chronic limb-threatening ischemia (CLTI) before revascularization. This study aimed to reveal whether the Wound, Ischemia and foot Infection (WIfI) classification, developed originally as a risk assessment tool for limb prognosis, would be useful in predicting the 2-year mortality risk in patients with CLTI in the era of GVG and WIfI. METHODS: We retrospectively analyzed 849 patients with CLTI who were primarily treated with endovascular therapy (EVT) between April 2010 and December 2016. The impact of baseline characteristics, including the WIfI classification on mortality risk, was investigated using the Cox proportional hazards regression model. RESULTS: During a mean follow-up of 19.3 months, 243 deaths were observed. The 2-year mortality rate was 32.3%. Multivariate analysis demonstrated that WIfI classification stages (p=0.037), in addition to male sex (p=0.010), age (p＜0.001), non-ambulatory status (p＜0.001), body mass index (p=0.002), and hemodialysis (p＜0.001), were independent predictors for an increased risk of mortality, while the Rutherford classification was not. CONCLUSIONS: WIfI classification stages were independently associated with mortality risk in patients with CLTI undergoing EVT, while the Rutherford classification was not. The WIfI classification would be a practical tool for planning the revascularization strategy in CLTI treatment.

Coadministration of endothelial and smooth muscle cells derived from human induced pluripotent stem cells as a therapy for critical limb ischemia.

Critical limb ischemia is a condition in which tissue necrosis occurs due to arterial occlusion, resulting in limb amputation in severe cases. Both endothelial cells (ECs) and vascular smooth muscle cells (SMCs) are needed for the regeneration of peripheral arteries in ischemic tissues. However, it is difficult to isolate and cultivate primary EC and SMC from patients for therapeutic angiogenesis. Induced pluripotent stem cells (iPSCs) are regarded as useful stem cells due to their pluripotent differentiation potential. In this study, we explored the therapeutic efficacy of human iPSC-derived EC and iPSC-derived SMC in peripheral artery disease model. After the induction of mesodermal differentiation of iPSC, CD34+ progenitor cells were isolated by magnetic-activated cell sorting. Cultivation of the CD34+ progenitor cells in endothelial culture medium induced the expression of endothelial markers and phenotypes. Moreover, the CD34+ cells could be differentiated into SMC by cultivation in SMC culture medium. In a murine hindlimb ischemia model, cotransplantation of EC with SMC improved blood perfusion and increased the limb salvage rate in ischemic limbs compared to transplantation of either EC or SMC alone. Moreover, cotransplantation of EC and SMC stimulated angiogenesis and led to the formation of capillaries and arteries/arterioles in vivo. Conditioned medium derived from SMC stimulated the migration, proliferation, and tubulation of EC in vitro, and these effects were recapitulated by exosomes isolated from the SMC-conditioned medium. Together, these results suggest that iPSC-derived SMC enhance the therapeutic efficacy of iPSC-derived EC in peripheral artery disease via an exosome-mediated paracrine mechanism.