Critical Limb Ischemia Patients Research Articles

Atorvastatin Treatment Significantly Increased the Concentration of Bone Marrow-Derived Mononuclear Cells and Transcutaneous Oxygen Pressure and Lowered the Pain Scale after Bone Marrow Cells Treatment in Patients with "No-Option" Critical Limb Ischaemia.

The present study investigated the outcomes and possible predictive factors of autologous bone marrow cells (BMCs) therapy in patients with "no-option" critical limb ischaemia (CLI). It was focused on exploring the clinical background and prior statin and renin-angiotensin system (RAS)-acting agents pharmacotherapy related to the therapeutic efficacy of BMCs treatment. In the present study, we reviewed thirty-three patients (mean age 64.9 ± 10 years; 31 males) with advanced CLI after failed or impossible revascularisation, who were treated with 40 mL of autologous BMCs by local intramuscular application. Patients with limb salvage and wound healing (N = 22) were considered as responders to BMCs therapy, and patients with limb salvage and complete ischemic wound healing (N = 13) were defined as super-responders. Logistic regression models were used to screen and identify the prognostic factors, and a receiver operating characteristics (ROC) curve, a linear regression, and a survival curve were drawn to determine the predictive accuracy, the correlation between the candidate predictors, and the risk of major amputation. Based on the univariate regression analysis, baseline C-reactive protein (CRP) and transcutaneous oxygen pressure (TcPO2) values were identified as prognostic factors of the responders, while CRP value, ankle-brachial index (ABI), and bone marrow-derived mononuclear cells (BM-MNCs) concentration were identified as prognostic factors of the super-responders. An area under the ROC curve of 0.768 indicated good discrimination for CRP > 8.1 mg/L before transplantation as a predictive factor for negative clinical response. Linear regression analysis revealed a significant dependence between the levels of baseline CRP and the concentration of BM-MNCs in transplanted bone marrow. Patients taking atorvastatin before BMCs treatment (N = 22) had significantly improved TcPO2 and reduced pain scale after BMCs transplant, compared to the non-atorvastatin group. Statin treatment was associated with reduced risk for major amputation. However, the difference was not statistically significant. Statin use was also associated with a significantly higher concentration of BM-MNCs in the transplanted bone marrow compared to patients without statin treatment. Patients treated with RAS-acting agents (N = 20) had significantly reduced pain scale after BMCs transplant, compared to the non-RAS-acting agents group. Similar results, reduced pain scale and improved TcPO2, were achieved in patients treated with atorvastatin and RAS-acting agents (N = 17) before BMCs treatment. Results of the Spearman correlation showed a significant positive correlation between CLI regression, responders, and previous therapy before BMCs transplant with RAS-acting agents alone or with atorvastatin. CRP and TcPO2 were prognostic factors of the responders, while CRP value, ABI, and BM-MNCs concentration were identified as predictive factors of the super-responders. Atorvastatin treatment was associated with a significantly increased concentration of BM-MNCs in bone marrow concentrate and higher TcPO2 and lower pain scale after BMCs treatment in CLI patients. Similarly, reduced pain scales and improved TcPO2 were achieved in patients treated with atorvastatin and RAS-acting agents before BMCs treatment. Positive correlations between responders and previous treatment before BMCs transplant with RAS-acting agents alone or with atorvastatin were significant.

Novel Glycomimetics Protect against Glycated Low-Density Lipoprotein-Induced Vascular Calcification In Vitro via Attenuation of the RAGE/ERK/CREB Pathway.

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.

CGMP modulates hemin-mediated platelet death

Background and aimsHemolysis is a known risk factor for thrombosis resulting in critical limb ischemia and microcirculatory disturbance and organ failure. Intravasal hemolysis may lead to life-threatening complications due to uncontrolled thrombo-inflammation. Until now, conventional antithrombotic therapies failed to control development and progression of these thrombotic events. Thus, the pathophysiology of these thrombotic events needs to be investigated to unravel underlying pathways and thereby identify targets for novel treatment strategies. MethodsHere we used classical experimental set-ups as well as high-end flow cytometry, metabolomics and lipidomic analysis to in-depth analyze the effects of hemin on platelet physiology and morphology. ResultsHemin does strongly and swiftly induce platelet activation and this process is modulated by the sGC-cGMP-cGKI signaling axis. cGMP modulation also reduced the pro-aggregatory potential of plasma derived from patients with hemolysis. Furthermore, hemin-induced platelet death evokes distinct platelet subpopulations. Typical cell death markers, such as ROS, were induced by hemin-stimulation and the platelet lipidome was specifically altered by high hemin concentration. Specifically, arachidonic acid derivates, such as PGE2, TXB2 or 12-HHT, were significantly increased. Balancing the cGMP levels by modulation of the sGC-cGMP-cGKI axis diminished the ferroptotic effect of hemin. ConclusionWe found that cGMP modulates hemin-induced platelet activation and thrombus formation in vitro and cGMP effects hemin-mediated platelet death and changes in the platelet lipidome. Thus, it is tempting to speculate that modulating platelet cGMP levels may be a novel strategy to control thrombosis and critical limb ischemia in patients with hemolytic crisis.

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

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

The relationship between hyperpolypharmacy and one-year outcomes in patients with critical limb ischemia undergoing below-knee endovascular therapy

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.

Pathology of Critical Limb Ischemia; Comparison of Plaque Characteristics Between Anterior and Posterior Tibial Arteries.

Though the number of patients with peripheral arterial disease (PAD) and critical limb ischemia (CLI) is increasing, few histopathological studies of PAD, particularly that involving below-the-knee arteries, has been reported. We analyzed the pathology of anterior tibial artery (ATA) and posterior tibial artery (PTA) specimens obtained from patients who underwent lower extremity amputation due to CLIMethods: Dissected ATAs and PTAs were subjected to ex-vivo soft X-ray radiography, followed by pathological examination using 860 histological sections. This protocol was approved by the Ethics Review Board of Nihon University Itabashi Hospital (RK-190910-01) and Kyorin University Hospital (R02-179). The calcified area distribution was significantly larger in PTAs than in ATAs on soft X-ray radiographic images (ATAs, 48.3% ±19.2 versus PTAs, 61.6% ±23.9; p＜0.001). Eccentric plaque with necrotic core and macrophage infiltration were more prominent in ATAs than in PTAs (eccentric plaque: ATAs, 63.7% versus PTAs, 49.1%; p＜0.0001, macrophage: ATAs, 0.29% [0.095 - 1.1%] versus PTAs, 0.12% [0.029 - 0.36%]; p＜0.001), histopathologically. Thromboembolic lesions were more frequently identified in PTAs than in ATAs (ATAs, 11.1% versus PTAs 15.8%; p＜0.05). Moreover, post-balloon injury pathology differed between ATAs and PTAs. Histological features differed strikingly between ATAs and PTAs obtained from CLI patients. Clarifying the pathological features of CLI would contribute to establishing therapeutic strategies for PAD, particularly disease involving below-the knee-arteries.

Randomized clinical trial to compare the efficacy of self-expanding bare metal nitinol stent and balloon angioplasty alone for below-the-knee lesions following successful balloon angioplasty: 1-year clinical outcomes.

This prospective, multicenter, randomized study aimed to compare the 1-year clinical outcomes after primary stenting with self-expanding bare metal nitinol stent (SENS) and plain old balloon angioplasty (POBA) in patients with critical limb ischemia (CLI) and below-the-knee (BTK) lesions. Overall, 119 patients with CLI and BTK lesions were randomized to POBA alone (POBA group, 61 patients) or primary stenting with SENS (stenting group, 58 patients) after achieving acceptable POBA results in target BTK lesions. Clinical outcomes including amputation and revascularization rates were prospectively compared for 1 year. After 1 year, similar incidence rates of individual clinical endpoints, including cardiac death (6.5% vs. 5.1%, p > 0.999), myocardial infarction (1.6% vs. 0.0%, p > 0.999), repeat revascularization (19.6% vs. 18.9%, p = 0.922), target lesion revascularization (13.1% vs. 17.2%, p = 0.530), and amputation (4.9% vs. 0.0%, p = 0.244), were observed. POBA appeared to have acceptable treatment outcomes compared with primary stenting with SENS after 1 year in CLI patients with BTK lesions undergoing percutaneous transluminal angioplasty (PTA).

Abstract 14745: Stem Cell Factor Associated With Critical Limb Ischemia in Patients With Peripheral Artery Disease

Introduction: Critical limb ischemia (CLI) and related amputation (AMP) are severe manifestations of peripheral artery disease (PAD). The pathobiology of CLI/AMP is multifactorial including chronic ischemia in the context of large vessel and microvascular disease. Novel biomarkers may identify potential pathways for new therapies to prevent and treat CLI. Hypothesis: Exploration of the proteome will yield insights into new proteins and hence pathways relevant in the pathogenesis and complications of PAD. Methods: A nested case-control study including 50 patients with CLI/AMP and 83 without was assembled from patients with PAD in the TRA2P-TIMI 50 trial for proteomic exploration using the Olink CVDII panel. Candidate markers were identified based on a false discovery rate (FDR) p-value <0.05 and then validated among 7,077 patients with PAD from TRA2P-TIMI 50 and FOURIER trials. Biomarkers were evaluated continuously & by quartile and analyses adjusted for age, sex, diabetes mellitus, and prior peripheral revascularization. Results/Data: A total of 12 protein biomarkers were significantly associated with CLI/AMP in the case-control sample at an FDR of 5% (Fig-Panel A). Three remained significantly associated with CLI/AMP in the validation step, the strongest of which was stem cell factor (SCF), a cytokine expressed by endothelial cells and involved in vasculogenesis. There was a significant inverse association between SCF and CLI/AMP (p-Bonferroni 0.00047). Examined by quartiles and adjusting for baseline differences (Panel B), a graded inverse association between SCF and CLI/AMP was observed (Q4 vs Q1 Adjusted OR 0.52, 95% CI: 0.34, 0.77; p=0.002). Conclusions: A proteomic approach to identifying novel biomarkers associated with CLI/AMP revealed a strong inverse risk relationship with SCF levels. These data suggest that SCF and its effects on vasculogenesis warrant further investigation as a pathway to prevent and treat CLI/AMP in patients with PAD.

Effects of iloprost in patients with critical limb ischemia: Results of a cohort study from the COPART registry

Iloprost has been proposed as an alternative to amputation in Critical Limb Ischemia (CLI) patients when revascularization was unsuccessful or not possible. Nonetheless, there is limited evidence of its benefit. The main objective was to evaluate the effectiveness of iloprost and the secondary objective was to evaluate its safety. In this cohort study including CLI patients from the COPART registry from 2006/10 to 2021/01, patients exposed to iloprost were matched with up to three unexposed patients according to age, sex, and Propensity Score (PS) for exposure to iloprost. The main outcome combined the occurrence of all-cause death and major amputations; survival was assessed over one-year using Kaplan-Meier estimates and Cox model analyses. Major Adverse Cardiovascular Events (MACE) were chosen as the safety outcome; the association with iloprost was estimated using a logistic regression model. Among 1850 CLI patients, 201 were exposed to iloprost (71.6% men; median age: 72 years vs. 72.1%; 75 years for unexposed). In 134 exposed patients matched to 375 unexposed patients, 14 major amputations and 24 deaths occurred in exposed patients (28.4%) vs. 33 and 46 respectively in the unexposed patients (20.9%). The hazard ratio (HR) was of 1.49 (95% Confidence Interval: 1.01-2.20). The association remained in the subgroup of "no option" patients (HR: 1.74; [1.01-2.20]). Regarding safety, 21/201 (10.7%) exposed patients experienced MACE vs. 146/1649 (9.41%) unexposed patients (unadjusted Odds Ratio [OR]: 1.17 [0.72-1.90]; adjusted OR: 1.23 [0.72-2.11]). The study did not find any benefit of iloprost in CLI patients and even suggested a deleterious effect.

Application of 3D Printing Insole by Hemodynamics in Older Patients with Critical Limb Ischemia: Protocol for a Randomized Clinical Trial.

Critical limb ischemia (CLI) is a severe condition characterized by inadequate blood flow to the lower extremities, often leading to tissue damage and amputation. CLI is characterized by microcirculatory dysfunction, muscle tissue necrosis, and inflammation. Patients may suffer from the traumatic pain and the increase of plantar pressure, and foot care for patients with CLI has become the "last mile" to improve their life quality. Traditional shoe insoles often lack individual customization, failing to address the unique anatomical needs and hemodynamic characteristics of patients. The study aims to investigate the effects of this innovative intervention on improving the clinical outcomes, and quality of life in CLI patients. This Critical Limb Ischemia Hemodynamic Insole Study is a randomized controlled study performed to explore the effect of a 3D printing insole on foot care of CLI patients. This study recruitment began on November 1, 2021. Patients with CLI confirmed by clinical symptoms and imaging were recruited as the research objects. Participants will be randomly assigned to either the experimental group, which will receive 3D-printed insoles customized based on their hemodynamics, or the control group, which will receive traditionally manufactured insoles. Both groups were followed up for up to 24 months after surgery, including claudication distance, claudication time, pain score, rehospitalization, etc. ChiCTR2100051857.

Vascular regeneration and skeletal muscle repair induced by long-term exposure to SDF-1α derived from engineered mesenchymal stem cells after hindlimb ischemia.

Despite recent progress in medical and endovascular therapy, the prognosis for patients with critical limb ischemia (CLI) remains poor. In response, various stem cells and growth factors have been assessed for use in therapeutic neovascularization and limb salvage in CLI patients. However, the clinical outcomes of cell-based therapeutic angiogenesis have not provided the promised benefits, reinforcing the need for novel cell-based therapeutic angiogenic strategies to cure untreatable CLI. In the present study, we investigated genetically engineered mesenchymal stem cells (MSCs) derived from human bone marrow that continuously secrete stromal-derived factor-1α (SDF1α-eMSCs) and demonstrated that intramuscular injection of SDF1α-eMSCs can provide long-term paracrine effects in limb ischemia and effectively contribute to vascular regeneration as well as skeletal muscle repair through increased phosphorylation of ERK and Akt within the SDF1α/CXCR4 axis. These results provide compelling evidence that genetically engineered MSCs with SDF-1α can be an effective strategy for successful limb salvage in limb ischemia.

The real-world data of lipid-lowering treatment in patients with peripheral artery disease and its association with severity of disease

BackgroundThe 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). MethodsA 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. ResultsStatin 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. ConclusionsStatin 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.

Impact of Optimal Medical Therapy on Reintervention and Survival Rates after Endovascular Infrapopliteal Revascularization.

Within this single-center cohort study, we investigated the impact of optimal medical therapy on all-cause mortality, major amputation-free survival and clinically driven target lesion revascularization (CD TLR) in 552 patients with peripheral arterial disease (PAD) undergoing endovascular infrapopliteal revascularization. From the overall cohort, 145 patients were treated for intermittent claudication (IC) and 407 were treated for critical limb ischemia (CLI). Optimal medical therapy (OMT) was defined as the presence of at least one antiplatelet agent, statin and ACE inhibitor or AT-2 antagonist based on guideline recommendations. About half (55.5%) of all patients were prescribed OMT at discharge, with a higher proportion in claudicants (62.1%) versus CLI patients (53.2%). Over three years of follow-up, survival was significantly better in patients with IC (80.6 ± 3.8% vs. 59.9 ± 2.9%; p < 0.001). There was a signal towards better survival in those patients receiving OMT (log-rank p = 0.09). Similarly, amputation-free survival (AFS) was significantly better in patients with IC (p = 0.004) and also in patients receiving OMT (78.8 ± 3.6%) compared to that in those without OMT (71.5 ± 4.2%; p = 0.046). Freedom from CD TLR within three years was significantly better in the IC group (p = 0.002), but there were no statistically significant differences for CD TLR dependent on the presence of OMT (p = 0.79). In conclusion, there is still an important underuse of OMT in patients undergoing infrapopliteal interventions, which is even more pronounced in CLI despite a signal for its benefit regarding all-cause mortality and major amputation-free survival.

Evaluation of the lower extremity blood supply in no-option critical limb ischemia patients with stem cell transplantation by time maximum intensity projection CT perfusion: A single-centre prospective study.

Cell therapy has had satisfactory safety and efficacy outcomes for no-option critical limb ischaemia (NO-CLI) patients. In the current study, we aimed to compare the image quality of ischaemic lower limb blood vessels shown on volumetric CT-based time maximum intensity projection CT perfusion (t-MIP CTP) versus single-phase CTA (sCTA). We also tried to quantify the blood flow of the ischaemic lower extremity based on the t-MIP technique, not only to precisely show the dynamic change in blood flow from before to after cell therapy but also to detect any relationship between this change and patient prognosis. A total of 31 patients with thromboangiitis obliterans (TAO)-induced NO-CLI who had been referred from the department of vascular surgery to undergo autologous stem cell transplantation into a single limb from January 2020 to March 2021 were prospectively enrolled in this study. Preoperative sCTA or t-MIP CTP and postoperative 1-month t-MIP CTP were performed in all patients. Clinical outcomes, including the 1-month ankle-brachial index (ABI) and 3-month CLI status, were also analysed. Image quality, including objective scores (attenuation, signal-to-noise ratio [SNR] and contrast-to-noise ratio [CNR]), subjective scores and collateral scores, was compared between preoperative sCTA and t-MIP CTP. Vascular volume was calculated as the total volume (mL) of lower limb arteries within the scanning range. All images and calculations were performed by 2 separate radiologists. Receiver operating characteristic curves were drawn to reveal the sensitivity and specificity of vascular volume and ABI in predicting prognosis. Both sCTA and t-MIP CTP images exhibited good quality for diagnosis. t-MIP CTP images showed significantly higher attenuation, SNR and CNR in all arterial segments (popliteal artery, anterior tibial artery, posterior tibial artery and peroneal artery). In subjective and collateral score evaluations, t-MIP CTP images were also significantly better than sCTA images (both p < .05). At 1 month after transplantation, both vascular volume and ABI showed significant improvement (both p < .01). At 3months after transplantation, 38.71% of patients (12/31) achieved CLI relief (Rutherford class < 4). Through the receiver operating characteristic (ROC) curve, the 1-month vascular volume increase ratio showed better ability to predict the 3-month prognosis (radiologist 1: AUC, 0.757; sensitivity, 0.750; specificity, 0.840; radiologist 2: AUC, 0.803; sensitivity, 0.500; specificity, 1.000) than the 1-month ABI increase ratio (AUC, 0.607; sensitivity, 0.230; specificity, 0.820) or 1-month ABI (AUC, 0.410; sensitivity, 0.080; specificity, 0.580). t-MIP CTP showed significantly higher-quality images of ischaemic limb vascularity than sCTA. t-MIP CTP can reveal the anatomical information of collaterals more accurately, which is of great importance for NO-CLI patients undergoing cell transplantation. The 1-month vascular volume increase ratio can predict the 3-month prognosis more precisely on this basis.

Stem Cell Therapy in Critical Limb Ischemia.

Critical limb ischemia (CLI), a serious outcome of peripheral artery disease, is frequently associated with morbid outcomes. The available treatment modalities do not provide satisfactory results, leading to marked morbidities such as joint contracture and amputations, resulting in a high economic burden. The peripheral vascular disease tends to cause more morbidity in patients with diabetes and atherosclerosis, given the pre-existing compromised perfusion of medium and small vessels in diabetic patients. With surgical procedures, the chance of vascular compromise further increases, inducing a significantly greater rate of amputation. Hence, the need for nonsurgical treatment modalities such as stem cell therapy (SCT), which promotes angiogenesis, is warranted. In CLI, SCT acts through neovascularization and the development of collateral arteries, which increases blood supply to the soft tissues of the ischemic limb, providing satisfactory outcomes. An electronic database search was performed in PubMed, SCOPUS, EMBASE, and ScienceDirect to identify published clinical trial data, research studies, and review articles on stem cell therapy in critical limb ischemia. The search resulted in a total of 2391 results. Duplicate articles screening resulted in 565 articles. In-depth screening of abstracts and research titles excluded 520 articles, yielding 45 articles suitable for full-text review. On review of full text, articles with overlapping and similar results were filtered, ending in 25 articles. SCT promotes arteriogenesis, and bone marrow-derived mesenchymal stromal cells produce significant effects like reduced morbidity, improved amputation-free survival (AFS ) rate, and improved distal perfusion even in "no-option" CLI patients. SCT is a promising treatment modality for CLI patients, even in those in whom endovascular and revascularization procedures are impossible. SCT assures a prolonged AFS rate, improved distal perfusion, improved walking distances, reduced amputation rates, and increased survival ratio, and is well-tolerated.

Report of a phase 1 clinical trial for safety assessment of human placental mesenchymal stem cells therapy in patients with critical limb ischemia (CLI)

BackgroundCritical limb ischemia (CLI) is associated with increased risk of tissue loss, leading to significant morbidity and mortality. Therapeutic angiogenesis using cell-based treatments, notably mesenchymal stem cells (MSCs), is essential for enhancing blood flow to ischemic areas in subjects suffering from CLI. The objective of this study was to evaluate the feasibility of using placenta-derived mesenchymal stem cells (P-MSCs) in patients with CLI.MethodsThis phase I dose-escalation study investigated P-MSCs in nine CLI patients who were enrolled into each of the two dosage groups (20 × 106 and 60 × 106 cells), delivered intramuscularly twice, two months apart. The incidence of treatment-related adverse events was the primary endpoint. The decrease in inflammatory cytokines, improvement in the ankle-brachial pressure index (ABI), maximum walking distance, vascular collateralization, alleviation of rest pain, healing of ulceration, and avoidance of major amputation in the target leg were the efficacy outcomes.ResultsAll dosages of P-MSCs, including the highest tested dose of 60 × 106 cells, were well tolerated. During the 6-month follow-up period, there was a statistically significant decrease in IL-1 and IFN-γ serum levels following P-MSC treatment. The blood lymphocyte profile of participants with CLI did not significantly differ, suggesting that the injection of allogeneic cells did not cause T-cell proliferation in vivo. We found clinically substantial improvement in rest pain, ulcer healing, and maximum walking distance after P-MSC implantation. In patients with CLI, we performed minor amputations rather than major amputations. Angiography was unable to demonstrate new small vessels formation significantly.ConclusionThe observations from this phase I clinical study indicate that intramuscular administration of P-MSCs is considered safe and well tolerated and may dramatically improve physical performance and minimize inflammatory conditions in patients with CLI.Trial registration: IRCT, IRCT20210221050446N1. Registered May 09, 2021.

Results of the tibioperoneal trunk repair in patients with advanced atherosclerosis

Objective: To study immediate and long-term results of the tibioperoneal trunk repair (plastic reconstruction or prosthetic repair) during femoropopliteal bypass.Materials and methods: In our retrospective cohort study we analyzed surgical treatment results of 109 patients with lower extremities atherosclerosis who were treated in the Vascular Surgery Unit of Interregional Clinical Diagnostic Center (Kazan, Russian Federation) from 2018 to 2020. 26 (23.8%) patients were hospitalized for stage IB-IIA acute arterial insufficiency with atherothrombosis, and 83 (76.1%) patients were admitted with critical limb ischemia (CLI) as a result of advanced atherosclerosis. Among the CLI patients, 43 (39.4%) of them had stage III chronic arterial insufficiency, and 40 (36.7%) patients had stage IV chronic arterial insufficiency. The study selection criteria included extensive femoral and popliteal arteries disease and significant stenosis or occlusion of the tibioperoneal trunk. TASC II type C lesions were detected in 2 (1.8%) patients, while 107 (98.2%) patients were diagnosed with TASC II type D lesions. Based on the GLASS classification, all 109 (100%) patients had FP grade 3-4 femoropopliteal lesions with concomitant IP grade 1-4 tibial lesion. The main group included 24 (22%) patients who underwent femoropopliteal bypass with plastic or prosthetic repair of the tibioperoneal trunk using an original technique. The control group included 85 (78%) patients who underwent bypass surgery without the tibioperoneal trunk repair. Isolated femorotibial bypass was performed in 7 (8.2%) patients, and 78 (91.7%) patients underwent femoropopliteal bypass with a reversed autogenous vein.Results: We followed up patients for 2 years after surgery. Immediate technical success was 97.24% (106/109). Graft thrombosis was reported in 3 cases. No difference between the groups was observed. Long-term graft patency was significantly higher in the main group (P = .044) and significantly associated with age (RR = 0.96; 95% CI of 0.92 to 1.00, P = .03), type 2 diabetes mellitus (RR = 2.10; 95% CI of 1.10 to 4.10, P = .03), and history of the tibioperoneal trunk repair (RR = 0.43; 95% CI of 0.18 to 1.00, P = .06). Variables associated with patency in the univariate regression at a significance level P ≤ .1 were included in a multivariate model that demonstrated the combined effect of predictors on the outcome.Conclusions: Femoropopliteal bypass with the tibioperoneal trunk repair improves treatment results in patients with extensive peripheral artery disease and immediately threatened limbs or a threat to a limb within 2 years.

One-year Outcomes Among Patients Undergoing Tibial Endovascular Reinterventions for Recurrent Critical Limb Ischemia

Angioplasty, stenting, and atherectomy for tibial occlusive disease are commonly performed among critical limb ischemia patients, but restenosis and occlusion significantly hinder long-term durability. For patients requiring reintervention for recurrent tibial occlusive disease, the impact on clinical benefit and patency equivalence is unclear. We compared 1-year outcomes following repeat tibial endovascular intervention(s) to the first (primary) tibial endovascular intervention. Procedural and long-term data from the Vascular Quality Initiative database were queried for patients with critical limb ischemia (Rutherford Class 4-6) undergoing endovascular intervention for isolated tibial occlusive disease (2010-2020). Outcomes included 1-year change from baseline in ambulatory status, functional status (Eastern Cooperative Oncology Group), disposition, minor amputation, and major adverse outcomes (death, below-knee amputation, above-knee amputation). Statistically significant and clinically relevant variables were included in multivariate logistic regression. We included 1871 patients underwent primary isolated tibial endovascular intervention for critical limb ischemia. Of those, 433 (23.1%) patients underwent tibial endovascular reintervention for recurrent disease (tissue loss 35.0%). 81.6% and 14.5% of patients underwent angioplasty and atherectomy, respectively, for primary intervention. Patients requiring repeat intervention(s) had significantly decreased clinical improvement after primary intervention (67.4% vs 77.9%; P < .001) and repeat intervention (67.8% vs 77.9%; P < .001) compared to patients with no reintervention (Table). Among the three groups, a minority of patients achieved improvement in functional status (22.2% vs 20.7% vs 21.9%; P = .84) and ambulatory status at 1-year (20.0% vs 18.6% vs 17.1%; P = .54). Approximately 50% of patients were fully ambulatory at 1 year (Table). After multivariate adjustment, patients with reintervention were 50% less likely to have a patent target vessel at 1-year after primary endovascular treatment vs patients having no reintervention (odds ratio [OR], 0.50; 95% CI, 0.31-0.79; P = .03). Patients with reintervention were also found to have increased risk for minor amputation compared to patients without reintervention (OR, 1.64; 95% CI, 1.20-2.23; P = .002). Repeat interventions significantly increased risk of minor amputation at 1-year compared to primary intervention (OR, 2.41; 95% CI, 1.53-3.80; P < .001). There was no significant difference in death or major amputation (below or above knee) (Table). Atherectomy was associated with significant reduction in high-grade stenosis at 1 year (>50%) after primary treatment compared to angioplasty (OR, 0.097; 95% CI, 0.018-0.52; P = .006). Major adverse outcomes after repeat endovascular tibial intervention for recurrent tibial occlusive disease were similar to those after primary tibial endovascular intervention. However, patients with recurrent tibial occlusive disease requiring reintervention had decreased symptom improvement after primary and repeat treatment, decreased target lesion patency, and increased risk of minor amputation.TableOne-year outcomes following tibial endovascular intervention for critical limb ischemiaPrimary endovascular intervention (no future intervention), n = 1438Primary endovascular intervention (future reintervention), n = 433Repeat endovascular intervention (2+ interventions), n = 143P valueDeath335 (23.3)86 (19.9)39 (27.3).14Symptom improvementn = 1094n = 380n = 115 Regression72 (6.6)35 (9.2)13 (11.3)<.001 No change170 (15.5)89 (23.4)24 (20.9) Improvement852 (77.9)256 (67.4)78 (67.8)Patency (patent)755/827 (91.3)259/298 (86.9)77/89 (86.5).05>50% Stenosis27/160 (16.9)14/75 (18.7)2/20 (10.0).66Functional status changen = 517n = 198n = 64.87 Regression173 (33.5)72 (36.4)25 (39.1) No change229 (44.3)85 (42.9)25 (39.1) Improvement115 (22.2)41 (20.7)14 (21.9)Ambulation status (ambulatory)565/1075 (52.6)200/377 (53.1)60/112 (53.6).69Ambulatory status changen = 1072n = 377n = 111.54 Regression303 (28.3)113 (30.0)26 (23.4) No change555 (51.8)194 (51.5)66 (59.5) Improvement214 (20.0)70 (18.6)19 (17.1)Disposition changen = 358n = 137n = 40.28 Needs advanced care206 (57.5)68 (49.6)23 (57.5) No change152 (42.5)69 (50.4)17 (42.5)Postoperative ABI1.15 ± 0.501.12 ± 0.541.09 ± 0.62.63Amputationn = 1168n = 396n = 118 All cause370 (31.7)152 (38.4)56 (47.5)<.001 Below knee173 (14.8)58 (14.6)15 (12.7).83 Above knee44 (3.8)16 (4.0)8 (6.8).29 Minor amputation (toe/ray/transmetatarsal)153 (16.1)78 (24.2)33 (34.7)<.001Values are number (%) or mean ± standard deviation. Open table in a new tab

Label extension, single-arm, phase III study shows efficacy and safety of stempeucel® in patients with critical limb ischemia due to atherosclerotic peripheral arterial disease

BackgroundPeripheral arterial disease (PAD) of lower extremities comprises a clinical spectrum that extends from asymptomatic patients to critical limb ischemia (CLI) patients. 10% to 40% of the patients are at the risk of primary amputation. This study was planned in “no-option” patients of CLI due to atherosclerotic PAD to assess the efficacy and safety of pooled, allogeneic, adult human bone marrow-derived mesenchymal stromal cells which is already approved for marketing in India for CLI due to Buerger’s disease.MethodsThis was a single-arm, multi-centric, phase III study where mesenchymal stromal cells was injected as 2 million cells/kg body weight in the calf muscle and around the ulcer. Twenty-four patients of lower extremity CLI due to PAD with Rutherford III-5 or III-6 and ankle–brachial pressure index ≤ 0.6 and having have at least one ulcer with area between 0.5 and 10 cm2 were included in the study. These patients were evaluated over 12 months from drug administration.ResultsOver a period of 12 months, statistical significant reduction of rest pain and ulcer size along with improvement in ankle–brachial pressure index and ankle systolic was observed. The quality of life of patients improved together with increase in total walking distance and major amputation-free survival time.ConclusionMesenchymal stromal cells may be a feasible option to treat “no-option” patients with atherosclerotic PAD.Trial registration This study is registered prospectively in National Institutes of Health and Clinical Trials Registry—India (CTRI) website: CTRI/2018/06/014436. Registered 6th June 2018. http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=24050&EncHid=&userName=stempeutics.

Skeletal Muscle Bioenergetics in Critical Limb Ischemia and Diabetes

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