Autologous cell therapy in diabetes‑associated critical limb ischemia: From basic studies to clinical outcomes (Review).
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SUBMITTER: Magenta A
PROVIDER: S-EPMC8285046 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposePatients with diabetes and critical limb threatening ischemia (CLTI) are at significantly higher risk of limb loss and death. Here we evaluate the outcomes of orbital atherectomy (OA) for treatment of CLTI in patients with and without diabetes.MethodsRetrospective analysis of the LIBERTY 360 study was performed to evaluate baseline demographics, and peri-procedural outcomes between patients with CLTI, and with and without diabetes. Hazard ratios (HRs) were determined with Cox regression to examine the impact of OA in patients with diabetes and CLTI over a 3-year follow-up.ResultsA total of 289 patients (201 with diabetes, 88 without diabetes) with Rutherford classification 4-6 were included. Patients with diabetes had higher proportion of renal disease (48.3% vs 28.4%, p=0.002), prior minor/major limb amputation (26% vs 8%, p<0.005), and presence of wounds (63.2% vs 48.9%, p=0.027). Operative times, radiation dosage, and contrast volume were similar between groups. The rate of distal embolization was higher in patients with diabetes (7.8% vs 1.9%, p=0.01; OR 4.33 [0.99, 18.88], p=0.05). However, at 3-years post-procedure, patients with diabetes had no differences in freedom from target vessel/lesion revascularization (HR 1.09, p=0.73), major adverse events (MAE; HR 1.25, p=0.36), major target limb amputation (HR 1.74, p=0.39), and death (HR 1.11, p=0.72).ConclusionThe LIBERTY 360 observed high limb preservation and low MAEs in patients with diabetes and CLTI. Higher distal embolization was observed with OA in patients with diabetes, but OR did not indicate a significant difference in risk between groups.
| S-EPMC10103796 | biostudies-literature
Project description:BackgroundContemporary patterns in management and outcomes of critical limb ischemia among United States veterans are unknown.MethodsWe used Veterans Health Administration data to identify patients admitted for critical limb ischemia between 2005 and 2014. We examined temporal trends in incidence, management, and outcomes.ResultsA total of 20 938 veterans with critical limb ischemia were hospitalized between 2005 and 2014. Mean age was 67.8 years. Incidence decreased from 0.3 to 0.24 per 1000 persons from 2005 to 2013, P<0.01. During the study period, there was a temporal increase in use of revascularization within 90 days of hospitalization-endovascular (11.2% in 2005 to 18.4% in 2014), surgical (23.8% in 2005 to 26.4% in 2014), and hybrid (6.2% in 2005 to 13.1% in 2014, P value for trend <0.01). Statin prescriptions increased from 47.4% in 2005 to 60.9% in 2014 (P value for trend <0.01). There was a significant decline in risk-adjusted mortality (11.8% in 2005 to 9.7% in 2014) and major amputation (19.8% in 2005 to 12.9% in 2014; P value for trend <0.01 for both) at 90 days. In adjusted analyses, revascularization was associated with a lower risk of mortality (RR, 0.45 [95% CI, 0.41-0.50]; P<0.001) and major amputation at 90 days (RR, 0.23 [95% CI, 0.21-0.26]; P<0.001). Nearly half of the patients who underwent amputation did not receive an invasive vascular procedure within the preceding 90 days. There was large site-level variation in the use of revascularization (median rate, 41.7% [interquartile range, 12.5%-53.2%]). Differences in patient case-mix explained only 8% of site-level variation in receipt of revascularization.ConclusionsOver the past decade, use of revascularization increased among veterans with critical limb ischemia, which was accompanied by a reduction in mortality and major amputation. However, opportunities to further improve care in this high-risk population still remain.
| S-EPMC8641646 | biostudies-literature
Project description:Critical limb ischemia (CLI) is a major cause of limb loss and mortality among patients with advanced peripheral artery disease. Our objective was to evaluate the gender-specific differences in patient characteristics and clinical outcomes among patients with CLI. We performed a retrospective analysis of 97 women and 122 men presenting with CLI who underwent angiography from 2006 to 2010. Baseline demographics, procedural details, and lesion characteristics were assessed for each patient. Kaplan-Meier analysis was used to assess long-term patient and lesion-level outcomes. Cox proportional hazard modeling was used to evaluate the relationship between gender and major adverse cardiovascular events (MACE). Compared to men, women were less likely to have a history of coronary artery disease (39% vs 54%, p = 0.02) or diabetes (57% vs 70%, p = 0.05) but had similar baseline medical therapy. At angiography, women were more likely to have significant femoropopliteal (77% vs 67%, p = 0.02) and multi-level infrainguinal disease (63% vs 51%, p = 0.02). Women were also more likely to undergo multi-vessel percutaneous intervention (69% vs 55%, p = 0.05), but had similar rates of limb salvage after percutaneous intervention or surgical bypass (HR 0.94 [95% CI 0.45-1.94], p = 0.9). During follow-up, women had higher rates of subsequent major adverse cardiovascular events (HR 1.63 [95% CI 1.01-2.63], p = 0.04). In conclusion, women with CLI are more likely to present with femoropopliteal and multi-level infrainguinal disease. Despite similar rates of limb salvage, women with CLI have an increased rate of subsequent major adverse cardiovascular events.
| S-EPMC3786085 | biostudies-literature
Project description:Critical limb ischemia (CLI) represents the most advanced stage of peripheral arterial obstructive disease (PAOD) with a severe obstruction of the arteries which markedly reduces blood flow to the extremities and has progressed to the point of severe rest pain and/or even tissue loss. Recent therapeutic strategies have focused on restoring this balance in favor of tissue survival using exogenous molecular and cellular agents to promote regeneration of the vasculature. These are based on stimulation of angiogenesis by extracellular and cellular components. This review article carries out a systematic analysis of the most recent scientific literature on the application of stem cells in patients with CLI. The results obtained from the detailed analysis of the recent literature data have confirmed the beneficial role of cell therapy in reducing the rate of major amputations in patients with CLI and improving their quality of life.
| S-EPMC4537766 | biostudies-literature
Project description:Peripheral artery disease (PAD) is one of the major vascular complications in individuals suffering from diabetes and in the elderly that can progress to critical limb ischemia (CLI), portending significant burden in terms of patient morbidity and mortality. Over the last two decades, stem cell therapy (SCT) has risen as an attractive alternative to traditional surgical and/or endovascular revascularization to treat this disorder. The primary benefit of SCT is to induce therapeutic neovascularization and promote collateral vessel formation to increase blood flow in the ischemic limb and soft tissue. Existing evidence provides a solid rationale for ongoing in-depth studies aimed at advancing current SCT that may change the way PAD/CLI patients are treated.
| S-EPMC5735649 | biostudies-literature
Project description:The purpose of this Phase I open label nonrandomized trial was to assess the safety and efficacy of autologous bone marrow mononuclear cell (ABMNC) therapy in promoting amputation-free survival (AFS) in patients with critical limb ischemia (CLI).Between September 2005 and March 2009, 29 patients (30 limbs), with a median age of 66 years (range, 23-84 years; 14 male, 15 female) with CLI were enrolled. Twenty-one limbs presented with rest pain (RP), six with RP and ulceration, and three with ulcer only. All patients were not candidates for surgical bypass due to absence of a patent artery below the knee and/or endovascular approaches to improving perfusion was not possible as determined by an independent vascular surgeon. Patients were treated with an average dose of 1.7 ± 0.7 × 10(9) ABMNC injected intramuscularly in the index limb distal to the anterior tibial tuberosity. The primary safety end point was accumulation of serious adverse events, and the primary efficacy end point was AFS at 1 year. Secondary end points at 12 weeks posttreatment were changes in first toe pressure (FTP), toe-brachial index (TBI), ankle-brachial index (ABI), and transcutaneous oxygen measurements (TcPO(2)). Perfusion of the index limb was measured with positron emission tomography-computed tomography (PET-CT) with intra-arterial infusion of H(2)O(15). RP, using a 10-cm visual analogue scale, quality of life using the VascuQuol questionnaire, and ulcer healing were assessed at each follow-up interval. Subpopulations of endothelial progenitor cells were quantified prior to ABMNC administration using immunocytochemistry and fluorescent-activated cell sorting.There were two serious adverse events; however, there were no procedure-related deaths. Amputation-free survival at 1 year was 86.3%. There was a significant increase in FTP (10.2 ± 6.2 mm Hg; P = .02) and TBI (0.10 ± 0.05;P = .02) and a trend in improvement in ABI (0.08 ± 0.04; P = .73). Perfusion index by PET-CT H(2)O(15) increased by 19.3 ± 3.1, and RP decreased significantly by 2.2 ± 0.6 cm (P = .02). The VascuQol questionnaire demonstrated significant improvement in quality of life, and three of nine ulcers (33%) healed completely. KDR(+) but not CD34(+) or CD133(+) subpopulations of ABMNC were associated with improvement in limb perfusion.This Phase I study has demonstrated safety, and the AFS rates suggest efficacy of ABMNC in promoting limb salvage in "no option" CLI. Based on these results, we plan to test the concept that ABMNCs improve AFS at 1 year in a Phase III randomized, double-blinded, multicenter trial.
| S-EPMC3102148 | biostudies-literature
Project description:IntroductionOur study was designed to investigate the safety and efficacy of combined autologous bone marrow mononuclear cell (MNC) and gene therapy in comparison to conventional drug therapy in patients with critical limb ischemia (CLI).Material and methodsThirty-two patients with CLI persisting for 12-48 months (average time 27.5 months) were randomized into 2 groups, each group consisting of 16 patients. In the first group, administration of autologous bone marrow MNC and vascular endothelial growth factor (VEGF) plasmid was performed. The patients from the second group were treated pharmacologically with pentoxifylline. Ankle-brachial index (ABI) was measured and angiography was performed before and finally 3 months after treatment. The pain was evaluated using the Visual Analog Scale (VAS) before and after 3 months.ResultsAnkle-brachial index improved significantly from 0.29 ±0.21 to 0.52 ±0.23 (p < 0.001) in 12 patients (75.0%) 3 months after the experimental therapy in group 1. In this group angiography showed the development of collateral vessels. Ischemic ulcers healed completely in 11 patients (68.75%). In group 2 the ABI did not improve in any patient; moreover the complete healing of skin ulcers was not found in any of the patients of this group. Amputation was performed in 4 (25.0%) patients in group 1, and in 8 patients (50%) from group 2.ConclusionsThese data after 3-month follow-up indicate that intramuscular injection of MNC combined with gene therapy in patients with chronic CLI is safe, and a more feasible and effective method of treatment than the conventional therapy. However, both therapies are limited by the degree of microcirculation damage.
| S-EPMC4424239 | biostudies-literature
Project description:Cell therapy is a progressively growing field that is rapidly moving from preclinical model development to clinical application. Outcomes obtained from clinical trials reveal the therapeutic potential of stem cell-based therapy to deal with unmet medical treatment needs for several disorders with no therapeutic options. Among adult stem cells, mesenchymal stem cells (MSCs) are the leading cell type used in advanced therapies for the treatment of autoimmune, inflammatory and vascular diseases. To date, the safety and feasibility of autologous MSC-based therapy has been established; however, their indiscriminate use has resulted in mixed outcomes in preclinical and clinical studies. While MSCs derived from diverse tissues share common properties depending on the type of clinical application, they markedly differ within clinical trials in terms of efficacy, resulting in many unanswered questions regarding the application of MSCs. Additionally, our experience in clinical trials related to critical limb ischemia pathology (CLI) shows that the therapeutic efficacy of these cells in different animal models has only been partially reproduced in humans through clinical trials. Therefore, it is crucial to develop new research to identify pitfalls, to optimize procedures and to clarify the repair mechanisms used by these cells, as well as to be able to offer a next generation of stem cell that can be routinely used in a cost-effective and safe manner in stem cell-based therapies targeting CLI.
| S-EPMC6558400 | biostudies-literature
Project description:Our goal was to evaluate early results of the clinical application of autologous whole bone marrow stem cell transplantation (AWBMSCT) for critical limb ischemia (CLI) in patients with Buerger's disease. We retrospectively analyzed the data of 58 limbs of 37 patients (mean age, 43.0 years; range, 28-63 years; male, 91.9%) with Buerger's disease with CLI who were treated with AWBMSCT from March 2013 to December 2014. We analyzed Rutherford category, pain score, pain-free walking time (PFWT), total walking time (TWT), ankle brachial pressure index (ABPI), and toe brachial pressure index (TBPI), and investigated wound healing and occurrence of unplanned amputations. The mean follow-up duration was 11.9 ± 7.2 months (range, 0.9-23.9 months) and 100%, 72.4%, and 74.1% of patients were available to follow-up 1, 3 and 6 months after AWBMST, respectively. At 6 months, patients demonstrated significant improvements in Rutherford category (P < 0.0001), pain score (P < 0.0001), PFWT (P < 0.0001) and TBPI (P < 0.0001). ABPI was increased compared to baseline, but the difference was not significant. A total of 76.5% ischemic wounds achieved complete or improved healing. AWBMSCT is a safe and effective alternative or adjunctive treatment modality to achieve clinical improvement in patients with CLI.
| S-EPMC4726399 | biostudies-other
Project description:Critical limb ischemia (CLI) is a severe form of peripheral artery disease associated with high morbidity and mortality. The primary therapeutic goals in treating CLI are to reduce the risk of adverse cardiovascular events, relieve ischemic pain, heal ulcers, prevent major amputation, and improve quality of life (QoL) and survival. These goals may be achieved by medical therapy, endovascular intervention, open surgery, or amputation and require a multidisciplinary approach including pain management, wound care, risk factors reduction, and treatment of comorbidities. No-option patients are potential candidates for the novel angiogenic therapies. The application of genetic, molecular, and cellular-based modalities, the so-called therapeutic angiogenesis, in the treatment of arterial obstructive diseases has not shown consistent efficacy. This article summarizes the current status related to the management of patients with CLI and discusses the current findings of the emerging modalities for therapeutic angiogenesis.
| S-EPMC3761355 | biostudies-literature