Severe Critical Limb Ischemia Research Articles

Nationwide study of six-month readmissions in critical limb ischemia: Predictors and impact of revascularization strategies.

There is a paucity of data regarding six-month readmissions in critical limb ischemia patients and the influence of management strategy during index-admission [endovascular, surgical, hybrid procedure, medical therapy, and amputation]. We aimed to investigate the incidence, predictors, and impact of management strategies on six-month readmission in patients with critical limb ischemia. A secondary analysis of the Nationwide Readmissions Database (2016-2017) was conducted. Propensity score matching was performed for subgroup analysis. We identified 50,058 patients with primary diagnosis of critical limb ischemia. Six-month all-cause and critical limb ischemia-related readmission rate was 52.36% and 10.86%, respectively. The risk of all-cause readmission was lower with amputation but was similar among other subgroups. Patients receiving surgical [HR 0.62, CI(0.48-0.79), p < 0.001] and hybrid procedure [HR 0.65 (0.46-0.93), p = 0.02] had lower risk of unplanned critical limb ischemia-related readmission compared to endovascular, though the risk of unplanned revascularization/amputation during readmission was similar between the three strategies. The risk of non-critical limb ischemia-related readmission was higher with surgical [HR 1.13, CI(1.04-1.23), p = 0.003] and hybrid procedure [HR 1.17, CI(1.08-1.28), p < 0.001], driven by increased procedure-related/wound complications. Eventhough endovascular patients were older with more severe critical limb ischemia presentation, a lower proportion received home-health or placement upon discharge from index-admission. This could account for higher readmission without higher repeat revascularization in endovascular group. The risk of critical limb ischemia and non-critical limb ischemia-related readmission differ according to the management strategy. Significant differences in discharge disposition exist depending on revascularization strategy. Study findings identify opportunities for reducing readmissions by focusing on nonprocedural aspects like wound-care, discharge planning and placement.

Limb Salvage in Patients With Severe Critical Limb Ischemia (CLI) After Referral for a Second Opinion to a Dedicated CLI Center.

The complexity of critical limb ischemia (CLI) requires dedicated multidisciplinary teams of different care providers, who will supervise the full cycle of CLI care. Until CLI treatment is fully centralized, such dedicated teams may work as second-opinion tools before major amputation is undertaken in CLI patients. The aim of the study is to assess the effectiveness of a well-timed referral to a dedicated CLI-center of patients scheduled to major amputation elsewhere. A retrospective analysis of all CLI-patients treated in our department between January 2019 and March 2020 was conducted. Only patients scheduled for a major amputation elsewhere and referred to our clinic were included. Primary endpoint was amputation-free survival, whereas technical success, limb salvage, minor amputation rate, re-admission at 30 days, and frequency of medication change from other disciplines were the secondary endpoints. Sixteen patients with 19 treated limbs were identified and included in this analysis. The WIfI (wound, infection and foot ischemia) clinical stage on admission was 2 in 4 limbs (21%), 3 in 5 limbs (26%), and 4 in 10 limbs (53%). All patients underwent advanced endovascular revascularization. Minor amputation was performed in 8 patients (42%). Amputation-free survival at 6 months was 93% with limb salvage rate of 100%. Technical success and re-admission rates at 30 days was 95% and 6%, respectively. There was a medication adjustment from other specialties in 13 (81%) patients. Patients in severe stages of CLI scheduled to major amputation reached high limb salvage and survival rate, since they are referred for a second opinion to a dedicated multidisciplinary CLI team.

Venous distal bypass should be considered as the gold standard to finally attempt limb salvage in patients with severe critical limb ischemia and diabetic foot, or under dialysis.

Venous distal bypass should be considered as the gold standard to finally attempt limb salvage in patients with severe critical limb ischemia and diabetic foot, or under dialysis.

Limb Preservation Using Edetate Disodium-based Chelation in Patients with Diabetes and Critical Limb Ischemia: An Open-label Pilot Study.

BackgroundIn 2015, there were 30.3 million patients with diabetes in the US, including 25.2% of people ages 65 or older and 108,000 hospitalizations for non-traumatic amputations. Severe diabetic limb disease includes critical limb ischemia (CLI ) due to an infrapopliteal disease with foot pain and ischemic ulcerations including gangrene. Environmentally acquired toxic metals, such as lead and cadmium, have been associated with cardiovascular disease. Thus, we designed the present unblinded pilot study to determine whether there was a signal of benefit for edetate disodium-based infusions in patients with critical limb ischemia.MethodsThis was an open-label pilot study in 10 patients with diabetes and critical limb ischemia. Each patient received up to 50 edetate disodium-based infusions and was assessed for safety, clinical efficacy, metal excretion, and quality of life. The primary endpoint was to assess the effect of edetate disodium-based therapy plus vitamins in patients with diabetes and infra-popliteal peripheral artery disease presenting with severe CLI and determine if there were improvements in vascular flow parameters.ResultsWe enrolled 10 (60% male) predominantly Caucasian (90%) subjects. The mean age was 75.3 (8.0) years. Smoking was reported by 30%. There were 70% with coronary artery disease (30% had prior coronary artery bypass grafting) and 50% had a prior lower-extremity amputation, three having previous minor amputations and two major amputations. There were no major adverse cardiovascular events during the infusion phase through the one-year follow-up. Patients completing 40 infusions demonstrated complete wound healing and improvement in the quality of life.ConclusionPatients with diabetes and CLI treated with a regimen of edetate disodium-based infusions demonstrated a potential signal of benefit and preliminary evidence of safety. The Trial to Assess Chelation Therapy in Critical Limb Ischemia (TACT3a), a randomized double-blind, placebo-controlled clinical trial now in progress, will further test these findings.

Simultaneous SFA Angioplasty/Stent Plus Popliteal Distal Bypass for Limb Salvage

Introduction: Treatment of severe critical limb ischemia (CLI) due to Superficial Femoral Artery (SFA) and below-the-knee (BTK) vessels' involvement could be compromised by the lack of a Great Saphenous Vein (GSV) suitable in its entire length. The purpose of this study is to assess the efficacy of a hybrid endovascular and open lower limbs arterial reconstruction in these patients with multilevel, advanced CLI. We combined two different techniques, each one largely validated for different level of intervention (endovascular for SFA, surgical for BTK), and we aimed to assess the efficacy of such an hybrid arterial reconstruction in patients with multilevel CLI in the lack of suitable autologous vein. Methods: From 2005 to 2019, we performed hybrid endovascular and surgical treatment for limb salvage in SFA-BTK CLI. This consisted of percutaneous transluminal angioplasty (PTA) with or without stenting of the SFA, along with distal origin vein graft bypass. Inclusion criteria were: Rutherford category 5 or 6, lack of a suitable GSV, patency of the popliteal artery, steno-obstructive lesions of the SFA, lesions of the three crural vessels > 5 cm in length each. The follow-up was performed with duplex scan surveillance of both the bypass graft and PTA sites. Results: The hybrid treatment was performed in 34 patients. 56% of the SFA steno-obstructive lesions were treated with simple PTA, except for the application of a bare metal stent in one patient (3%), while in all the SFA occlusions PTA was completed with covered stents (41%). Thirty-four popliteal-to-distal vein bypass grafts have been performed. There were no perioperative PTA or bypass graft failures. Clinical improvement was achieved in 26 (76%) patients. Overall, primary, assisted primary and secondary patency, limb salvage, and survival rates were 65%, 70%, 68%, and 75% at 5 years, respectively (Graph 1 and Graph 2). Conclusion: A hybrid strategy in multilevel SFA-BTK CLI is a well established approach. Additional studies are warranted to validate these results.Graph 2View Large Image Figure ViewerDownload Hi-res image Download (PPT) Disclosure: Nothing to disclose

Simultaneous Superficial Femoral Artery Angioplasty/Stent Plus Popliteal Distal Bypass for Limb Salvage

Treatment of severe critical limb ischemia (CLI) due to superficial femoral artery (SFA) and below-the-knee (BTK) vessels' involvement could be compromised by the lack of a great saphenous vein (GSV) suitable in its entire length. The purpose of this study is to assess the efficacy of a hybrid endovascular and open lower limbs arterial reconstruction in these patients with multilevel, advanced CLI. From 2005 to 2019, we performed hybrid endovascular and surgical treatment for limb salvage in SFA-BTK CLI. This consisted of percutaneous transluminal angioplasty (PTA) with or without stenting of the SFA, along with distal origin vein graft bypass. Inclusion criteria were Rutherford category 5 or 6, lack of a suitable GSV, patency of the popliteal artery, steno-obstructive lesions of the SFA, lesions of the 3 crural vessels >5cm in length each. The follow-up was performed with duplex scan surveillance of both the bypass graft and PTA sites. The hybrid treatment could be performed in 34 patients. Fifty-six percent of the SFA steno-obstructive lesions were treated with simple PTA, except for the application of a bare metal stent in one patient (3%), while in all the SFA occlusions PTA was completed with covered stents (41%). Thirty-four popliteal-to-distal vein bypass grafts bypass grafts have been performed. There were no perioperative PTA or bypass graft failures. Clinical improvement was achieved in 26 (76%) patients. Overall, primary and secondary patency, limb salvage, and survival rates were 65%, 68%, 75%, and 75% at 5years, respectively. A hybrid strategy in multilevel SFA-BTK CLI is a well-established approach. Additional studies are warranted to validate these results.

Living a burdensome and demanding life: A qualitative systematic review of the patients experiences of peripheral arterial disease.

BackgroundPeripheral arterial disease (PAD) has a significant negative impact on the quality of life of individuals. Understanding the experiences of people living with PAD will be useful in developing comprehensive patient-centred secondary prevention therapies for this population.AimThe aim of this study is to identify first-hand accounts of patients’ experiences of living with PAD.MethodsSix databases (CINALH, PsyclNFO, MEDLINE, AMED, EMBASE, Social citation index/Science citation index via Web of Science (WOS)) and reference lists of identified studies were searched until September 2017 (updated February 2018). Qualitative studies reporting patients’ account of living with PAD were eligible for inclusion. A framework thematic synthesis was implemented.ResultsFourteen studies with 360 participants were included. Pain and walking limitation were recurrent among the varied symptom descriptions. Patients’ ignorance and trivialisation of symptoms contributed to delays in diagnosis. Inadequate engagement in disease understanding and treatment decisions meant patients had poor attitudes towards walking treatments and unrealistic expectations about surgery. Depending on symptom progression, patients battle with walking impairment, powerlessness, and loss of independence which were a source of burden to them. Lack of disease understanding is central through patients’ journey with PAD and, although they subsequently began adaptation to long term living with PAD, many worried about their future.ConclusionsDisease understanding is vital across the illness trajectory in patients with PAD. Although certain experiences are common throughout patient journey, some might be unique to a particular stage (e.g. unrealistic expectation about surgery, or rationale of walking in spite of pain in a supervised exercise program). Given that PAD is an overarching construct ranging from the mildest form of intermittent claudication to severe critical limb ischemia with ulceration and gangrene, consideration of important patient constructs specific to each stage of the disease may enhance treatment success. Systematic review registration CRD42017070417.

Circulating Small Non-coding RNAs as Biomarkers for Recovery After Exhaustive or Repetitive Exercise

Circulating microRNAs have proven to be reliable biomarkers, due to their high stability, both in vivo in the circulation, and ex vivo during sample preparation and storage. Small nucleolar RNAs (snoRNAs) are a different type of small non-coding RNAs that can also be reliably measured in plasma, but have only been studied sporadically. In this study, we aimed to identify RNA-biomarkers that can distinguish between different exercise regimes and that entail clues about muscle repair and recovery after prolonged exhaustive endurance exercise. We compared plasma microRNA profiles between two cohorts of elite cyclists, subjected to two different types of exercise regimes, as well as a cohort of patients with peripheral artery disease (PAD) that were scheduled to undergo lower limb amputation, due to critical limb ischemia. In elite athletes, muscle tissue recovers quickly even after exhaustive exercise, whereas in PAD patients, recovery is completely impaired. Furthermore, we measured levels of a specific group of snoRNAs in the plasma of both elite cyclists and PAD patients. Using a multiplex qPCR screening, we detected a total of 179 microRNAs overall, of which, on average, 161 microRNAs were detected per sample. However, only 30 microRNAs were consistently expressed in all samples. Of these, two microRNAs, miR-29a-3p and miR193a-5p, that responded differently two different types of exercise, namely exhaustive exercise and non-exhaustive endurance exercise. Using individual rt/qPCR, we also identified a snoRNA, SNORD114.1, which was significantly upregulated in plasma in response to endurance exercise. Furthermore, two microRNAs, miR-29a-3p and miR-495-3p, were significantly differentially expressed in athletes compared to PAD patients, but only following exercise. We suggest that these two microRNAs could function as markers of impaired muscle repair and recovery. In conclusion, microRNAs miR-29a-3p and miR-193a-5p may help us distinguish between repeated exhaustive and non-exhaustive endurance exercise. MicroRNA miR-29a-3p, as well as miR-495-3p, may further mark impaired muscle recovery in patients with severe critical limb ischemia. Furthermore, we showed for the first time that a circulating snoRNA, SNORD114.1, is regulated in response to exercise and may be used as biomarker.

Correction to: Percutaneous Deep Venous Arterialization for Severe Critical Limb Ischemia in Patients With No Option of Revascularization: Early Experience From Two European Centers.

The fifth author's name was incorrectly published as "M. Messas". The correct name is "E. Messas". The original article has been corrected.

Percutaneous Deep Venous Arterialization for Severe Critical Limb Ischemia in Patients With No Option of Revascularization: Early Experience From Two European Centers.

To report our initial experience of fully percutaneous deep venous arterialization (pDVA) for the treatment of chronic critical limb ischemia (cCLI) after failed distal angioplasty. pDVA was performed in five consecutive patients by creating an arteriovenous fistula (AVF) between a below the knee artery and its satellite deep vein. In this early experience, only patients with failed prior interventional attempts at establishing flow with no distal targets for an arterial bypass were selected. Early technical success was defined as successful AVF creation and retrograde venous perfusion of the wound site. Patient demographics, procedural details, morbidity/mortality and wound healing outcomes were assessed prospectively. Patients were followed up in wound care centers, and graft patency was documented on duplex ultrasound. All five consecutive patients (mean age 58years) underwent successful pDVA without any procedural complications. There were neither 30-day major adverse limb events nor major cardiovascular complications. Three out of the five patients (60%) had clinical improvement as observed by resolution of rest pain and complete wound healing. At the 1-month FU, one patient died and one patient received a major amputation. The median wound healing time was 39weeks. pDVA is a safe and feasible vascularization alternative in patients with end-stage/no-option CLI. The early experience highlights the need for a multidisciplinary approach including a dedicated wound care service.

Critical limb ischaemia and the response to bone marrow-derived cell therapy according to tcPO2 measurement.

Cell therapy is an emerging potential biotherapy for critical limb ischaemia (CLI) patients who are not eligible for revascularization. However, the findings on this technique's efficacy are inconsistent. Trials investigating this topic focused on the more severe CLI patients who were often beyond any therapy. Therefore, identifying those who may truly benefit from cell transplantation is now warranted. To this end, we studied the prognostic value of tcPO2 for major amputation after 1 year in patients treated with bone marrow-derived cells. CLI patients ineligible for revascularization were included in a cell-therapy pilot study. On inclusion, patients underwent tcPO2 measurement in supine and sitting positions. For a tcPO2 < 10 mmHg in the supine position, the vascular reserve was defined by tcPO2 > 30 mmHg in the sitting position. Patients were administered intramuscular injections of mononuclear cells derived from aspirated bone marrow. In total, 25 patients (a lower limbs) were included for analysis. At inclusion, 11 lower limbs had tcPO2 at rest > 10 mmHg, and 16 lower limbs had a tcPO2 < 10 mmHg. The success probability for cell therapy was 0.79 (95 % CI 0.38-0.94) and 0.44 (95 % CI 0.18-0.67), respectively (p = 0.1). Of the 16 limbs with tcPO2 < 10 mmHg, the success rate was considerably higher in patients demonstrating a tcPO2 increase in a sitting position of over 30 mmHg (6/8, success probability 0.71, 95 % CI 0.26-0.92) compared to those without (2/8, success probability 0.15, 95 % CI 0.01-0.48, p = 0.03). For patients with chronic CLI for whom cellular therapy is a therapeutic option, a tcPO2 < 10 mmHg at rest, without vascular reserve (i. e. < 30 mmHg when sitting), is a prognostic indicator for poor outcome. .

Clinical effects of single or double tibial artery revascularization in critical limb ischemia patients with tissue loss

ObjectiveThe achievement of single vessel inflow to the wound is an acceptable end point of peripheral vascular intervention for patients with critical limb ischemia (CLI) with tissue loss. However, CLI patients often have multitibial artery lesions. We evaluated the clinical effects of single or double tibial artery revascularization for CLI patients. MethodsThis study was conducted retrospectively in a single center. Between April 2007 and January 2015, we treated 123 CLI patients (137 limbs) who had lesions in both the anterior tibial artery and the posterior tibial artery. Of these, single tibial artery (anterior or posterior tibial artery) revascularization was performed in 84 limbs (group S) and double tibial artery (both anterior and posterior tibial arteries) revascularization was performed in 53 limbs (group D). ResultsThe wound healing rate was significantly higher (87% vs 79%; P = .003), the time to wound healing was shorter (median, 83 vs 142 days; P = .01), and the repeat peripheral vascular intervention rate was lower (15% vs 35%; P = .03) in group D than in group S. The wound healing rate was nearly similar between the 2 groups in patients with a low clinical stage as assessed by Society for Vascular Surgery Wound, Ischemia, and foot Infection (90% in group D vs 93% in group S; P = .20); however, the wound healing rate was significantly higher in group D in patients with a high clinical stage (85% vs 72%; P = .007). ConclusionsThe achievement of double vessel inflows to the wound by double tibial artery revascularization positively affects wound healing, particularly in severe CLI patients.

Successful endovascular treatment for thrombotic in-stent iliac occlusion with in-house-devised optimo®-Like embolic protection system

Introduction: In practical settings of endovascular treatment,wesometimes encounter difficulties in treating lesions with massive thrombi, which may cause distal thromboembolism. Case Presentation: We encountered a case of severe critical limb ischemia involving in-stent iliac occlusion with massive thrombi. We had to overcome the critical issue of how to treat the massive thrombi in the iliac artery while avoiding thromboembolism. Therefore, we devised a very simple but possibly very useful protection system without any special devices based on the concept of the Optimo® balloon-tipped occlusion catheter. Conclusions: Although various endovascular treatment (EVT) devices and techniques have since been developed, little tips and tricks during EVT procedures are sometimes markedly useful.

Conservative Treatment in Selected Patients with Severe Critical Limb Ischemia

To assess the outcome of conservative treatment of severe critical limb ischemia (CLI) classified as Rutherford 5/6. The preferred therapy for CLI is either endovascular revascularization or bypass surgery. With a growing aged population with more serious comorbidities, these therapies are not always a viable option. Primary amputation leads to decreased mobility and a reduced quality of life. There is a lack of literature regarding the outcome of conservative therapy. Hospital charts were reviewed of all patients who were diagnosed with Rutherford classification 5-6 and received conservative treatment and lacked interventional options. Outcome measures were mortality, complete wound closure, and limb salvage rate. 38 patients were included with a median age of 80 years (range 57-97). The amputation rate during follow-up was 16%. In 58% of patients, complete wound closure was achieved. All-cause mortality was 58% with a 2-year survivability rate of 55%. Conservative management in our selected patients with CLI results in a moderate rate of wound closure and acceptable amputation rates albeit with a high mortality rate. For patients not eligible for endovascular revascularization or bypass surgery, conservative treatment could be a viable option besides primary limb amputation.

Multilevel Bypass Grafting: Is it Worth it?

Traditionally, multilevel arterial disease has been treated with an inflow procedure only but simultaneous multilevel bypass graft procedures have been attempted. However, these procedures are potentially high risk. We report our single-center experience of performing multilevel bypass grafts over the last 15years. We retrospectively identified patients undergoing simultaneous aortoiliac and infrainguinal bypasses between January 1996 and January 2011 at a single district general hospital. There were 32 multilevel procedures performed. Indication for surgery was acute ischemia in 10 (31.3%), critical ischemia without tissue loss in 10 (31.3%), with tissue loss in 10 (31.3%), and claudication in 2 (6.3%). In 23 (71.9%) cases inflow was restored using a direct iliofemoral or aortofemoral reconstruction. In the remaining 9 (28.1%), an extra-anatomic bypass was constructed. Two (6.3%) patients died within 30days of surgery. Twenty-nine (90.6%) patients survived to discharge. Twenty-eight patients (87.5%) were alive 1 year after surgery. Limb salvage was 96.9%, 85.7%, and 75.9% at 30days, 1year, and 5years, respectively. Twelve (37.5%) patients required a total of 19 further ipsilateral vascular procedures. Our results demonstrate that multilevel bypass procedures can be performed with good long-term outcomes and acceptable mortality, in what is typically a high-risk group with extensive comorbidities. In patients with severe critical limb ischaemia and tissue loss, who have a combination of aortoiliac and infrainguinal disease, there are significant benefits to a primary multilevel grafting procedure.

Therapeutic Approach to CLI with Tissue Loss—A Comparative Prospective Cohort Study in Finland and Japan

To compare the demographics, chosen treatment options, and 1-year outcome of patients with severe critical limb ischemia (Fontaine IV) in 2 different patient cohorts. A total of 118 consecutive patients with an ischemic tissue lesion in a lower extremity referred for the first time to the vascular surgery outpatient clinic of Helsinki University Hospital and 96 patients referred to the Division of Vascular Surgery of the Tokyo Medical and Dental University Hospital were included in this comparative analysis. Kaplan-Meier estimates were used to assess survival, leg salvage, and amputation-free survival (AFS). Propensity score analysis was used to adjust for differences between the study groups. The median age of the study cohorts was greater in Finland than in Japan (80 vs. 69 years, P < 0.001). The prevalence of coronary artery disease and hypertension were greater in the Finnish cohort (72% vs. 41%, P < 0.001 and 86% vs. 51%, P < 0.001, respectively). The prevalence of male gender (77% vs. 42%, P < 0.001), cerebrovascular disease (35% vs. 20%, P = 0.015), end-stage renal disease (35% vs. 5%, P < 0.001), and current smoking (64% vs. 21%, P < 0.001) was greater in the Japanese cohort. The prevalence of diabetes did not differ between the cohorts (52% vs. 47%, P = 0.286). The proportion of independently ambulant patients at referral was greater in Finland (80% vs. 54%, P < 0.001). In Helsinki and Tokyo, the initial treatment was bypass, an endovascular procedure, conservative treatment, and amputation in 42% vs. 41%, 24% vs. 14%, 24% vs. 41%, and 10% vs. 5% of the cases, respectively. One-year survival, leg salvage, and AFS were 65% vs. 71% (P = 0.326), 82% vs. 74% (P = 0.216), and 59% vs. 55% (P = 0.573) in the Finnish and Japanese cohorts, respectively. AFS was significantly better in ambulant than in nonambulant patients in the combined data (68% vs. 36%, P < 0.001). Adjusted propensity score analysis showed no statistical difference in survival between the study cohorts. The pattern of comorbid conditions in these 2 patient cohorts is significantly different, but the outcome did not differ significantly between cohorts.

Sequential Compression Biomechanical Device Versus Primary Amputation in Patients With Critical Limb Ischemia

Patients with critical limb ischemia (CLI), who are unsuitable for intervention, face the consequence of primary amputation. Sequential compression biomechanical device (SCBD) therapy provides a limb salvage option for these patients. To assess the outcome of SCBD in patients with severe CLI who are unsuitable for revascularization. Primary end points were limb salvage and 30-day mortality. From 2005 to 2012, 189 patients with severe CLI were not suitable for revascularization. In all, 171 joined the SCBD program. We match controlled 75 primary amputations. All patients were Rutherford category 4 or higher. Sustained clinical improvement was 68% at 1 year. Mean toe pressure increased from 19.9 to 35.42 mm Hg, P < .0001. Mean popliteal flow increased from 35.44 to 55.91 cm/sec, P < .0001. The 30-day mortality was 0.6%. Limb salvage was 94% at 5 years. Freedom from major adverse clinical events was 62.5%. All-cause survival was 69%. Median cost of managing a primary amputation patient is €29,815 compared to €3,985 for SCBD. We treated 171 patients with artassist at a cost of €681,965. However, primary amputation for 75 patients cost €2,236,125. The SCBD therapy is a cost-effective and clinically effective solution in patients with CLI having no option of revascularization. It provides adequate limb salvage while providing relief of rest pain without any intervention.

Sequential compression biomechanical device in patients with critical limb ischemia and nonreconstructible peripheral vascular disease

Critical limb ischemia (CLI) patients who are unsuitable for intervention face the dire prospect of primary amputation. Sequential compression biomechanical device (SCBD) therapy provides a limb salvage option for these patients. This study assessed the outcome of SCBD in severe CLI patients who otherwise would face an amputation. Primary end points were limb salvage and 30-day mortality. Secondary end points were hemodynamic outcomes (increase in popliteal artery flow and toe pressure), ulcer healing, quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TwiST), and cost-effectiveness. From 2004 to 2009, we assessed 4538 patients with peripheral vascular disease (PVD). Of these, 707 had CLI, 518 underwent intervention, and 189 were not suitable for any intervention. A total of 171 patients joined the SCBD program for 3 months. All patients were Rutherford category ≥4. Median follow-up was 13 months. Mean toe pressure increased from 39.9 to 55.42 mm Hg, with a mean difference in toe pressure of 15.49 mm Hg (P = .0001). Mean popliteal flow increased from 35.44 to 55.91 cm/s, with mean difference in popliteal flow of 20.47 cm/s (P < .0001). Mortality at 30 days was 0.6%. Median amputation-free survival was 18 months. Limb salvage at 3.5 years was 94%. Freedom from major adverse clinical events (MACE) at 4.5 years was 62.5%. We treated 171 patients with SCBD at a cost of €681,948, with an estimated median per-patient cost of treatment with SCBD of €3988. SCBD therapy is a cost-effective and clinically efficacious solution in CLI patients with no option of revascularization. It provides adequate limb salvage and ameliorated amputation-free survival while providing relief of rest pain without any intervention.

Beneficial Effects of VEGF Secreted from Stromal Cells in Supporting Endothelial Cell Functions: Therapeutic Implications for Critical Limb Ischemia

Critical limb ischemia (CLI) is the end stage of peripheral vascular disease (PVD). One third of CLI patients progresses to leg amputation with high associated morbidity and mortality. In no-option patients with end-stage critical limb ischemia, bone marrow cell transplantation has shown promising results, improving leg perfusion to the level of reducing major amputations and allowing limb salvage. We recently reported the successful application of an innovative protocol based on repeated autologous bone marrow cell transplantation, which resulted in an effective and feasible strategy for achieving long-term revascularization in patients with severe CLI. In an effort to understand the clinical benefit provided by stem cells therapy in patients with CLI, we characterized the marrow-derived stromal cells of CLI patients and we provided a correlation between the in vitro features of these cells and the clinical follow up at 12 months. We showed that cells derived from CLI patients had a reduced capacity to proliferate, adhere, and migrate, but that they stimulated proliferation and migration of endothelial cells through the release of VEGF-A, supporting the idea that the paracrine mechanisms underpinned the biological effects of long-term angiogenesis in CLI patients.

Successful Bone Marrow Transplantation Reveals the Lack of Endothelial Progenitor Cells Mobilization in a Patient With Critical Limb Ischemia: A Case Report

Restoring blood flow to ischemic tissue is a prerequisite for treatment of ischemic diseases. Cell-based therapy based on bone marrow transplantation is a promising option for patients with critical limb ischemia (CLI). The efficacy of cell therapies to augment neovascularization seems to involve endothelial progenitor cells (EPCs); however, the mechanisms underlying the efficacy have not been fully elucidated. Herein we have described the case of a young patient with severe CLI, who experienced a 24-month beneficial clinical response to autologous bone marrow transplantation. The exceptional amelioration enabled him to perform standardized maximal treadmill exercise test that demonstrated lack of exercise-induced EPC mobilization, despite adequate stromal-derived factor 1 and vascular endothelial growth factor responses. Therefore, tissue ischemia is not sufficient to promote the recruitment of EPCs that have been demonstrated to be involved in the recovery from ischemia. The local implantation of marrow-derived elements may provide cells and/or trophic factors, which have the capacity to augment angiogenesis, opening new approaches to the etiopathogenesis of the disease.