No-option Critical Limb Ischemia Patients Research Articles

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.

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.

Duplex and Angiographic-Assisted Evaluation of Outcomes of Endovascular Embolization after Surgical Deep Vein Arterialization for the Treatment No-Option Critical Limb Ischemia Patients.

To report early and mid-term outcomes of the arterialization of the deep venous system in no-option critical limb-threatening ischemia (CLTI) using duplex ultrasound and angiographic evaluation to improve limb perfusion. A single-center prospective study of patients with no-option CLTI treated with hybrid surgical arterialization of the deep venous circulation and staged endovascular embolization of the venous collateral. Embolization was performed using a controlled-release spiral, within two weeks after bypass surgery. Patients were assessed for clinical status, wound healing, median transcutaneous partial pressure of O2 (TcPO2), and post-operative duplex ultrasound evaluating peak systolic velocity (PSV), end diastolic velocity (EDV), and resistance index (RI) to assess foot perfusion and bypass features. Primary endpoint analysis was primary technical success, limb salvage, patency rates, and clinical improvement. Secondary endpoints were 30-day and long-term mortality, major cardiovascular events (MACE), including myocardial infarction or stroke, and serious adverse events (SAE). Five patients with no-option CLTI were treated at our center using the hybrid deep vein arterialization technique. Clinical stage was grade 3 in one patient and grade 4 in the remaining four. Mean age was 65.8 years (range 49-76 years), and two patients were affected by Buerger's disease. Primary technical success was achieved in all patients, and all the bypasses were patent at the angiographic examination. At 30-day and at average follow-up of 9.8 months (range 2-24 months), mortality, major cardiovascular events (MACE), and serious adverse events (SAE) were not reported, with a primary patency and limb salvage rates of 100%. Three patients required minor amputation. Clinical improvement was demonstrated in all patients with granulation, resolution of rest pain, or both. Median TcPO2 values rose from 10 mm Hg (range 4-25) before the procedure to 35 (range 31-57) after surgery, and to 59 mm Hg (range 50-76) after the staged endovascular procedure. In our initial experience, the arterialization of the deep venous circulation, with subsequent selective embolization of the venous escape routes from the foot, seems a feasible and effective solution for limb salvage in patients with no-option CLTI and those in the advanced wound, ischemia, and foot infection (WIfI) clinical stage.

Characteristics and Outcome for Persons with Diabetic Foot Ulcer and No-Option Critical Limb Ischemia.

The study aimed to evaluate clinical and vascular characteristics, as well as outcomes, for diabetic persons with foot ulceration and no-option critical limb ischemia (CLI). The study group included a sample of patients admitted to our diabetic foot unit because of a new diabetic foot ulcer and CLI. All subjects were managed using a limb salvage protocol which includes lower-limb revascularization. According to whether or not the revascularization procedure was a success, patients were respectively divided into two groups: successfully treated CLI patients (ST-CLI) and no-option CLI patients (NO-CLI). Failed revascularization was considered in the case of technical recanalization failure of occluded vessels (inability to overcome the obstruction) and/or absence of arterial flow to the foot. Limb salvage, major amputation, and death after 1 year of follow-up were evaluated and compared between the two groups. Overall, 239 patients were included, 74.9% belonging to ST-CLI and 25.1% to NO-CLI. NO-CLI patients reported more cases of ischemic heart disease (80 vs. 62.1, p = 0.008), heart failure (63.3 vs. 32.4%, p < 0.0001), and end-stage renal disease (ESRD) (60 vs. 25.7%) than ST-CLI patients. In addition, more vessels were affected in the NO-CLI group (5.2 ± 1.6 vs. 4 ± 1.5, p < 0.0001), and there was more involvement of tibio-peroneal trunk (50 vs. 30.2%, p = 0.006), anterior tibial (93.3 vs. 82.7, p = 0.03), posterior tibial (93.3 vs. 73.7%, p = 0.0005), peroneal (70 vs. 48%, p = 0.002), and below-the-ankle arteries (73.3 vs. 39.1%, p < 0.0001) than ST-CLI. The 1 year outcomes for the whole population were 69.9% limb salvage, 10.9% major amputation, and 19.2% death. The outcomes for NO-CLI and ST-CLI were, respectively, as follows: limb salvage (13.8 vs. 73.4%, p < 0.0001), amputation (30 vs. 4.5%, p = 0.0001), and mortality (50 vs. 8.9%, p < 0.0001). NO-CLI patients showed a more severe pattern of peripheral arterial disease (PAD) with distal arterial lesions and worse outcomes than ST-CLI.

Peripheral Arterial Disease in Persons with Diabetic Foot Ulceration: a Current Comprehensive Overview.

In developed countries, the prevalence of persons with diabetes and peripheral arterial disease (PAD) is approximately 50%. The presence of PAD is associated with non-healing ulcers, major amputation, cardiovascular morbidity, and mortality. It is estimated that persons with diabetes, foot ulceration and PAD have 50% of 5-years mortality rate. Therefore, subjects with ischemic diabetic foot ulcers (DFUs) should be considered a special group of patients with specific clinical characteristics, general health status and prognosis. In persons with ischemic DFUs, an early diagnosis and treatment are mandatory to reduce the risk of worse outcomes such as major amputation. Revascularization of occluded lower extremity arteries is the main treatment to restore blood flow in the foot and promote wound healing. Nonetheless, there are several unmet needs in the management of diabetic subjects with PAD and foot ulceration as medical therapy, diagnostic criteria and indications for revascularization, revascularization strategy and technical approach as well as the management of no-option critical limb ischemia patients. It is a common opinion that there is an evolution of PAD features in diabetic persons, which seems to present a more aggressive pattern. This may be related to the frequent presence of concomitant comorbidities such as renal failure which could influence the characteristics of atherosclerotic plaques and their distribution. The aim of this review is to commence a complete overview and state of the art in the treatment of patients with diabetes, PAD, and foot ulceration and to describe the current challenges and future perspectives.

P4710Impact of therapeutic angiogenesis using autologous bone marrow-derived mononuclear cells implantation in critical limb ischemia with collagen disease

Abstract Background Many patients with collagen disease (CD), particularly systemic sclerosis (SSc) and collagen disease-associated vasculitis (CDV), develop critical limb ischemia (CLI) which leads to limb amputation. In SSc vasculopathy, intimal hyperplasia, abnormal vascular contraction, and intravascular micro thrombus due to autoimmune abnormalities are main causes of inadequate blood supply that lead to the development of CLI. Moreover, in CDV, presence of inflammation cells infiltrates and destruction of the vascular wall also lead to vascular stenosis or obstruction. However, conventional therapies including revascularization via surgical bypass showed poor outcomes in CLI patients with CD. Therefore, establishment of new methods to improve peripheral circulation for limb salvage are required. Purpose After discovering that circulating endothelial progenitor cells (EPCs) mobilized from the bone marrow participate in postnatal neovascularization, autologous bone marrow-derived mononuclear cells (BM-MNCs) has been performed as a new treatment for many no-option CLI patients caused by arteriosclerosis obliterans, thromboangiitis obliterans or CD. In this study, we would like to assess the long-term clinical outcomes after autologous BM-MNCs implantation in CLI patients with SSc and CDV. Methods This study was a retrospective, multicenter, observational, and non-controlled study. We assessed no-option CLI patients with CD who were performed the autologous BM-MNCs implantation in 10 institutes. Overall survival (OS), major-amputation-free (MAF) and amputation-free survival (AFS) rates were primary endpoints of this study. In addition, we assessed improvements of ischemic pain as visual analogue scale (VAS) scores. Safety endpoints were defined as cardiovascular events and all-cause adverse events within 6 months after implantation. Results A total of 69 patients (39 with SSc–related diseases (SSc group) and 30 with CDV (CDV group)), were included in this study. The median follow-up duration was 36.5 months. The 10-year OS rate was 59.1% in the SSc group and 82.4% in the CDV group, respectively. The 10-year MAF rates were 97.4% and 82.6%, respectively. The 10-year AFS rates were 57.6% and 67.8%, respectively (Figure 1). The number of major or minor amputations in the SSc group trended to be less than that in the CDV group. In addition, significant improvement in VAS scores were observed in both groups (Figure 2). No patients died, no cardiovascular events, and no severe adverse events associated with BM-MNCs implantation were noted within 6 months after this therapy in both groups. Figure 1 Conclusions The BM-MNCs implantation may be feasible in no-option CLI patients with CD. Improvement of ischemic symptoms by BM-MNCs implantation was significant in both groups and, in the SSc group, limb salvage rate tended to be higher than the CDV group.

Impact of Therapeutic Angiogenesis Using Autologous Bone Marrow-Derived Mononuclear Cells Implantation in Critical Limb Ischemia With Scleroderma - Subanalysis of the Long-Term Clinical Outcomes Survey.

Many patients with collagen disease (CD), particularly scleroderma (SSc), develop critical limb ischemia (CLI), which leads to limb amputation. However, conventional therapies, including revascularization via surgical bypass, showed poor outcomes in CLI patients with CD. Many CLI patients with SSc showed poor responses to combination therapies including intravenous iloprost, PDE-5 inhibitors, and bosentan. Therefore, new methods of improving the peripheral circulation for limb salvage are required. This study was a subanalysis of the long-term clinical outcomes after autologous bone marrow-derived mononuclear cells (BM-MNC) in CLI patients with SSc. Methods and Results: We assessed no-option CLI patients with CD who underwent BM-MNC implantation at 10 institutes; 69 patients (39 with SSc-related diseases (SSc group) and 30 with other CDs (non-SSc group)), were included. The median follow-up duration was 36.5 months. The 10-year overall survival rate was 59.1% in the SSc group and 82.4% in the non-SSc group. The 10-year major amputation-free rates were 97.4% and 82.6%, respectively. The number of major or minor amputations in the SSc group trended to be less than that in the non-SSc group. Significant improvements in visual analog scale scores were observed in both groups. The BM-MNC implantation may be feasible in no-option CLI patients with CD. In the SSc group, limb salvage rate tended to be higher than in the non-SSc group.

TCT-367 First Report Showing the Very Long-term Outcomes of Therapeutic Angiogenesis Using Bone Marrow-derived Mononuclear Cell Therapy in No-option Critical Limb Ischemia Patients With Scleroderma

Many patients with critical limb ischemia (CLI) require limbs amputation when conventional therapeutic options fail or are not indicated, particularly patients with collagen disease-associated vasculitis (CDV). Augmenting new blood vessel formation is an important way to salvage ischemic tissue.

Efficacy and Safety of Autologous Cell-based Therapy in Patients with No-option Critical Limb Ischaemia: A Meta-Analysis.

Revascularisation therapy is the current gold standard of care for critical limb ischemia (CLI), although a significant proportion of patients with CLI either are not fit for or do not respond well to this procedure. Recently, novel angiogenic therapies such as the use of autologous cellbased therapy (CBT) have been examined, but the results of individual trials were inconsistent. To pool all published studies that compared the safety and efficacy of autologous CBT derived from different sources and phenotypes with non cell-based therapy (NCT) in CLI patients. We searched Medline, Embase, Cochrane Library and ClinicalTrials.gov from 1974-2017. Sixteen randomised clinical trials (RCTs) involving 775 patients receiving the following interventions: mobilised peripheral blood stem cells(m-PBSC), bone marrow mononuclear cells(BM-MNC), bone marrow mesenchymal stem cells(BM-MSC), cultured BM-MNC(Ixmyelocel-T), cultured PB cells(VesCell) and CD34+ cells were included in the meta-analysis. High-quality evidence (QoE) showed similar all-cause mortality rates between CBT and NCT. AR reduction by approximately 60% were observed in patients receiving CBT compared to NCT (moderate QoE). CBT patients experienced improvement in ulcer healing, ABI, TcO2, pain free walking capacity and collateral vessel formation (moderate QoE). Low-to-moderate QoE showed that compared to NCT, intramuscular BM-MNC and m-PBSC may reduce amputation rate, rest pain, and improve ulcer healing and ankle-brachial pressure index, while intramuscular BM-MSC appeared to improve rest pain, ulcer healing and pain-free walking distance but not AR. Efficacy of other types of CBT could not be confirmed due to limited data. Cell harvesting and implantation appeared safe and well-tolerated with similar rates of adverse-events between groups. Implantation of autologous CBT may be an effective therapeutic strategy for no-option CLI patients. BM-MNC and m-PSBC appear more effective than NCT in improving AR and other limb perfusion parameters. BM-MSC may be beneficial in improving perfusion parameters but not AR, however, this observation needs to be confirmed in a larger population of patients. Generally, treatment using various sources and phenotypes of cell products appeared safe and well tolerated. Large-size RCTs with long follow-up are warranted to determine the superiority and durability of angiogenic potential of a particular CBT and the optimal treatment regimen for CLI.

Long-Term Clinical Outcomes Survey of Bone Marrow-Derived Cell Therapy in Critical Limb Ischemia in Japan.

The Therapeutic Angiogenesis by Cell Transplantation (TACT) trial demonstrated the efficacy and safety of autologous bone marrow-derived mononuclear cells (BM-MNCs) in patients with critical limb ischemia (CLI). The present study aimed to assess the long-term clinical outcomes of therapeutic angiogenesis using autologous BM-MNC implantation under advanced medical treatment in Japan.Methods and Results:The study was retrospective, observational, and non-controlled. We assessed no-option CLI patients who had BM-MNC implantation performed in 10 institutes. Overall survival (OS), major amputation-free (MAF), and amputation-free survival (AFS) rates were primary endpoints of this study. The median follow-up duration was 31.7 months. The 10-year OS rate was 46.6% in patients with arteriosclerosis obliterans (ASO) (n=168), 90.5% in patients with thromboangiitis obliterans (TAO) (n=108), and 67.6% in patients with collagen disease-associated vasculitis (CDV) (n=69). The 10-year MAF rate was 70.1%, 87.9%, and 90.9%, respectively. The 10-year AFS rate was 37.8%, 80.9%, and 61.2%, respectively. Major adverse cardiovascular events occurred in 6.0% of patients with ASO, 1.9% of patients with TAO, and no patients with CDV. Therapeutic angiogenesis using autologous BM-MNC implantation may be feasible and safe in patients with no-option CLI, particularly those with CLI caused by TAO or CDV.

Safety and Effectiveness of Bone Marrow Cell Concentrate in the Treatment of Chronic Critical Limb Ischemia Utilizing a Rapid Point-of-Care System.

Critical limb ischemia (CLI) is the end stage of lower extremity peripheral vascular disease (PVD) in which severe obstruction of blood flow results in ischemic rest pain, ulcers and/or gangrene, and a significant risk of limb loss. This open-label, single-arm feasibility study evaluated the safety and therapeutic effectiveness of autologous bone marrow cell (aBMC) concentrate in revascularization of CLI patients utilizing a rapid point-of-care device. Seventeen (17) no-option CLI patients with ischemic rest pain were enrolled in the study. Single dose of aBMC, prepared utilizing an intraoperative point-of-care device, the Res-Q™ 60 BMC system, was injected intramuscularly into the afflicted limb and patients were followed up at regular intervals for 12 months. A statistically significant improvement in Ankle Brachial Index (ABI), Transcutaneous Oxygen Pressure (TcPO2), mean rest pain and intermittent claudication pain scores, wound/ ulcer healing, and 6-minute walking distance was observed following aBMC treatment. Major amputation-free survival (mAFS) rate and amputation-free rates (AFR) at 12 months were 70.6% and 82.3%, respectively. In conclusion, aBMC injections were well tolerated with improved tissue perfusion, confirming the safety, feasibility, and preliminary effectiveness of aBMC treatment in CLI patients.

Phase II Clinical Trial of CD34+ Cell Therapy to Explore Endpoint Selection and Timing in Patients With Critical Limb Ischemia

A prior phase I/IIa clinical trial provided evidence for safety, feasibility and potential efficacy of i.m. injection of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ cells in patients with critical limb ischemia (CLI). A phase II trial of CD34+ cell therapy was conducted in patients with CLI to explore endpoint selection and timing. No-option CLI patients (n=11) underwent i.m. transplantation of G-CSF-mobilized CD34+ cells isolated by magnetic sorting. Ischemic rest pain scales improved from week 2 vs. baseline (P<0.05). Skin perfusion pressure (P=0.0175), transcutaneous partial oxygen pressure (P=0.0446) and pain-free walking distance (P=0.0056) improved from week 2, total walking distance from week 8 (P=0.0182) and toe brachial pressure index from week 12 (P=0.0174) vs. baseline. These parameters peaked at week 36 or 52. Rutherford's category improved from week 24 vs. baseline (P=0.0065). CLI-free ratio serially increased and peaked (85.7%) at week 36. Serial change in Rutherford's category correlated with that in Rest Pain Scale (P=0.0374), but not with that in any physiological parameters. Ischemic rest pain scales and physiological parameters improved relatively early after cell therapy, then plateaued later accompanied by recovery from the CLI state. Rutherford's category and CLI-free ratio at week 36 or later may be suitable endpoints in cell therapy clinical trials for CLI. Functional parameters should be evaluated independently of such clinical endpoints for ischemia severity. ( URL: https://dbcentre3.jmacct.med.or.jp/jmactr/Default.aspx. Unique identifier: JMA-IIA00022)

Effect of Autologous Transplantation of Bone Marrow Cells Concentrated With the MarrowXpress System in Patients With Critical Limb Ischemia

Critical limb ischemia (CLI), a vascular disease affecting lower limbs, with high morbidity and mortality, is becoming a challenge due to the aging of the population. Patients without direct revascularization options have the worst outcomes. To date, 25% to 40% of CLI patients are not candidates for surgical or endovascular approaches, facing a major amputation as the ultimate option. This study sought to assess the safety and efficacy of transplantation of autologous bone marrow concentrates in “no-option” patients to restore blood perfusion by collateral flow and limb salvage. We performed a nonrandomized, noncontrolled pilot study for no-option CLI patients using intra-arterial infusion of autologous bone marrow concentrate. Variation of blood perfusion parameters, evaluated by laser doppler flowmetry after 6 and 12 months, was set as primary endpoint. Thirteen enrolled patients showed improvements in objective measurements of perfusion. This uncontrolled study provided evidence that transplantation of autologous bone marrow concentrates was well tolerated by CLI patients without significant adverse effects, demonstrating improved perfusion, confirming the feasibility and safety of the procedure.

Stem Cell Therapy in PAD

Critical limb ischemia (CLI) continues to form a substantial burden on Western health care. Despite recent advances in surgical and radiological vascular techniques, a large number of patients is not eligible for these revascularisation procedures and faces amputation as their ultimate treatment option. Growth factor therapy and stem cell therapy – both therapies focussing on augmenting postnatal neovascularisation – have raised much interest in the past decade. Based on initial pre-clinical and clinical results, both therapies appear to be promising strategies to augment neovascularisation and to reduce symptoms and possibly prevent amputation in CLI patients. However, the underlying mechanisms of postnatal neovascularisation are still incompletely understood. Both fundamental research as well as large randomised trials are needed for further optimisation of these treatment options, and will hopefully lead to needed advances in the treatment of no-option CLI patients in the near future.

Use of a non-specific immunomodulation therapy as a therapeutic vasculogenesis strategy in no-option critical limb ischemia patients

Background/aimsInflammatory mediators contribute to the impairment of vasculogenesis by reducing endothelial progenitor cells (EPCs) mobilization in atherosclerotic vasculopathy.We tested the hypothesis that administration of an oxygen/ozone mixture (IMT) might counteract this pathophysiological mechanism and enhance limb tissue perfusion in patients with critical limb ischemia (CLI). MethodsRandomized patients with rest pain or ischemic ulcers and transcutaneous oxygen tension (TcPO2) <40mmHg and/or toe pressure <50mmHg received placebo (n=74) or a non-specific immunomodulation therapy (IMT) (n=77), autologous blood exposed to oxygen/ozone gas mixture by intragluteal injection, on day 1, 2, 7, and once a week thereafter for at least 22 weeks. Patients were evaluated for changes in TcPO2, levels of circulating EPCs (CD34/KDR-positive cells) and inflammation (tumor necrosis factor-α—TNF-α). ResultsTcPO2 and CD34/CD133-positive cells increased at 22 weeks in IMT group (P<0.01) whereas no changes were observed in placebo group. TNF-α levels decreased at 6 months in IMT group (P<0.001) whereas no changes were observed in placebo group. There was a strong positive correlation between CD34/KDR-positive cells and TcPO2 (r=0.56, P<0.01). Moreover, there was an inverse correlation between CD34/KDR-positive cells and TNF-α (r=−0.51, P<0.01). ConclusionsIntramuscular injection of IMT may improve wound healing and limb salvage in patients with CLI.

Issue Highlights

HomeCirculationVol. 115, No. 10Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published13 Mar 2007https://doi.org/10.1161/circ.115.10.1177Circulation. 2007;115:1177REMOTE MAGNETIC NAVIGATION TO GUIDE ENDOCARDIAL AND EPICARDIAL CATHETER MAPPING OF SCAR-RELATED VENTRICULAR TACHYCARDIA, by Aryana et al.Catheter mapping of ventricular tachycardia is challenging because of tissue heterogeneity in diverse scar-related disease substrates as well as limitations in maneuverability and accessibility to critical regions of the ventricular endocardium and epicardium. In this issue of Circulation, Aryana and colleagues report their clinical results obtained by using a remote magnetic navigation system combined with electroanatomic mapping to identify areas of interest related to ventricular tachycardia, while using a limited amount of fluoroscopy exposure. Although the majority of epicardial and endocardial ventricular sites could be safely and effectively mapped remotely, because of current limitations of the magnetic navigation catheter, most patients required additional manual ablation using an irrigated catheter to ablate fully the ventricular tachycardia substrates. See p 1191.RENAL INSUFFICIENCY FOLLOWING CONTRAST MEDIA ADMINISTRATION TRIAL (REMEDIAL): A RANDOMIZED COMPARISON OF 3 PREVENTIVE STRATEGIES, by Briguori et al.Exposure to radiocontrast media can lead to transient and permanent renal failure in high-risk patients such as those with preexisting moderate or severe renal failure. Current methods to prevent contrast-induced nephrotoxicity include volume expansion with saline and limitation of contrast volume. Other strategies have been proposed, including N-acetylcysteine (NAC), sodium bicarbonate infusion, and ascorbic acid. The study by Briguori et al was a 2-center, randomized, double-blind study of 3 strategies to prevent contrast-induced nephrotoxicity in 326 patients with moderate chronic renal disease undergoing coronary or peripheral angiography. Moderate renal failure was defined as a creatinine concentration of 2 to 8 mg/dL. Patients were randomized to saline plus NAC, sodium bicarbonate infusion plus NAC, or saline plus ascorbic acid plus NAC. Contrast-induced nephropathy defined as an increase in creatinine concentration by 25% occurred in 9.9%, 1.9%, and 10.3%, respectively. The sodium bicarbonate infusion plus NAC produced significantly better results than the other regimens (P=0.019). Other measures of contrast-induced nephrotoxicity showed similar results. In addition, similar results were seen in high-risk subgroups such as those with diabetes. These findings support the use of volume expansion with sodium bicarbonate plus NAC as a more effective strategy in preventing contrast-induced nephrotoxicity than saline plus NAC or saline plus ascorbic acid and NAC. See p 1211.USE OF A CONSTITUTIVELY ACTIVE HYPOXIA-INDUCIBLE FACTOR-1α TRANSGENE AS A THERAPEUTIC STRATEGY IN NO-OPTION CRITICAL LIMB ISCHEMIA PATIENTS: PHASE I DOSE-ESCALATION EXPERIENCE, by Rajagopalan et al.Critical limb ischemia is a serious manifestation of peripheral atherosclerosis associated with limb loss in a considerable number of patients. Although surgery and percutaneous transluminal angioplasty may provide improvement in some patients, in others, amputation is the only option. Several systems in the body sense hypoxia, among them the hypoxia-inducible factor-1α. Such ischemia-sensing systems activate protective pathways in the body to limit tissue damage. In the study by Rajagolpalan et al, therefore, the authors tested whether a constitutively active transcription factor of hypoxia-inducible factor-1α transfected with an adenovirus would be safe and potentially ameliorate symptoms and improve outcome in patients with critical limb ischemia and no other options. No serious adverse events of this treatment were noted, but peripheral edema disease progression and ischemia were still common. In approximately half of the hypoxia-inducible factor-1α treated patients, however, complete pain resolution was noted at 1 year and ulcer healing in almost one third. Although very preliminary, this study suggests that this novel gene therapy approach in critical limb ischemia should be pursued further and may, if confirmed in larger studies, offer a treatment for those patients with no other options. See p 1234.Visit http://circ.ahajournals.org:Images in Cardiovascular MedicineHuge Pericardial Hemangioma Imaging. See p e315. Download figureDownload PowerPointCardiovocal Syndrome Associated With Huge Left Atrium. See p e318.Infarction-Like Electrocardiographic Changes Due to a Myocardial Metastasis From a Primary Lung Cancer. See p e320.CorrespondenceSee p e322. Previous Back to top Next FiguresReferencesRelatedDetails March 13, 2007Vol 115, Issue 10 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.115.10.1177 Originally publishedMarch 13, 2007 PDF download Advertisement

Use of a Constitutively Active Hypoxia-Inducible Factor-1α Transgene as a Therapeutic Strategy in No-Option Critical Limb Ischemia Patients

Critical limb ischemia, a manifestation of severe peripheral atherosclerosis and compromised lower-extremity blood flow, results in a high rate of limb loss. We hypothesized that adenoviral delivery of a constitutively active form of the transcription factor hypoxia-inducible factor-1alpha (ie, Ad2/HIF-1alpha/VP16 or HIF-1alpha) into the lower extremity of patients with critical limb ischemia would be safe and might result in a durable clinical response. This phase I dose-escalation program included 2 studies: a randomized, double-blind, placebo-controlled study and an open-label extension study. In total, 34 no-option patients with critical limb ischemia received HIF-1alpha at doses of 1x10(8) to 2x10(11) viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1alpha and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1alpha patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1alpha in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1alpha/VP16 (1x10(11) and 2x10(11) viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1alpha patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. HIF-1alpha therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.