Stage Of Peripheral Arterial Disease Research Articles

The association of malnutrition with mortality and amputation outcomes in critical limb ischemia: a systematic review

Abstract Introduction Critical limb ischemia (CLI) is a severe stage of peripheral arterial disease with high mortality. Malnutrition has been recognized as a potentially modifiable risk factor that may be prognostic of mortality and amputation outcomes in CLI. Great variability exists in the measurement of malnutrition including surrogate markers such as albumin level and body mass index (BMI) but also validated tools including geriatric nutritional risk index (GNRI) and controlling nutritional status (CONUT). Purpose To conduct a systematic review examining the association of malnutrition with mortality and amputation outcomes in patients with CLI. Methods A systematic literature search of AMED, CINAHL, Cochrane Library, Medline, Embase, Pubmed, Scopus, Web of Science, and Google Scholar was conducted through September 12, 2020. The review protocol was registered in PROSPERO. Only CLI patients were included. It was limited by adult human studies and those after 1982, when CLI was first defined. Eligible studies were randomized controlled trials, cohort studies, and case-control studies while case series, case reports, editorials, conference abstracts, and non-English studies were excluded. Malnutrition measured by albumin, BMI, or a validated malnutrition assessment tool was included. Outcomes of interest were mortality, any amputation, amputation free survival (AFS), major adverse limb events (MALE), major adverse cardiovascular events (MACE), or a composite of these. Two reviewers independently performed screening, data extraction, and quality assessment with a third independent reviewer resolving disagreements. Results 3290 initial studies were found. The final 33 eligible studies were from 7 countries published between 2002 to 2020. Of these 30 were retrospective cohort studies, three were prospective cohort studies, and none were randomized controlled trials. No studies were at serious or critical risk of bias by evaluation with ROBINS-I quality tool. The average sample size was 553 patients (range N=21–5110). The median age was 72 years and 67.1% were male. The prognostic association of malnutrition and outcomes varied by malnutrition tool used. Malnutrition as measured by the validated tools of GNRI and CONUT was associated with all mortality outcomes, except for GNRI and cardiovascular mortality. The malnutrition surrogate markers of albumin and BMI were only associated with mortality outcomes in 62.5–75% of results. The validated nutrition tools were also consistently prognostic of amputation outcomes in all results, whereas surrogate markers only in 62.5–67%. Overall malnutrition by validated tools was prognostic in 14/15 (93.3%) of results while surrogate markers in 29/42 (69%) of results. See table 1. Conclusion Malnutrition is prognostically associated with mortality and amputation outcomes in CLI. This association is most consistent when malnutrition is assessed by a validated tool. Funding Acknowledgement Type of funding sources: None.

Effects of semaglutide on functional capacity in patients with type 2 diabetes and peripheral arterial disease: rationale and design of the STRIDE trial

Abstract Background/Introduction Lower extremity peripheral arterial disease (PAD) is a severe form of atherosclerotic cardiovascular (CV) disease. The classical symptom is intermittent claudication (IC), associated with limited walking ability and poor health-related quality of life (QoL). Type 2 diabetes (T2D) is one of the leading causes of PAD; ∼30% of patients with PAD have T2D. While anti-atherosclerotic drugs and lifestyle changes are recommended, there are no effective drugs to specifically improve functional outcomes in PAD and T2D. Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved as an adjunct to diet and exercise for glycaemic control in patients with T2D. In the T2D SUSTAIN clinical trial programme, once-weekly (OW) subcutaneous semaglutide 0.5 and 1.0 mg was superior for glycaemic control and weight loss vs placebo and a range of approved antidiabetic drugs. In SUSTAIN 6, a dedicated CV outcomes trial, OW semaglutide resulted in a 26% reduction in three-point major adverse CV events (MACE) compared with placebo in patients with T2D at high CV risk, leading to its approval for MACE risk reduction in those with T2D and CV disease in the USA. Evidence suggests this may be partly attributable to the anti-inflammatory and anti-atherosclerotic effects of semaglutide, which may also apply to PAD. Purpose The STRIDE trial will demonstrate the effect of OW semaglutide 1.0 mg vs placebo on walking ability in patients with T2D and PAD with IC. Methods STRIDE is a 52-week, randomised, double-blind, placebo-controlled, phase 3b trial. Trial design and eligibility criteria are shown in the Figure; ∼800 patients will be randomised 1:1 to OW semaglutide 1.0 mg or placebo, both added to standard of care. The primary endpoint is change in maximum walking distance on a constant load treadmill test from baseline to week 52. Secondary confirmatory endpoints include changes in pain-free walking distance and PAD-specific, health-related patient-reported outcomes (Vascular QoL Questionnaire-6) from baseline to week 52. Results The trial started in October 2020 and is currently recruiting, with ∼120 sites in ∼20 countries across Asia, Europe, and North America. Conclusion STRIDE is the first and only dedicated PAD outcomes trial with a GLP-1RA and thus presents a unique trial design. While major adverse limb events typically occur in the later stages of PAD, STRIDE instead measures the effect of OW semaglutide on functional outcomes such as walking ability and QoL, which affect everyday living in patients with PAD and IC. STRIDE data will provide important clinical insights regarding the role of OW semaglutide in patients with T2D and PAD. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Novo Nordisk A/S

Acute and long-term outcomes of ST-elevation myocardial infarction in cancer patients

Abstract Background Myocardial infarctions (MI) and cancer are each very serious morbidities. To evaluate their interaction in the “real world”, a retrospective analysis was performed in patients with ST-elevation MI (STEMI) and pre-existing cancer. Methods Anonymized data from patients admitted to hospital between 2010 and 2017 due to STEMI were analyzed from 24 months before and up to nine years after the index hospitalization by one of Germany's largest statutory Health Insurance Funds (Allgemeine Ortskrankenkasse - AOK). Qualitative data were tested via two-sided Chi-squared test and quantitative data were tested using a two- sided Wilcoxon test. The eight year overall survival (OS) rate was determined with a Kaplan Meier estimator. The endpoint OS was analysed using multivariable Cox-regression model. Results From 175,262 STEMI patients, 27,213 had cancer (15.5%). Most frequent were skin (24.9%), prostate (17.0%), colon (11.0%), breast (10.9%), urinary tract (10.6%), and lung cancer (5.2%). STEMI patients with malignancies were older, presented more often with coronary three-vessel-disease, classical risk factors, atrial arrhythmias, kidney disease, heart failure, cerebrovascular and peripheral artery disease (PAD) (each p<0.001). They showed more often previous MI, percutaneous coronary interventions (PCI), cardiac surgery, and stroke (all p<0.001). Acute PCIs were applied approximately 2–6 percent points less frequently compared to those without (w/o) cancer, with less drug-eluting and more often bare metal stents (all p<0.001). In-hospital adverse events occurred more frequently in cancer. Eight-year survival was 57.3% (95% CI 57.0% – 57.7%) w/o cancer, and ranged between 41.2% and 19.2% in distinct cancer types. Multivariable Cox regression for death during follow-up found e.g. lung cancer (HR 2.04, 95% CI 1.92–2.17), PAD stage 4–6 (HR 1.78, 95% CI 1.72–1.84) and previous stroke (HR 1.44, 95% CI 1.31–1.54) to have the strongest effect, while obesity (HR 0.95, 95% CI 0.93–0.97) was associated with lower mortality (all p<0.001). Conclusion In this large “real world” health insurance data from Germany, prognosis after STEMI was markedly reduced but differed widely between cancer types. No withholding of revascularization therapies in cancer patients could be observed. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Federal Joint Committee, Innovation Committee (G-BA, Innovationsfonds, number 01VSF18051).

Sexual Dysfunction Following Aortoiliac Surgery

Objective: The purpose is to determine the incidence of erectile dysfunction (ED) in patients with aortoiliac occlusive disease and compare the change of ED after open surgery and endovascular repair. Materials and Methods: A prospective and comparative study in a single center from January 2013 to October 2015, 103 male patients admitted for extensive aortoiliac occlusive lesions. The erectile function (EF) was evaluated using a questionnaire. All patients filled out the questionnaire preoperatively and postoperatively after 1 year. Results: This study enrolled two groups: 48 patients underwent endovascular treatment and 55 patients underwent open surgery (aortofemoral or aorto-iliac bypasses). Preoperatively, 45.8% of patients were functionally impotent; there was no difference EF depending on the stage of peripheral arterial disease or the severity of obstructive aortoiliac lesions. Postoperative impotence was twice as common in those with minor dysfunction preoperatively, deterioration of EF occurred in 16.2% in the surgical group, and 2.1% in the endovascular group, with a very significant difference (P = 0.0001). In multivariate analysis, adjusted to preoperative EF was significantly more impaired postoperatively after median laparotomy (heart rate: 24.80 confidence interval = 95% [3.17–51.80], P < 0.0001). Conclusion: Sexual dysfunction is a frequent and often missed comorbidity in vascular surgery patients, especially after aortoiliac surgery. Hence, it must be diagnosed and evaluated in preoperatively in the choice of the therapeutic approach. For that endovascular treatment offers a less invasive alternative to open surgery and allows patients to maintain its sexual function intact and improve the quality of life.

Endothelial function in patients with critical and non-critical limb ischemia undergoing endovascular treatment.

Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease. CLI patients, compared to non-CLI, achieve worse treatment outcomes and generate higher costs. The aim of the study was to compare endothelial function and clinical outcomes in CLI and non-CLI patients after percutaneous transluminal angioplasty (PTA). In this prospective, follow-up study, 30 CLI patients and 40 non-CLI patients underwent PTA. Endothelial function was assessed based on flow mediated dilatation (FMD), reactive-hyperemia index (RHI), while the ankle-brachial index, toe-brachial index and the Rutherford scale were used for peripheral artery disease progression evaluation. The results were assessed before PTA, as well as 1, 3, 6 and 12 months after the procedure. There were no differences at the baseline regarding to endothelial function between both groups. Neither FMD nor RHI changed after PTA in any of the groups, although there was a difference in median RHI value between CLI and non-CLI patients regarding the 1st and 6th month of the follow-up (RHI6-RHI1 = 0.08 in CLI and -0.15 in non-CLI; P = 0.01). The larger baseline intima-media thickness (IMT) in the CLI group allowed to predict a greater number of re-intervention (P = 0.01) and major adverse event rates (P = 0.03). CLI patients presented larger decrease in the Rutherford scale compared to non-CLI (P <0.001). Baseline IMT was predictive for re-interventions and major adverse event rates. Although neither of groups exhibited significant changes in endothelial function, we proved differences between them regarding to changes in RHI.

Hispanics and African Americans Receive Lower Extremity Endovascular Interventions in the Late Stages of Peripheral Artery Disease With Higher Risks of Amputation

Racial minorities have experienced health care-related inequities and poor surgical outcomes. This study aims to investigate the current disparities in lower extremity endovascular (LEE) procedures indicated for peripheral artery disease among the racial groups.

Early and eighteen month clinical outcomes of first UK case of percutaneous deep vein arterialisation (pDVA) to treat \u201cno option\u201d chronic limb-threatening ischemia using the LimFlow system

BackgroundChronic limb-threatening ischaemia (CLTI) in cases where there are no further standard treatment options for limb salvage represents the most advanced stage of peripheral arterial disease. For these “no-option” CLTI patients, an experimental treatment of foot vein arterialisation (FVA) was first described in 1912, however, it was never widely adopted as outcomes varied significantly most likely due to the complexity of the surgical intervention and lack of standardisation. In recent years there have been significant developments in performing FVA fully percutaneously and standardising the procedure with the introduction of specific indications for patient selection, a dedicated set of devices and structured follow up. This case represents the first UK use of the dedicated LimFlow System as a standardised procedure to perform percutaneous deep vein arterialisation (pDVA) in a “no option” CLTI patient according to the latest treatment recommendations in the literature, with outcomes out to 18 months post-procedure.Case presentationWe present the case of a 78 year old male diabetic patient with a history of contralateral below knee amputation who presented with ischaemic rest pain and dry gangrene involving his left heel and first and second toes. Following review by the lower limb multi-disciplinary team at our institution, the patient was deemed to have no surgical or endovascular treatment options, apart from major amputation, as there was no suitable target for either angioplasty or bypass. He was therefore referred as a candidate for percutaneous deep vein arterialisation (pDVA) with the LimFlow System (LimFlow SA, France). After screening of the patient according to the indications for use, the pDVA procedure was successfully performed resulting in complete resolution of ischaemic rest pain immediately following the procedure, and adequate revascularisation of the foot. Following the index procedure, the subject went on to have minor amputation of the first, second and third toes 2 months post initial procedure with further secondary angioplasty procedures to optimise the flow throughout the arterialised circuit up to 4 months after the initial procedure. He underwent elective completion transmetatarsal amputation at 13 months post index procedure. The surgical wounds post minor amputation and the heel wound showed continued healing, especially after secondary optimisation of the pDVA outflow, with tissue epithelialisation by 6 months and complete healing by 18 months after the index procedure.ConclusionsThis case report demonstrates the clinical outcomes of a technically-successful standardised pDVA procedure with the LimFlow system including both limb salvage and wound healing at 18 months. It also highlights the importance of close clinical and radiological surveillance post-index procedure and the requirement for re-interventions to optimise wound healing.

The Role of Mitochondrial Function in Peripheral Arterial Disease: Insights from Translational Studies.

Recent evidence demonstrates an involvement of impaired mitochondrial function in peripheral arterial disease (PAD) development. Specific impairments have been assessed by different methodological in-vivo (near-infrared spectroscopy, 31P magnetic resonance spectroscopy), as well as in-vitro approaches (Western blotting of mitochondrial proteins and enzymes, assays of mitochondrial function and content). While effects differ with regard to disease severity, chronic malperfusion impacts subcellular energy homeostasis, and repeating cycles of ischemia and reperfusion contribute to PAD disease progression by increasing mitochondrial reactive oxygen species production and impairing mitochondrial function. With the leading clinical symptom of decreased walking capacity due to intermittent claudication, PAD patients suffer from a subsequent reduction of quality of life. Different treatment modalities, such as physical activity and revascularization procedures, can aid mitochondrial recovery. While the relevance of these modalities for mitochondrial functional recovery is still a matter of debate, recent research indicates the importance of revascularization procedures, with increased physical activity levels being a subordinate contributor, at least during mild stages of PAD. With an additional focus on the role of revascularization procedures on mitochondria and the identification of suitable mitochondrial markers in PAD, this review aims to critically evaluate the relevance of mitochondrial function in PAD development and progression.

Effectiveness of Home-Based Pain-Free Exercise versus Walking Advice in Patients with Peripheral Artery Disease: A Randomized Controlled Trial.

Exercise therapy in the intermediate stages of peripheral artery disease (PAD) represents an effective solution to improve mobility and quality of life (QoL). Home-based programs, although less effective than supervised programs, have been found to be successful when conducted at high intensity by walking near maximal pain. In this randomized trial, we aim to compare a low-intensity, pain-free structured home-based exercise (SHB) program to an active control group that will be advised to walk according to guidelines. Sixty PAD patients aged > 60 years with claudication will be randomized with a 1:1 ratio to SHB or Control. Patients in the training group will be prescribed an interval walking program at controlled speed to be performed at home; the speed will be increased weekly. At baseline and after 6 months, the following outcomes will be collected: pain-free walking distance and 6-min walking distance (primary outcome), ankle-brachial index, QoL by the VascuQoL-6 questionnaire, foot temperature by thermal camera, 5-time sit-to-stand test, and long-term clinical outcomes including revascularization rate and mortality. The home-based pain-free exercise program may represent a sustainable and cost effective option for patients and health services. The trial has been approved by the CE-AVEC Ethics Committee (898/20). Registration details: Clinicaltrials.gov NCT04751890 [Registered: 12 February 2021].

Use of the Ranger Paclitaxel-Coated Balloon in Patients With Chronic Limb-Threatening Ischemia: Short-Term Safety and Efficacy Results From Singapore

Chronic limb-threatening ischemia, also known as critical limb ischemia (CLI), is the most advanced stage of peripheral arterial disease (PAD), and patients have high risk of major lower-limb amputation and mortality. An endovascular-first approach has become the preferred revascularization strategy for these patients. The aim of the study was to evaluate the safety and short-term efficacy of the Ranger paclitaxel-coated balloon (PCB; Boston Scientific) in the setting of CLI. Methods. This was a single-center, single-arm, multi-investigator, prospective study of CLI patients who underwent endovascular revascularization using the Ranger PCB from July 2019 to November 2019 at Singapore General Hospital in Singapore. Data were retrieved from the Vascular Quality Initiative database recently set up at this institution. Primary lesion patency, amputation-free survival (AFS), freedom from target-lesion revascularization (TLR), and complete wound healing were the efficacy endpoints of interest at 6 months post intervention. Results. A total of 84 patients (87 limbs; 229 lesions) were enrolled. Fifty-one of the 84 patients (60.7%) were men. Baseline characteristics included diabetes mellitus in 76/84 patients (90.5%), chronic renal impairment in 25/84 patients (29.8%), and Rutherford category 6 foot wounds in 22/87 limbs (24.7%). TASC D lesions were present in 63/229 lesions (27.9%) and moderate/severe vessel wall calcification was present in 167/229 lesions (72.9%). Immediate technical success was achieved in 218/229 lesions (95.2%) with no device-related mortality at 30 days. Primary patency rates at 3 months and 6 months were 76/82 (92.7%) and 69/81 (85.2%), respectively. Six-month primary patency rates of below-the-knee (BTK) lesions treated with and without Ranger balloons were 89/94 (94.7%) and 34/41 (82.9%), respectively (P=.03). Six-month AFS occurred in 68/78 (87.2%) and freedom from TLR occurred in 73/81 (90.1%). Six-month complete wound healing rate was respectable, at 28/50 (56.0%). Conclusion. Use of the Ranger PCB showed favorable outcomes and short-term patency rates, especially in the BTK region, in what is an otherwise challenging patient cohort. Extended follow-up is awaited to evaluate the long-term safety and efficacy of the balloon.

Patients with critical limb ischemia (CLI) not suitable for revascularization: the “dark side” of CLI

Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease (PAD). Its prognosis is poor, with high rates of limb amputation and cardiovascular mortality. The international guidelines consider limb revascularization as the first line of the treatment strategy for CLI. However, despite the progress of revascularization techniques, many patients with CLI are still considered not suitable for these procedures and treated with conservative limb treatments. We have consulted the most important guidelines on PAD and CLI published over the past two decades focusing on the epidemiology, treatment, and outcomes of CLI patients not suitable for revascularization. Our review shows that only the TASC guidelines report 25% of CLI patients conservatively treated. Regarding the treatments, all the guidelines agree that the conservative treatment is based on the best medical management of cardiovascular risk factors associated with pain drugs and wound management. Other treatments such as prostanoids, spinal cord stimulation, vasodilators, or angiogenic therapies have shown uncertain positive outcomes in reducing limb amputation and mortality. In conclusion, this work outlines the scarce consideration that the guidelines have had about these patients over the past two decades. However, this review tries to draw the main novelties and possible future treatments for the better management of this group of patients still resident in the “dark side” of the CLI.

Multispectral optoacoustic tomography of peripheral arterial disease based on muscle hemoglobin gradients-a pilot clinical study.

BackgroundCurrent imaging assessment of peripheral artery disease (PAD) relies on anatomical cross-sectional visualizations of the affected arteries. Multispectral optoacoustic tomography (MSOT) is a novel molecular imaging technique that provides direct and label-free visualizations of soft tissue perfusion and oxygenation.MethodsMSOT was prospectively assessed in a pilot trial in healthy volunteers (group n1=4, mean age 31, 50% male and group n3=4, mean age 37.3, 75% male) and patients with intermittent claudication (group n2=4, mean age 72, 75% male, PAD stage IIb). We conducted cuff-induced ischemia (group n1) and resting state measurements (groups n2 and n3) over the calf region. Spatially resolved mapping of oxygenated (HbO2), deoxygenated (Hb) and total (THb) hemoglobin, as well as oxygen saturation (SO2), were measured via hand-held hybrid MSOT-Ultrasound based purely on hemoglobin contrast.ResultsCalf measurements in healthy volunteers revealed distinct dynamics for HbO2, Hb, THb and SO2 under cuff-induced ischemia. HbO2, THb and SO2 levels were significantly impaired in PAD patients compared to healthy volunteers (P<0.05 for all parameters). Revascularization led to significant improvements in HbO2 of the affected limb.ConclusionsClinical MSOT allows for non-invasive, label-free and real-time imaging of muscle oxygenation in health and disease with implications for diagnostics and therapy assessment in PAD.

Intermittent Administration of Nitroglycerin Sublingual Powder Compared with Placebo in Outpatients with Peripheral Artery Disease: Results of a Randomised Proof of Concept Study

Treatment of peripheral artery disease (PAD), Fontaine Stage IIb with vasoactive substances is of limited efficacy and does not last beyond the active treatment. Glyceryl trinitrate (GTN) is a vasodilating agent that relaxes vascular smooth muscle cells. The aim was to prove the concept that GTN sublingual powder has sustained clinical efficacy and adequate safety in these patients. This was a multicentre, randomised, double blind, placebo controlled, forced titration, proof of concept study (phase IIa). Patients had a treadmill test at baseline, after 12 weeks of GTN/placebo administration, and at 19 and 26 weeks (without treatment). Primary objectives were an increase in initial claudication distance (ICD) and absolute claudication distance (ACD) at 12 weeks. Ninety-five patients were screened and 73 randomised, of which 53 patients completed the 12 week treatment phase (GTN 26, placebo 27). At a baseline ICD of 59.2±32.8m (GTN) and 57.5±39.7m (placebo), GTN led to a placebo corrected ICD increase of 23.2% vs. baseline (p=.35). Baseline ACD was 105.3±52.9m (GTN) and 106.1±95.0m (placebo), and GTN led to a placebo corrected increase of 3.6% (p=.44), with substantial interindividual variation. The change in claudication distance was greater in patients with an ICD of ≥50m at baseline (ΔICD 29.3%; p=.19), and an ACD≥100m (ΔACD 8.5%; p=.40). The effect lasted beyond the active treatment period as shown by a 49.3% increase in ICD (p=.31) and a 20.6% increase in ACD (p=.21) by week 26. GTN sublingual powder was well tolerated. Intermittent treatment with nitroglycerin sublingual powder may represent a potential treatment option for patients with PAD stage Fontaine IIb, with an immediate and a sustained effect. The observed increases in ACD and ICD were however not statistically significant in this phase IIa proof of concept study. Further studies are required.

Intra-muscular administration of autologous bone marrow mononuclear cells reduces opioid dependency in patients with critical limb threatening ischemia.

Background and Hypothesis &#x0D; Critical limb-threatening ischemia (CLTI) is a severe limitation in perfusion of the lower extremities. It is the most advanced stage of peripheral arterial disease. Characterized by unremitting rest pain and/or gangrene, the CLTI patient population has an excessively high rate of opioid use and addiction. The MOBILE Trial was a Phase II multi-center, double-blinded placebo controlled trial designed to assess the safety and efficacy of autologous bone marrow cells (ABMC) in treating patients with CLTI. Our central hypothesis is that cell therapy may provide trophic effects in the treated limb that may decrease opioid requirements. &#x0D; &#x0D; Project Methods &#x0D; The primary endpoint of the MOBILE Trial was amputation-free survival at 52 weeks. Secondary endpoints included limb perfusion measures, ambulatory function, quality of life (VascuQol), pain assessment with a visual analog score, and opioid requirements, as tabulated by prescriptions reported to us. A post-hoc statistical analysis using ANOVA was conducted to describe changes in pain and quality of life measures along the study, and Fisher’s test to compare the incidence of new opioid prescriptions between treatment groups. &#x0D; &#x0D; Results &#x0D; There were no differences in quality of life and visual analog pain measures between the ABMC and placebo groups (P= 0.42). There was however a 36% decrease in new opioid prescriptions in the ABMC groups as compared to placebo (P = 0.058, HR: -0.44-1.012). This reduction did not correlate with changes in limb perfusion measures, gender, age, diagnosis of diabetes, or Rutherford score. &#x0D; &#x0D; Discussion &#x0D; The results of this analysis demonstrate an effect of ABMC in reducing opioid use in a high-risk addiction patient population. These findings are consistent with other studies assessing mesenchymal stem cells in chronic pain syndromes. The effect of ABMC did not correlate with changes in limb perfusion suggesting other beneficial trophic effects of cells in ischemic induced neuropathies. This discovery suggests a potential therapeutic strategy for reducing opioid dependency.

Mechanisms of ischemic skeletal muscle regeneration mediated by mechanically constrained human allogeneic mesenchymal stromal cells

Background and Hypothesis: Critical limb threatening ischemia (CLTI) is the end stage of peripheral arterial disease (PAD). CLTI presents a significant risk for lower extremity amputation, especially in diabetic patients with poor options for revascularization. Additionally, using a novel diabetic mouse model of CLTI, we have shown that IM injection of 3D cultured MSCs (spheroids) is more effective in promoting skeletal muscle regeneration of ischemic muscle than monolayer cultured MSC. We hypothesize that this result is due to the mechanical constrained nature of the MSC in spheroid form, which has been shown to alter the cellular phenotype. Alginate encapsulated cells are another form of mechanical confinement, and have additional benefits including resistance to immunological attack, making them a practical therapy for treatment of CLTI patients. &#x0D; &#x0D; Project Methods: In this work, cells were encapsulated in 2% alginate using a centrifugation method. Media from these cells along with others were analyzed for IL-10 and IL-33 using ELISA. Mouse tissue samples were stained with WGA-555 antibody and analyzed using a scanning microscope. Effects on tissue perfusion were measured with Laser Doppler Perfusion Imaging. At the time of this abstract, the media from encapsulated and naked MSCs is being used to culture myoblasts, looking at cell growth. &#x0D; &#x0D; Results: ELISA results did not show significant increases in IL-10 or IL-33 for encapsulated vs. non-encapsulated cells. LDPI has shown an increased perfusion rate for hindlimbs treated with encapsulated MSCs vs naked MSCs. Muscle fiber analysis is ongoing, but initial data appears promising. &#x0D; &#x0D; Conclusion and Potential Impact: This experiment provides a starting point for improving and expanding cell therapy for critical limb ischemia, potentially resulting in better outcomes for diabetic patients and preventing lower limb amputations. The encapsulation process also has value in other types of cell therapy, as it could protect cells from host defenses and increase dwell time.

Endothelial function indicators in patients with critical limb ischemia compared to patients with limb claudication – one-year follow-up period after endovascular revascularisation

Abstract Background Critical limb ischemia (CLI) is the most advanced stage of peripheral arterial disease. Limb revascularization is considered the first line of treatment. Purpose The aim of the study was to compare endothelial function and clinical outcomes in CLI and non-CLI patients during a 12-month follow-up period after endovascular treatment (PTA). Methods The study was conducted as a prospective, single-centre, follow-up evaluation. The authors recruited 30 CLI and 40 non-CLI patients. The following markers of endothelial dysfunction were evaluated: flow-mediated dilatation (FMD), reactive-hyperaemia index (RHI), arterial pulse-waveform analysis (aPWA) indices and clinical markers such as ankle-brachial index, toe-brachial index and Rutherford scale. Results Better clinical improvement may be observed in patients with CLI - the mean Rutherford grade significantly decreased in the CLI group (p&amp;lt;0.001). These patients also have better endothelial response to revascularization – CLI patients continue to have improved RHI up to 6 months after PTA, where in non-CLI patients, improvement was only noted during the first month. The mean FMD value did not change significantly during the follow-up in either of the groups. When comparing selected intervals, the FMD values in the CLI and non-CLI groups improved during the first month of observation and then decreased between the 1st and 6th month of follow-up. Finally, in CLI patients, baseline intima-media thickness predicts the number of reinterventions and major adverse events. Conclusions Patients with CLI differ significantly from patients with claudication based on clinical response and endothelial changes after revascularization. Figure 1. A) Kaplan-Meier survival curves according to CLI and non-CLI status for all study endpoints. B) Kaplan-Meier survival curves according to CLI and non-CLI status for reinterventions. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Collegium Medicum of Jagiellonian University - internal grant

Concomitant Chronic Venous Insufficiency in Patients With Peripheral Artery Disease: Insights From MR Angiography

Both arterial and venous vascular disease processes can coexist in the same patient. Understanding the symptomatic overlap and prevalence will lead to a better diagnosis and targeted therapies. This was a retrospective observational study assessing imaging studies of patients with known peripheral arterial disease (PAD) for the presence of chronic venous insufficiency (CVI). One in five patients was found to have CVI on magnetic resonance angiography; however, not all of these patients had had documentation in the medical record of a diagnosis of CVI. Patients with coexisting PAD and CVI found on imaging studies had had a more advanced stage of PAD than those without CVI. It can be difficult to differentiate between PAD and CVI in patients with symptoms that can be common to both disease entities. Patients with more advanced stages of PAD with ulcerations or gangrene are more likely to have coexisting CVI. The clinical management of patients with mixed arterial and venous disease could need to include treatment options for both PAD and CVI for healing and/or limb salvage.

Double VEGF/HGF Gene Therapy in Critical Limb Ischemia Complicated by Diabetes Mellitus

Critical leg ischemia (CLI) complicated by diabetes mellitus (DM), which is a very common and dangerous disease, represents the ultimate stage of peripheral arterial disease. Patients are treated with antiplatelet drugs, statins and limb revascularization, but a significant number of patients are not candidate for revascularization. Literature shows that in such cases, gene therapy could be a perfect therapeutic option. The aim of our study was to evaluate efficacy of double vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) gene therapy in patients with CLI complicated by DM. We observed that 90 days after administration, serum level of VEGF and ankle-brachial index increased significantly (p < 0.001) and rest pain decreased significantly compared with the control group (p < 0.002). Moreover considerable improvement in vascularization was observed in computed tomography angiography (P = 0.04). Based on the results of this study, we suggest that the therapy with pIRES/VEGF165/HGF bicistronic plasmid administration is a safe and effective method of treatment of patients with both CLI and DM.Graphical abstract

Risk Models and Scores in Patients with Peripheral Artery Disease and Chronic Limb-threatening Ischemia: A Comprehensive Review

Peripheral artery disease (PAD) affects more than 200 million patients worldwide and chronic limbthreatening ischemia (CLTI) is the most advanced stage of PAD with very high morbidity and mortality rates. Cardiovascular medicine is trending towards a more personalized approach where each individual patient will be managed according to specific risk factors, disease characteristics, expectations related to their disease and individualized assessment of potential outcomes. For this reason, a number of risk models and scores have been developed during the last few years. Our aim in this comprehensive review article is to provide an overview of selected risk models and scores for patients with PAD and CLTI. Given that some of the published scores were of low quality (minimal discriminatory ability), we included scores that were already externally validated or scores that had promising initial findings. Available scoring systems were grouped in the five following categories according to their utility: i) scores that can detect asymptomatic patients who should be screened for PAD, ii) scores for assessment of functional status and quality of life in patients with PAD, iii) scores assessing risk for amputation and other major adverse limb events among patients with CLTI, iv) scores for the optimal revascularization strategy in each patient and scores predicting successful procedural outcomes; v) scores predicting short or long-term cardiovascular and limb related outcomes after either revascularization or at least angiographic assessment. Limitations of available scoring systems include development and validation in specific populations, lack of external validation (for some of them) and also lack of synchrony with current era endovascular technology. However, with further optimization of current scores and the development of new scores, the field of PAD and CLI can be transitioned to a personalized medicine approach.

Endovascular Stenting for Critical Limb Ischemia Patient with Superficial Femoral Artery Occlusive Disease: A Case Report

BACKGROUND: Critical limb ischemia (CLI) is a terminal stage of peripheral arterial disease (PAD), in the absence of intervention, may lead to lower extremity amputation or death. In cases where medical management is not effective or severe cases of PAD, endovascular and surgical interventions are indicated. 2 Endovascular interventions become a first-line approach of CLI management and have advanced considerably within the past decade. 1,3 CASE DESCRIPTION: A 73-year old female with complain of left leg pain, accompanied with necrotic wound since 6 months ago. Duplex ultrasound showed no-flow from proximal to distal left superficial femoral artery (SFA). From CT-Angiography showed total occlusion from proximal left SFA to proximal poplitea artery about 7,2cm with collateral vessels. She was diagnosed with CLI left inferior extremity Fontaine IV Rutherford III. Angiography inferior extrimities was performed with total occlusion from proximal to distal left SFA with collateral vessels run to distal. We deployed a self-expanding stent with size 6mmx100mmx120cm at proximal-mid SFA. The patient showed improvement and was discharged after 5-days observation DISCUSSION: Patients with CLI have high risk of limb-loss without revascularization and high short term risk of cardiovascular events. Endovascular revascularization of femoro-popliteal occlusive offers lower initial risks than open surgery, with grade IIB-recommendation for lesion less than 25cm. Clinical success of endovascular stenting on CLI usually synonymous to limb salvage CONCLUSION:Favorable results can be achieved with endovascular stenting approach in patients with CLI, where close follow-up treatment afterwards can save limb loss.