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Background: The scope of clinical guidelines for the management of chronic limb-threatening ischemia (CLTI) is limited to atherosclerotic disease of the lower-extremity arteries. This study aimed to reveal the clinical features and prognoses of CLTI due to inflammatory nonatherosclerotic etiologies undergoing revascularization. Methods: DECOPON (DatabasE of ChrOnic limb-threatening ischemia Presenting ischemic ulcer and gangrene due to nON-atherosclerotic disease) is a multicenter retrospective study that evaluated 465 limbs of 414 patients with CLTI undergoing revascularization for ischemic tissue loss with inflammatory nonatherosclerotic etiologies between 2010 and 2020. Clinical features and prognoses were compared with 930 limbs of 809 patients with atherosclerotic CLTI during the same period. Results: The frequency of conventional atherosclerotic risk factors was significantly lower in the inflammatory nonatherosclerotic group. The inflammatory nonatherosclerotic group had more severe WIfI (wound, ischemia, and foot infection) W and fI grades, and more frequent infrapopliteal and inframalleolar artery diseases with a rarer presence of arterial calcification (all p < 0.05). Adjunctive therapy was more frequently performed in the inflammatory nonatherosclerotic group (p < 0.05). The inflammatory nonatherosclerotic group had a lower incidence rate of wound healing (0.64-fold, p < 0.001) and a higher incidence rate of major reintervention (2.30-fold, p = 0.006), whereas the risk ratio of all-cause mortality was 0.83-fold (p = 0.067). The association of inflammatory nonatherosclerotic disease with the delayed wound healing and the susceptibility to major reintervention remained significant even after adjustment for covariates (both p < 0.001). Conclusions: Patient, limb, and lesion characteristics of inflammatory nonatherosclerotic CLTI were considerably different from those of atherosclerotic CLTI. Inflammatory nonatherosclerotic CLTI was less likely to heal than atherosclerotic CLTI. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes mellitus (T2DM) is a significant risk factor for the development of critical limb ischemia (CLI), the most advanced stage of peripheral arterial disease. The concurrent existence of T2DM and CLI often leads to adverse outcomes, namely limb amputation. Objective: To identify biomarkers for improving the screening of CLI in high-risk people with T2DM. Methods: We investigated metabolome profiles in serum samples of 113 T2DM people with CLI (n = 23, G2) and without CLI (n = 45, G0: no lower limb stenosis (LLS) and n = 45, G1: LLS < 50%), using hydrogen nuclear magnetic resonance (1H NMR) approach. Principle component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) were used to analyze 1H NMR data. Results: Twenty potential metabolites that could discriminate people with T2DM and CLI (G2) from non-CLI patients without LLS (G0) were determined in serum samples. The correct percent of classification for the PLS-DA model for the test set samples was 85% (n = 20) and 100% (n = 5) for G0 and G2 groups, respectively. Non-CLI patients with LLS < 50% (G1) were projected on the PCA abstract space built using 20 discriminatory metabolites. Eleven people with T2DM and LLS < 50% were prospectively followed, and their ankle-brachial index (ABI) was measured after 4 years. A promising agreement existed between the PCA model's predictions and those obtained by ABI values. Conclusion: The findings suggest that confirmation of blood potential metabolic biomarkers as a complement to ABI for screening of CLI in a large group of high-risk people with T2DM is needed. [ABSTRACT FROM AUTHOR]

The prognostic significance of the six-minute walk distance for lower extremity events in people with peripheral artery disease (PAD) is unknown. This longitudinal study assessed whether a poorer six-minute walk distance at baseline was associated with higher rates of subsequent lower extremity atherosclerotic disease events in PAD. A total of 369 patients (mean age 69.4 ± 10.0 years; mean ankle-brachial index (ABI) 0.67 ± 0.17; 31% women; 30% black individuals) from Chicago-area medical centers with PAD were enrolled. Participants underwent baseline six-minute walk testing and returned for annual study visits. Lower extremity events consisted of one or more of the following: ABI decline greater than 15% or medical record adjudicated lower extremity revascularization, critical limb ischemia, or amputation. At a mean follow-up of 33.3 months, lower extremity events occurred in 66/123 (53.7%) people in the first (worst) tertile of six-minute walk performance, 55/124 (44.4%) in the second tertile, and 56/122 (45.9%) in the third (best) tertile. After adjusting for age, sex, race, ABI, comorbidities, and other confounders, participants in the first (worst) tertile of six-minute walk distance at baseline had higher rates of lower extremity events during follow-up, compared to those in the best tertile at baseline (HR = 1.74, 95% CI 1.17-2.60, p = 0.0067). Among people with PAD, a poorer six-minute walk distance was associated with higher rates of subsequent lower extremity PAD-related events after adjusting for confounders. Further study is needed to determine whether interventions that improve six-minute walk distance can reduce lower extremity adverse events in people with PAD.

Background: Critical limb ischemia represents an advanced stage of peripheral arterial disease. Angioplasty improves blood flow to the limb; however, some patients progress irreversibly to lower limb amputation. Few studies have explored the predictive potential of biomarkers during postangioplasty outcomes. Aim: To evaluate the behavior of endothelial progenitor cells in patients with critical limb ischemia, in relation to their postangioplasty outcome. Methods: Twenty patients with critical limb ischemia, candidates for angioplasty, were enrolled. Flow-mediated dilation, as well as endothelial progenitor cells (subpopulations CD45+/CD34+/CD133+/CD184+ and CD45+/CD/34+/KDR[VEGFR-2]+ estimated by flow cytometry) from blood flow close to vascular damage, were evaluated before and after angioplasty. Association with lower limb amputation during a 30-day follow-up was analyzed. Results: Endothelial progenitor cells were related with flow-mediated dilation. A higher number of baseline EPCs CD45+CD34+KDR+, as well as an impaired reactivity of endothelial progenitor cells CD45+CD34+CD133+CD184+ after angioplasty, were observed in cases further undergoing major limb amputation, with a significant discrimination ability and risk (0.75, specificity 0.83 and RR 4.5 p < 0.05). Conclusions: Endothelial progenitor cells were related with endothelial dysfunction, whereas a higher baseline number of the subpopulation CD45+CD34+KDR+, as well as an impaired reactivity of subpopulation CD45+CD34+CD133+CD184+ after angioplasty, showed a predictive ability for major limb amputation in patients with critical limb ischemia. [ABSTRACT FROM AUTHOR]

• The treatment of critical limb ischemia due to extensive diffuse vascular disease presents a complex medical challenge. • Distraction histogenesis techniques represent new methods for treating Critical limb ischemia. • Applying dynamic distraction techniques may yield a superior therapeutic outcomes and reducing associated complications. Critical limb ischemia (CLI) is the most serious stage of lower limb arterial disease, often presenting as severe ischemic resting pain, ulcer or tissue gangrene. The treatments for CLI pose a medical challenge. Despite the various treatments available for CLI, there is still no treatment that is entirely effective and acceptable to all patients. Patients with CLI are often elderly and have complex medical conditions, multiple comorbidities, and limited surgical tolerance. Among CLIs, patients with Transatlantic Inter-Society Consensus (TASC) grade D typically exhibit long-segmental and diffuse vascular lesions in their lower extremity arteries, often accompanied by microvascular lesions. It is obviously difficult to reopen multiple extensive segmental vessels with open bypass surgery or endovascular treatment within the limited surgical time, and such methods are ineffective in improving microcirculation. As emerging techniques for lower limb microcirculation reconstruction, tibial cortex transverse distraction and periosteal distraction are both forms of distraction histogenesis (DH) technology, their efficacy in treating CLI is verified, yet their associated treatment parameters still have potential for optimization. Existing biomechanical researches suggest that dynamic stretching may yield superior biological outcomes compared to static stretching, we hypothesize that employing dynamic stretching in tissue distraction techniques may yield a better therapeutic effect, thereby enhancing the efficacy of DH techniques for CLI and reducing the associated complications. [ABSTRACT FROM AUTHOR]

Background: Peripheral artery disease (PAD) affects 200 million people worldwide and is associated with impaired quality of life, increased morbidity, and mortality. Supervised exercise therapy (SET) and lower-extremity revascularization (LER) are both proven strategies to improve patient symptoms. Short and long-term functional outcomes after LER for symptomatic PAD in a large, international cohort have not previously been described. Methods: The VOYAGER PAD trial (ClinicalTrials. gov identifier: NCT02504216) enrolled subjects after LER for symptomatic PAD (Rutherford category 2-6). Participants completed the Walking Impairment Questionnaire (WIQ) at baseline, 1, 3 and 6 months, and every 6 months thereafter. The primary outcome analysis was degree of difficulty walking two blocks at each of the aforementioned time points. Difficulty walking three blocks and climbing one flight of stairs at these time points was also analyzed. Data about supervised and home exercise therapy before or after revascularization were not collected in the VOYAGER PAD trial. Results: Of the 5614 VOYAGER PAD participants completing the WIQ at baseline, three-quarters presented with claudication and one-quarter with critical limb ischemia. Of these, the majority (62% with claudication and 74% with CLI) reported inability or much difficulty walking two blocks prior to LER. Walking improved after LER regardless of revascularization strategy, but one-fifth with claudication and one-third with CLI reported continued inability or much difficulty walking two blocks 1 month after LER. Participants who reported improved walking ability 1 month after LER experienced a durable functional result out to 3 years. Although the proportion of participants reporting significant baseline difficulty climbing one flight of stairs or walking three blocks differed, the trend in immediate and sustained improvement after LER was similar to that observed for walking two blocks. Conclusion: In this large, international cohort undergoing LER for symptomatic PAD, nearly two-thirds reported inability or much difficulty walking two blocks at baseline. Although many participants reported improved walking ability after LER, a substantial proportion remained severely disabled. These observations may help motivate providers, patients, and medical systems to improve awareness and engagement in SET referral after LER. [ABSTRACT FROM AUTHOR]

Introduction: Patients with critical limb ischemia (CLI) can undergo endovascular peripheral vascular intervention (PVI) to restore blood flow and decrease risk of amputation. As a potential indicator of quality for CLI care, we sought to describe 30-day major amputation rates following PVI. We also examined rate variability, and patient-level and sitelevel factors predicting amputations, using a national electronic health record (EHR) database. Methods: Using the Cerner Health Facts de-identified EHR database, patients with CLI diagnosis codes undergoing PVI were identified. The rate of amputation within 30 days of PVI was calculated. Risk ratios predicting amputation were derived using a mixed effects Poisson regression model adjusting for 16 patient and clinical factors. Median risk ratios (MRRs) were calculated to quantify site-level variability in amputations. Results: A total of 20,204 PVI procedures for CLI from 179 healthcare sites were identified. Mean age at procedure was 69.0 ± 12.6 years, 58.0% were male, and 29.6% were persons of color. Amputation within 30 days of PVI occurred after 570 (2.8%) procedures. Malnutrition, previous amputation, diabetes, and being of Black race were predictors of amputation. Amputation rates across sites ranged from 0.0% to 10.0%. The unadjusted MRR was 1.40 (95% CI 1.35-1.46), which was attenuated after adjusting for patient-level factors (MRR 1.30, 95% CI 1.26-1.34) and site characteristics (MRR 1.11, 95% CI 1.09-1.13). Conclusions: Among PVI procedures for CLI treatment, 30-day amputation rates varied across institutions. Although patient-level factors explained some variability, site-level factors explained most variation in the rates of these outcomes. [ABSTRACT FROM AUTHOR]

Background: This retrospective comparative cohort study evaluated the clinical outcome of angiosome-guided endovascular arterial reconstructions in chronic limb-threatening ischemia (CLTI) due to multilevel peripheral artery disease (PAD). Methods: Patients treated in an endovascular fashion for CLTI with tissue loss due to multilevel PAD were analyzed. Limbs were classified as having undergone either angiosome-guided (direct) revascularization (DR) or nonangiosomic (indirect) revascularization (IR). DR was defined as uninterrupted in-line flow to the affected angiosome, revascularization through the pedal arch was also considered direct. Groups were adjusted with propensity score (PS) matching and compared for amputation-free survival (AFS), freedom from major adverse limb events (MALE), and healing rate at 12 months. Results: A total of 174 patients (81 men, mean age 70.0 ± 10.4 y) were included. PS matching produced two groups of 55 patients each: DR (24 men, mean age 71.7 ± 10.7 y) and IR (26 men, mean age 72.0 ± 9.4 y). The matched groups had no significant differences in baseline variables. At 12 months there were no significant differences in AFS (73.2% vs 71.6%; p = 0.841), freedom from MALE (71.7% vs 66.1%; p = 0.617), and healing rate (72.7% vs 72.0%; p = 1.000) between DR and IR, respectively. Conclusion: This study failed to support the use of angiosome concept in CLTI due to multilevel disease. [ABSTRACT FROM AUTHOR]

Jihad A Mustapha,1,2 Zsuzsanna Igyarto,3 David O’Connor,4 Ehrin J Armstrong,5,6 Anthony R Iorio,7 Vickie R Driver,8 Fadi Saab,2 Ann N Behrens,3 Brad J Martinsen,3 George L Adams9 1College of Osteopathic Medicine, Michigan State University, E. Lansing, MI, USA; 2Advanced Cardiac & Vascular Amputation Prevention Centers, Grand Rapids, MI, USA; 3Cardiovascular Systems, Inc., St. Paul, MN, USA; 4Hackensack University Medical Center, Hackensack, NJ, USA; 5Denver VA Medical Center, Denver, CO, USA; 6Anschutz Medical Campus, University of Colorado, Denver, CO, USA; 7Foot Center of New York, New York College of Podiatric Medicine, New York, NY, USA; 8Department of Orthopedics, Brown University School of Medicine, Providence, RI, USA; 9North Carolina Heart and Vascular, Rex Hospital, UNC School of Medicine, Raleigh, NC, USACorrespondence: Jihad A MustaphaAdvanced Cardiac & Vascular Amputation Prevention Centers, 1525 East Beltline NE, Suite 101, Grand Rapids, MI 49525, USATel +1 616-447-8220Email jihadmustapha@acvcenters.comBackground: High-risk patients with advanced peripheral artery disease (PAD), including critical limb ischemia (CLI), are often excluded from peripheral endovascular device intervention clinical trials, leading to difficulty in translating trial results into real-world practice. There is a need for prospectively assessed studies to evaluate peripheral endovascular device intervention outcomes in CLI patients.Methods: LIBERTY 360 is a prospective, observational, multi-center study designed to evaluate the procedural and long-term clinical outcomes of peripheral endovascular device intervention in real-world patients with symptomatic lower-extremity PAD. One thousand two hundred and four patients were enrolled and stratified based on Rutherford Classification (RC): RC2-3 (N=501), RC4-5 (N=603), and RC6 (N=100). For this sub-analysis, RC5 and RC6 patients (RC5-6; N=404) were pooled and 1-year outcomes were assessed.Results: Procedural complications rarely (1.7%) resulted in post-procedural hospitalization and 89.1% of RC5-6 patients were discharged to home. Considering the advanced disease state in RC5-6 patients, there was a high freedom from 1-year major adverse event rate of 65.5% (defined as target vessel revascularization, death to 30 days, and major target limb amputation). At 1 year, freedom from major amputation was 89.6%. Wounds identified at baseline on the target limb had completely healed in 172/243 (70.8%) of the RC5-6 subjects by 1 year. Additionally, the overall quality of life, as measured by VascuQoL, improved from baseline to 1 year.Conclusion: LIBERTY investigated real-world PAD patients with independent oversight of outcomes. This analysis of LIBERTY RC5-6 patients demonstrates that peripheral endovascular device intervention can be successful in CLI patients, with low rates of major amputation and improvement in wound healing and quality of life through 1-year follow-up.LIBERTY 360, https://clinicaltrials.gov/ct2/show/NCT01855412, ClinicalTrials.gov Identifier: NCT01855412.Keywords: amputation, critical limb ischemia, CLI, endovascular therapy

Background: Critical limb ischemia represents an advanced stage of peripheral arterial disease. Angioplasty improves blood flow to the limb; however, some patients progress irreversibly to lower limb amputation. Few studies have explored the predictive potential of biomarkers during postangioplasty outcomes. Aim: To evaluate the behavior of endothelial progenitor cells in patients with critical limb ischemia, in relation to their postangioplasty outcome. Methods: Twenty patients with critical limb ischemia, candidates for angioplasty, were enrolled. Flow-mediated dilation, as well as endothelial progenitor cells (subpopulations CD45+/CD34+/CD133+/CD184+ and CD45+/CD/34+/KDR[VEGFR-2]+ estimated by flow cytometry) from blood flow close to vascular damage, were evaluated before and after angioplasty. Association with lower limb amputation during a 30-day follow-up was analyzed. Results: Endothelial progenitor cells were related with flow-mediated dilation. A higher number of baseline EPCs CD45+CD34+KDR+, as well as an impaired reactivity of endothelial progenitor cells CD45+CD34+CD133+CD184+ after angioplasty, were observed in cases further undergoing major limb amputation, with a significant discrimination ability and risk (0.75, specificity 0.83 and RR 4.5 p < 0.05). Conclusions: Endothelial progenitor cells were related with endothelial dysfunction, whereas a higher baseline number of the subpopulation CD45+CD34+KDR+, as well as an impaired reactivity of subpopulation CD45+CD34+CD133+CD184+ after angioplasty, showed a predictive ability for major limb amputation in patients with critical limb ischemia.

The management of peripheral artery disease with no revascularization options can be challenging due to the very limited treatment options available and the high rate of major amputation which is linked to increased mortality and poor quality of life. Using a distal venous bed as an alternative bypass runoff seems to be a viable option when arterial reconstruction is not feasible. We report our experience with distal venous arterialization for limb salvage in non-reconstructable critical limb ischemia and describe the configuration used to achieve venosome directed revascularization in a patient with concomitant varicose veins. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is a progressive atherosclerotic disease associated with high rates of morbidity and mortality. Symptomatic PAD typically presents with claudication, and symptom severity strongly associates with reduced health-related quality of life (HRQoL). Existing treatment strategies for PAD are aimed at reducing symptom severity and improving functional outcomes. However, there is a need to incorporate patient-reported outcome measures (PROMs) into PAD treatment and research in order to provide more patient-centered care. This review will discuss the impact of PAD on HRQoL, existing PROMs available to assess PAD-related HRQoL, utilization of PROMs in research studies and registries, and challenges and solutions related to the integration of PROMs into research and clinical settings. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is the most severe manifestation of peripheral artery disease (PAD) and is characterized by high rates of morbidity and mortality. As with most severe cardiovascular disease manifestations, Black individuals disproportionately present with CLI. Accordingly, there remains a clear need to better understand the reasons for this discrepancy and to facilitate personalized therapeutic options specific for this population. Gastrocnemius muscle was obtained from White and Black healthy adult volunteers and patients with CLI for whole transcriptome shotgun sequencing (WTSS) and enrichment analysis was performed to identify alterations in specific Reactome pathways. When compared to their race-matched healthy controls, both White and Black patients with CLI demonstrated similar reductions in nuclear and mitochondrial encoded genes and mitochondrial oxygen consumption across multiple substrates, indicating a common bioenergetic paradigm associated with amputation outcomes regardless of race. Direct comparisons between tissues of White and Black patients with CLI revealed hemostasis, extracellular matrix organization, platelet regulation, and vascular wall interactions to be uniquely altered in limb muscles of Black individuals. Among traditional vascular growth factor signaling targets, WTSS revealed only Tie1 to be significantly altered from White levels in Black limb muscle tissues. Quantitative reverse transcription polymerase chain reaction validation of select identified targets verified WTSS directional changes and supports reductions in MMP9 and increases in NUDT4P1 and GRIK2 as unique to limb muscles of Black patients with CLI. This represents a critical first step in better understanding the transcriptional program similarities and differences between Black and White patients in the setting of amputations related to CLI and provides a promising start for therapeutic development in this population. [ABSTRACT FROM AUTHOR]

Ascertainment bias is a well-recognized source of bias in research, but few studies have systematically analyzed sources of ascertainment bias in randomized trials in which blinding is not possible and endpoint assessment is not protocolized. In the current study, we sought to evaluate differences in the clinical practice patterns of trial investigators with respect to bias in the ascertainment of pre-revascularization patient risk and the incidence of secondary endpoints post-revascularization. We conducted a cross-sectional survey of active investigators (n = 936) from the Best Endovascular Versus Best Surgical Therapy for Patients with Critical Limb Ischemia (BEST-CLI) trial. The total survey response rate was 19.6% (183/936). Vascular surgeons were more likely than nonsurgical interventionalists to order tests for cardiac complications after both surgical bypass (p < 0.001) and endovascular revascularization (p = 0.038). Post-procedure, investigators were more likely to order additional testing for cardiac complications in open surgery versus endovascular cases (7% vs 16% never, 41% vs 65% rarely, 43% vs 17% sometimes, 9% vs 2% always, respectively; p < 0.0001). Significant variation in practice patterns exist in the pre- and post-procedure assessment of cardiac risk and events for patients with CLI undergoing revascularization. Variation in the ascertainment of risk and outcomes according to the type of revascularization procedure and physician specialty should be considered when interpreting the results of clinical studies, such as the BEST-CLI trial. ClinicalTrials.gov Identifier: NCT02060630 [ABSTRACT FROM AUTHOR]

To learn more about PAD, read the Vascular Disease Patient Information Page on "Peripheral Artery Disease".[1] With CLI, leg artery blockages are so severe that sufficient blood flow cannot reach the legs and feet. Keywords: amputation; chronic limb-threatening ischemia (CLTI); critical limb ischemia (CLI); diabetic foot ulcer; peripheral artery disease (PAD) EN amputation chronic limb-threatening ischemia (CLTI) critical limb ischemia (CLI) diabetic foot ulcer peripheral artery disease (PAD) 228 231 4 04/12/21 20210401 NES 210401 What is critical limb ischemia (CLI)? The primary treatment for CLI is to restore blood flow to the affected leg in order to relieve symptoms of leg pain and provide enough blood flow to heal any leg and foot wounds. Amputation, chronic limb-threatening ischemia (CLTI), critical limb ischemia (CLI), peripheral artery disease (PAD), diabetic foot ulcer. [Extracted from the article]

Critical limb ischemia (CLI) constitutes the most advanced form of peripheral artery disease (PAD) and is characterized by ischemic rest pain, tissue loss and/or gangrene. Optimized medical care and risk factor modification in addition to revascularization could reduce the incidence of cardiovascular events and major adverse limb events, improving patients' quality of life and promising higher survival rates. Adequate adherence to cardioprotective medications, including antithrombotic therapy (e.g., antiplatelets, anticoagulants), cholesterol-lowering agents (e.g., statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors), angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and smoking cessation should be strongly encouraged for patients with CLI. This review examines these guideline-recommended therapies in terms of cardiovascular and limb-related risk reduction in patients with CLI. [ABSTRACT FROM AUTHOR]

There is a paucity of data on the outcomes and revascularization strategies for critical limb ischemia (CLI) among patients with chronic kidney disease (CKD). Hence, we conducted a nationwide analysis to evaluate the trends and outcomes of hospitalizations for CLI with CKD. The National Inpatient Sample database (2002–2015) was queried for hospitalizations for CLI. The trends of hospitalizations for CLI with CKD were reported, and endovascular versus surgical revascularization strategies for CLI with CKD were compared. The main study outcome was in-hospital mortality. The analysis included 2,139,640 hospitalizations for CLI, of which 484,224 (22.6%) had CKD. There was an increase in hospitalizations for CLI with CKD (Ptrend = 0.01), but a reduction in hospitalizations for CLI without CKD (Ptrend = 0.01). Patients with CLI and CKD were less likely to undergo revascularization compared with patients without CKD. CLI with CKD had higher rates of in-hospital mortality (4.8% vs 2.5%, adjusted odds ratio (OR) 2.01; 95% CI 1.93–2.11) and major amputation compared with no CKD. Revascularization for CLI with CKD was associated with lower rates of mortality (3.7% vs 5.3%, adjusted-OR 0.78; 95% CI 0.72–0.84) and major amputation compared with no revascularization. Compared with endovascular revascularization, surgical revascularization for CLI with CKD was associated with higher rates of in-hospital mortality (4.7% vs 2.7%, adjusted-OR 1.67; 95% CI 1.43–1.94). In conclusion, this contemporary observational analysis showed an increase in hospitalizations for CLI among patients with CKD. CLI with CKD was associated with higher in-hospital mortality compared with no CKD. Compared with endovascular therapy, surgical revascularization for CLI with CKD was associated with higher in-hospital mortality. [ABSTRACT FROM AUTHOR]

The association between active smoking and wound healing in critical limb ischemia (CLI) is unknown. Our objective was to examine in a retrospective cohort study whether active smoking is associated with higher incomplete wound healing rates in patients with CLI undergoing endovascular interventions. Smoking status was assessed at the time of the intervention, comparing active to no active smoking, and also during follow-up visits at 6 and 9 months. Cox regression analysis was conducted to compare the incomplete wound healing rates of the two groups during follow-up. A total of 264 patients (active smokers: n = 41) were included. Active smoking was associated with higher rates of incomplete wound healing in the 6-month univariate Cox regression analysis (hazard ratio (HR) for incomplete wound healing: 4.54; 95% CI: 1.41–14.28; p = 0.012). The 6-month Kaplan–Meier (KM) estimates for incomplete wound healing were 91.1% for the active smoking group versus 66% for the non-current smoking group. Active smoking was also associated with higher rates of incomplete wound healing in the 9-month univariable (HR for incomplete wound healing: 2.32; 95% CI: 1.11–4.76; p = 0.026) and multivariable analysis (HR for incomplete wound healing: 9.09; 95% CI: 1.06–100.0; p = 0.044). The 9-month KM estimates for incomplete wound healing were 75% in the active smoking group versus 54% in the non-active smoking group. In conclusion, active smoking status at the time of intervention in patients with CLI is associated with higher rates of incomplete wound healing during both 6- and 9-month follow-up. [ABSTRACT FROM AUTHOR]

Purpose: Analyze the impact of endovascular revascularization on major amputation rates and wound healing for patients with diabetic foot ulcers (DFUs). Materials and Methods: Single-center retrospective study from 2014–2018 including 314 patients with DFUs submitted to endovascular revascularizations. Group A—patients with a successful endovascular revascularization (n = 285; 90.8%); Group B—patients submitted to a failed attempt of endovascular revascularization (n = 29; 9.2%). Baseline data were not significantly different between the 2 groups (p > 0.05). Both groups were compared regarding: major amputation rates; wound healing, mortality and adverse events. Survival and regression analyses were used. Results: Mean follow-up time was 734.1 ± 610.2 days. Major amputation rates were 3.9% versus 24.1% (p < 0.0001) and complete wound healing was 53.7% versus 20.7% (p < 0.0001) for patients from Group A versus Group B, respectively. Major adverse events were registered in 2 patients (one from each group); minor adverse events included 10 patients from Group A and 2 patients from Group B (p = 0.3654). Major amputation rates were: 3.9% versus 27.5% at 1 year; 4.6% versus 27.5% at 2–5 years for Group A versus Group B, respectively (p < 0.0001). Survival rates were: 87.8% at 1 year; 84.4% at 2 years; and 77.9% at 5 years with no significant differences between groups. Predictors for major amputation included failed revascularization (p < 0.0001), older age (p = 0.0394), prior stroke (0.0018), dialysis (0.0476). Predictors for mortality included older age (p < 0.0001) and coronary artery disease (p = 0.0388). Conclusion: Endovascular revascularization for patients with DFUs is safe and has a significant impact on limb salvage and wound healing. [ABSTRACT FROM AUTHOR]

Patients with critical limb ischemia have nonhealing wounds and/or ischemic rest pain and are at high risk for amputation and mortality. Accurate evaluation of foot perfusion should help avoid unnecessary amputation, guide revascularization strategies, and offer efficient surveillance for patency. Our aim is to review current modalities of assessing foot perfusion in the context of the practical clinical management of patients with critical limb ischemia. [ABSTRACT FROM AUTHOR]

High-intensity statins are recommended for patients with peripheral artery disease (PAD). Critical limb ischemia (CLI) is the most advanced presentation of PAD. The benefit of statins in the CLI population is unclear based on the existent studies. Our objective was to perform a systematic review and meta-analysis regarding the efficacy of statin therapy in patients with CLI. PRISMA guidelines were followed. PubMed, EMBASE, and Cochrane CENTRAL databases were reviewed up to April 30, 2019. The primary outcomes included amputation rates and all-cause mortality. Secondary outcomes included primary patency rates, amputation-free survival and major adverse cardiac or cerebrovascular events (MACCE). Risk of bias was assessed with the Robins-I tool for observational studies. A random-effects model meta-analysis was performed. Heterogeneity was assessed with I2. Funnel plots and Egger's test were used to assess publication bias. Nineteen studies including 26,985 patients with CLI were included in this systematic review. Among patients with known data on statin status, 12,292 (49.6%) were on statins versus 12,513 (50.4%) not on statins. Patients treated with statins were 25% less likely to undergo amputation (HR 0.75; 95% CI: 0.59–0.95; I2 = 79%) and 38% less likely to have a fatal event (HR 0.62; 95% CI: 0.52–0.75; I2 = 41.2%). Statin therapy was also associated with increased overall patency rates and lower incidence of MACCE. There was substantial heterogeneity in the analysis for amputation and amputation-free survival (I2 > 70%). In conclusion, statins are associated with decreased risk for amputation, mortality, and MACCE, as well as increased overall patency rates among patients with CLI. Future studies should assess whether other lipid-lowering medications in addition to high-intensity statins can further improve outcomes among patients with CLI. (PROSPERO registration number: CRD42019134160) [ABSTRACT FROM AUTHOR]

There is a growing body of evidence that peripheral artery disease (PAD) may be impacted by depression. The objective of this study is to determine whether outcomes, primarily major amputation, differ between patients with depression and those without who presented to hospitals with critical limb ischemia (CLI), the end-stage of PAD. A retrospective cohort of patients hospitalized for CLI during 2012 and 2013 was identified from the National Inpatient Sample (NIS) using ICD-9 codes. The primary outcome was major amputation and secondary outcomes were length of stay and other complications. The sample included 116,008 patients hospitalized for CLI, of whom 10,512 (9.1%) had comorbid depression. Patients with depression were younger (64 ± 14 vs 67 ± 14 years, p < 0.001) and more likely to be female (55% vs 41%, p < 0.001), white (73% vs 66%, p < 0.001), and tobacco users (46% vs 41%, p < 0.001). They were also more likely to have prior amputations (9.8% vs 7.9%, p < 0.001). During the hospitalization, the rate of major amputation was higher in patients with comorbid depression (11.5% vs 9.1%, p < 0.001). In multivariable analysis, excluding patients who died prior to/without receiving an amputation (n = 2621), comorbid depression was associated with a 39% increased odds of major amputation (adjusted OR 1.39, 95% CI 1.30, 1.49; p < 0.001). Across the entire sample, comorbid depression was also independently associated with a slightly longer length of stay (β = 0.199, 95% CI 0.155, 0.244; p < 0.001). These results provide further evidence that depression is a variable of interest in PAD and surgical quality databases should include mental health variables to enable further study. [ABSTRACT FROM AUTHOR]

Endovascular therapy is a viable treatment option for symptomatic peripheral artery disease (PAD). Diabetes mellitus is a major risk factor for PAD. We evaluated the long-term impact of diabetes mellitus in patients with PAD who underwent endovascular therapy. In this prospective registry of 765 patients who underwent endovascular therapy for symptomatic PAD, 560 had diabetes and 205 did not have diabetes. Propensity score matching (PSM) analysis was performed to adjust for any potential confounders. The primary endpoints were 5-year major adverse cardiac and cerebrovascular events (MACE) and major adverse limb events (MALE). After PSM analysis, baseline clinical and limb characteristics were similar in patients with diabetes and in patients without diabetes. Patients with diabetes had a higher rate of major hematoma (> 4 cm) (9.9% vs 3.3%, p = 0.038). At 5-year clinical follow-up, patients with diabetes and patients without diabetes had similar rates of MACE (20.7% vs 20.7%, log rank p = 0.989) and MALE (19.8% vs 24.5%, log rank p = 0.312), as well as the individual endpoints. In subgroup analysis adjusted by PSM, female patients with diabetes had a higher risk of MALE (hazard ratio 0.31, 95% CI 0.13–0.69, p = 0.004). Although there was a higher rate of major hematoma, patients with diabetes who underwent endovascular therapy had similar 5-year cardiac and vascular outcomes compared with patients without diabetes. Bleeding avoidance strategies, including optimal antiplatelet and antithrombotic therapy, and meticulous vascular access techniques, are needed in patients with diabetes to reduce the risk of bleeding and its deleterious impact on morbidity and mortality. [ABSTRACT FROM AUTHOR]

Critical limb ischemia represents the advanced stage of peripheral artery disease, a health problem with increasing prevalence. Critical limb ischemia is associated with significant mortality, limb loss, pain, and diminished health-related quality of life. Public awareness and early diagnosis are necessary for an effective treatment with early risk factor modification, smoking cessation, and exercise therapy. Herein, we present an overview of the epidemiology as well as the clinical stages of the disease, and estimate that there are 6.5 million patients with critical limb ischemia in the US, Europe, and Japan based on global population-based studies. At least 75% of these patients, accounting for approximately 4.8 million patients, are amenable to endovascular therapy. [ABSTRACT FROM AUTHOR]

Evidence suggests that statin therapy in patients with peripheral artery disease (PAD) is beneficial yet use remains suboptimal. We examined trends in statin use, intensity, and discontinuation among adults aged ⩾ 40 years with incident severe PAD and a subset with critical limb ischemia (CLI) between 2002 and 2015 within an integrated healthcare delivery system. Discontinuation of statin therapy was defined as the first 90-day gap in treatment within 1 year following PAD diagnosis. We identified 11,059 patients with incident severe PAD: 31.1% (n = 3442) with CLI and 68.9% (n = 7617) without CLI. Mean (SD) age was 68.6 (11.3) years, 60.5% were male, 54.2% white, 23.2% Hispanic, and 16.2% black. Statin use in the year before diagnosis increased from 50.4% in 2002 to 66.0% in 2015 (CLI: 43.7% to 68.0%; without CLI: 53.1% to 64.2%, respectively). The proportion of patients on high-intensity statins increased from 7.3% in 2002 to 41.9% in 2015 (CLI: 7.2% to 39.4%; without CLI: 7.4% to 44.2%, respectively). Of the 40.5% (n = 4481) who were not on a statin in the year before diagnosis, 13.5% (n = 607) newly initiated therapy within 1 month (CLI: 10.1% (n = 150); without CLI: 15.3% (n = 457)). Following diagnosis, 12.5% (n = 660) discontinued statin therapy within 1 year (CLI: 15.5% (n = 202); without CLI: 11.5% (n = 458)). Although use of statins increased from 2002 to 2015, a substantial proportion of the overall PAD and CLI subpopulation remained untreated with statins, representing a significant treatment gap in a population at high risk for cardiovascular events and adverse limb outcomes. [ABSTRACT FROM AUTHOR]

Keywords: critical limb ischemia (CLI); exercise testing; peripheral artery disease (PAD); toe-brachial index (TBI); vascular diagnostics EN critical limb ischemia (CLI) exercise testing peripheral artery disease (PAD) toe-brachial index (TBI) vascular diagnostics 657 659 3 12/09/21 20211201 NES 211201 Toe-brachial indices (TBI) are being integrated into international guidelines[1],[2] due to their utility as an adjunct test for peripheral artery disease (PAD), particularly in diabetes populations.[3],[4] The addition of an exercise protocol has been demonstrated to improve diagnostic accuracy of the traditional ankle-brachial index (ABI).[5] However, there has been limited investigation of the effect of exercise on the accuracy of TBI. Diagnostic accuracy of postexercise toe-brachial index for identifying peripheral artery disease (PAD): A pilot study Peripheral artery disease (PAD), critical limb ischemia (CLI), exercise testing, toe-brachial index (TBI), vascular diagnostics. [Extracted from the article]

Aim: The present study aimed at identifying the pattern of patients with critical limb ischemia (CLI) compared with those with peripheral arterial occlusive disease (PAOD).

Peripheral artery disease (PAD) is caused by atherosclerotic occlusions of vessels outside the heart, particularly those of the lower extremities. Angiogenesis is one critical physiological response to vessel occlusion in PAD, but our understanding of the molecular mechanisms involved in angiogenesis is incomplete. Dual specificity phosphatase 5 (DUSP5) has been shown to play a key role in embryonic vascular development, but its role in post-ischemic angiogenesis is not known. We induced hind limb ischemia in mice and found robust upregulation of Dusp5 expression in ischemic hind limbs. Moreover, in vivo knockdown of Dusp5 resulted in impaired perfusion recovery in ischemic limbs and was associated with increased limb necrosis. In vitro studies showed upregulation of DUSP5 in human endothelial cells exposed to ischemia, and knockdown of DUSP5 in these ischemic endothelial cells resulted in impaired endothelial cell proliferation and angiogenesis, but did not alter apoptosis. Finally, we show that these effects of DUSP5 on post-ischemic angiogenesis are a result of DUSP5-dependent decrease in ERK1/2 phosphorylation and p21 protein expression. Thus, we have identified a role of DUSP5 in post-ischemic angiogenesis and implicated a DUSP5-ERK-p21 pathway that may serve as a therapeutic target for the modulation of post-ischemic angiogenesis in PAD. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is associated with skeletal muscle damage. However, the pathophysiology of the muscle damage is poorly understood. Toll-like receptors (TLR) have been attributed to play a role in ischemia-induced tissue damage but their role in skeletal muscle damage in CLI is unknown. TLR2 and TLR6 expression was found to be upregulated in skeletal muscle of patients with CLI. In vitro, ischemia led to upregulation of TLR2 and TLR6 by myotubes, and activation of the downstream TLR signaling pathway. Ischemia-induced activation of the TLR signaling pathway led to secretion of the pro-inflammatory cytokine interleukin-6 and muscle apoptosis, which were abrogated by neutralising TLR2 and TLR6 antibodies. Our study demonstrates that TLR2 and TLR6 are upregulated in ischemic muscle and play a role in ischemia-induced muscle damage. Thus, manipulating the TLR pathway locally may be of potential therapeutic benefit. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) represents a major health care burden. Despite the advent of screening and interventional procedures, the long-term clinical outcomes remain suboptimal, especially in patients with chronic kidney disease (CKD). While CKD and PAD share common predisposing factors, emerging studies indicate that their co-existence is not merely an association; instead, CKD represents a strong, independent risk factor for PAD. These findings implicate CKD-specific mediators of PAD that remain incompletely understood. Moreover, there is a need to understand the mechanisms underlying poor outcomes after interventions for PAD in CKD. This review discusses unique clinical aspects of PAD in patients with CKD, including high prevalence and worse outcomes after vascular interventions and the influence of renal allograft transplantation. In doing so, it also highlights underappreciated aspects of PAD in patients with CKD, such as disparities in revascularization and higher peri-procedural mortality. While previous reviews have discussed general mechanisms of PAD pathogenesis, focusing on PAD in CKD, this review underscores a need to probe for CKD-specific pathogenic pathways that may unravel novel biomarkers and therapeutic targets in PAD and ultimately improve the risk stratification and management of patients with CKD and PAD. [ABSTRACT FROM AUTHOR]

The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 – a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100. Patients were eligible if they persistently had reduced forefoot perfusion, by toe–brachial index (TBI) or skin perfusion pressure (SPP), following successful revascularization with angiographic demonstration of tibial arterial flow to the ankle. The primary efficacy end point was a 3-month wound healing score assessed by an independent wound core laboratory. The primary safety end point was major adverse limb events (MALE). Patients' mean age was 71 years, 33% were women, 79% had diabetes, and 8% had end-stage renal disease. TBI after revascularization was 0.26, 0.27, and 0.26 among the three groups (placebo, 8 mg, and 16 mg injections, respectively). Only 26% of wounds completely healed at 3 months, without any differences between the three groups (26.5%, 26.5%, and 25%, respectively). Similarly, there were no significant changes in TBI at 3 months. Three (2.8%) patients died and two (1.8%) had major amputations. Rates of MALE at 3 months were 8.8%, 20%, and 8.3%, respectively. While safe, JVS-100 failed to improve wound healing or hemodynamic measures at 3 months. Only one-quarter of CLI wounds healed at 3 months despite successful revascularization, highlighting the need for additional research in therapies that can improve microcirculation in these patients. ClinicalTrials.gov Identifier: NCT02544204 [ABSTRACT FROM AUTHOR]

Keywords: angioplasty; critical limb ischemia (CLI); endovascular therapy; peripheral artery disease (PAD); subintimal arterial flossing with the antegrade-retrograde intervention (SAFARI) EN angioplasty critical limb ischemia (CLI) endovascular therapy peripheral artery disease (PAD) subintimal arterial flossing with the antegrade-retrograde intervention (SAFARI) 207 209 3 04/12/21 20210401 NES 210401 Critical limb ischemia (CLI) is a severe clinical condition of ischemic pain at rest or tissue loss related to peripheral artery disease (PAD).[1],[2] Endovascular arterial revascularization plays a vital role in patients with CLI. The initial recanalization strategy is the antegrade approach, which is not feasible in approximately 20% of the patients.[3] In this study, we aimed to describe our outcomes of the subintimal arterial flossing with the antegrade-retrograde intervention (SAFARI) in patients with lower extremity tissue loss due to CLI. The patients' demographics, comorbidities, amputations, primary patency rates, limb salvage rates, and major amputation-free survival rates (AFS) are reported. [Extracted from the article]

Abstract Revascularization procedures to treat patients with peripheral artery disease are among the most common operations performed by vascular surgeons. However, there are major limitations to revascularizations, readmission rates due to procedural complications are high, and greater risks of cardiovascular and limb adverse outcomes have been reported for patients with peripheral artery disease undergoing limb revascularization. Specifically, surgical revascularization may be associated with increased generation of reactive oxygen species based on the ischemia reperfusion injury theory, as restored blood flow and reoxygenation of ischemic areas may be accompanied by increased oxidative stress. In this review, we present the current evidence regarding the effects of revascularization procedures on oxidative stress. We also discuss potential therapeutic interventions to prevent ischemia reperfusion injury–mediated tissue damage. [ABSTRACT FROM AUTHOR]

In this review 14 studies were identified reporting the treatment strategy in 4891 patients with Critical Limb Ischemia (CLI) with the aim to investigate if the strategy of treatment of the first episode of CLI has changed during the last 15–20 years. A computer research has been performed on PubMed and Scopus databases on November 2016. The used terms for the investigation about studies evaluating the strategy of treatment of CLI at the first-time presentation, have been “critical leg ischemia”, “critical limb ischemia”, “critical lower limb ischemia” along with the terms “placebo”, “medical treatment” and/or “conservative” revascularisation, surgical revascularisation, endovascular revascularisation, hybrid revascularisation and primary amputation. Studies were included if they were either retrospective or prospective and reporting the rate of patients who underwent to any form of revascularization, conservative treatment and primary amputation. The one-year limb and life survival rates have been reported as major outcomes. The pooled rate of revascularization was 72.5% (95% CI 80-64.96) of which 54.5%, surgical, 38.3% endovascular and 7.1% hybrid. The bivariate regression of revascularisation procedures has been with not significant increase, from 68% in 1993 to 88% in 2015. The endovascular procedures have shown a significant increase of the trend, from 2% to more the 50% (p 0.007), while surgical and hybrid procedures have not. The pooled rate of conservative treatment was 18% (95% CI 11.6–24.5%) with a not significant increasing trend and primary amputation pooled rate was 8.7% (95% CI 12.0-5,4) with a significant decreasing trend (p 0.009). The one-year limb survival rate was 75,4% (95% CI 81.5-69.3%) and the life survival was 76%. (95% CI 85.4-66.1%) both with a not significant increasing trend. In conclusion, this review highlights how the treatment strategy of the first CLI manifestation has changed over the last 15–20 years. It has shown an increase of the rate of revascularization procedures, particularly for endovascular and a significant reduction of the rate of primary amputations. The rate of patients treated conservatively appears to be unchanged and maybe influencing the rate of limb and life survival, that have remained unchanged. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine how postoperative skin perfusion pressure (SPP) as a measure of blood flow after revascularization affects limb prognosis in patients with critical limb ischemia (CLI). We retrospectively reviewed 223 consecutive bypass surgery cases performed in 192 patients with CLI during a 10-year period. SPP was measured 1-2 weeks before and after the procedure. An SPP of 40 mmHg was set as the cut-off value for revascularization. Patients were grouped according to their postoperative SPPs, and amputation-free survival (AFS) was analyzed. An SPP of = 40 mmHg was recovered in 75% of the patients, but no significant difference was found between this group and the group that did not reach 40 mmHg. On the other hand, the values increased by = 20 mmHg from the preoperative values in 70% of the patients. This group had a significantly better AFS than the group that did not increase by 20 mmHg. Logistic regression analysis revealed that (1) a preoperative SPP of < 20 mmHg and (2) a high serum albumin level (> 3.0 g/dL) were significant factors in increasing SPP by 20 mmHg. These results showed that an increase in SPP of = 20 mmHg after bypass surgery was associated with better limb prognosis. [ABSTRACT FROM AUTHOR]

Early-phase clinical trials in patients with critical limb ischemia (CLI) have shown positive results of mononuclear cell therapy. The current meta-analysis investigated whether cluster of differentiation (CD) 34+ mononuclear cell therapy (CD34+MCT) is effective for no-option CLI. Ten randomized controlled clinical studies of CD34+MCT for no-option CLI with 479 patients were identified and analyzed for pooled results. Compared to control groups, the CD34+MCT was associated with lower total amputation (odds ratio (OR): 0.45, p=0.01; 95% confidence interval (CI): 0.24-0.85) and a higher complete ulcer healing rate (OR: 2.80, p=0.008; 95% CI: 1.31-6.02), but showed no advantage in major amputation (OR: 0.58, p=0.11; 95% CI: 0.29-1.14) and all-cause mortality (OR: 0.82, p=0.62; 95% CI: 0.36-1.83). Studies with a high CD34+ cell dosage showed significant results in major amputation (OR: 0.38, p=0.002; 95% CI: 0.21-0.70), total amputation (OR: 0.31, p=0.0002; 95% CI: 0.17-0.57) and complete ulcer healing (OR: 7.58, p=0.0005; 95% CI: 2.40-23.88), which were not observed in the low-dose studies. However, inclusion of placebo-controlled studies showed no improvement of the CD34+MCT in total amputation (OR: 0.67, p=0.42; 95% CI: 0.25-1.79), major amputation (OR: 1.31, p=0.43; 95% CI: 0.67-2.54) or complete ulcer healing (OR: 1.52, p=0.27; 95% CI: 0.72-3.21), which were extremely significant in non-placebo-controlled studies (p<0.001). In conclusion, the significant results of CD34+MCT might not support its therapeutic benefit due to high placebo-effect risk and considerable heterogeneity caused by distinct cell doses. More sizable double-blinded, randomized, placebo-controlled trials with higher CD34+ cell dosage are needed in the future. [ABSTRACT FROM AUTHOR]

The clinical features of patients with critical limb ischemia (CLI) who responded to angiogenesis using autologous peripheral blood mononuclear cell transplantation (PB-MNC) have not yet been fully characterized, and there are no useful predictors to judge the curative effect in the early period after PB-MNC. This study sought to clarify the clinical features and predictors in patients with CLI who were successfully treated using PB-MNC. 30 consecutive patients [arteriosclerosis obliterans: 24 patients, thromboangiitis obliterans: 6 patients] who were diagnosed with major amputation despite maximal medical therapy were enrolled in this study. The study endpoint was major amputation within 3 months after PB-MNC. The collected data were evaluated for correlation between patients with and without major amputation within 3 months after PB-MNC. Six patients underwent major amputation and 1 patient underwent minor amputation. In the patients with major amputation, transcutaneous oxygen tension before PB-MNC and transplanted CD34-positive cells were lower than those of patients without major amputation. In the patients with amputation, interleukin-6 (IL-6) continued to increase after the first PB-MNC, and basic fibroblast growth factor (bFGF) decreased within 3 days after the first PB-MNC. PB-MNC was useful for the patients who were managed for inflammation and who had revascularization of the upper-popliteal arteries and two of the infra-popliteal arteries by endovascular and/or surgical revascularization. Variation in IL-6 and bFGF in the early period after PB-MNC could be useful predictors for the requirement of amputation within 3 months after PB-MNC. [ABSTRACT FROM AUTHOR]

The impact of heart failure (HF) on long-term survival in patients with critical limb ischemia (CLI) has not been well described. Outcomes stratified by left ventricular ejection fraction (EF) are also unknown. A single center retrospective chart review was performed for patients who underwent treatment for CLI from 2006 to 2013. Baseline demographics, procedural data and outcomes were analyzed. HF diagnosis was based on appropriate signs and symptoms as well as results of non-invasive testing. Among 381 CLI patients, 120 (31%) had a history of HF and 261 (69%) had no history of heart failure (no-HF). Within the HF group, 74 (62%) had HF with preserved ejection fraction (HFpEF) and 46 (38%) had HF with reduced ejection fraction (HFrEF). The average EF for those with no-HF, HFpEF and HFrEF were 59±13% vs 56±9% vs 30±9%, respectively. The likelihood of having concomitant coronary artery disease (CAD) was lowest in the no-HF group (43%), higher in the HFpEF group (70%) and highest in the HFrEF group (83%) (p=0.001). Five-year survival was on average twofold higher in the no-HF group (43%) compared to both the HFpEF (19%, p=0.001) and HFrEF groups (24%, p=0.001). Long-term survival rates did not differ between the two HF groups (p=0.50). There was no difference in 5-year freedom from major amputation or freedom from major adverse limb events between the no-HF, HFpEF and HFrEF groups, respectively. Overall, the combination of CLI and HF is associated with poor 5-year survival, independent of the degree of left ventricular systolic dysfunction. [ABSTRACT FROM AUTHOR]

Ankle-brachial indices (ABIs) are important for the assessment of disease burden among patients with peripheral artery disease. Although low values have been associated with adverse clinical outcomes, the association between noncompressible ABI (ncABI) and clinical outcome has not been evaluated among patients with critical limb ischemia (CLI). The present study sought to compare the clinical characteristics, angiographic findings and clinical outcomes of those with compressible (cABI) and ncABI among patients with CLI. Consecutive patients undergoing endovascular evaluation for CLI between 2006 and 2013 were included in a single center cohort. Major adverse cardiovascular events (MACE) were then compared between the two groups. Among 284 patients with CLI, 68 (24%) had ncABIs. These patients were more likely to have coronary artery disease (p=0.003), diabetes (p<0.001), end-stage renal disease (p<0.001) and tissue loss (p=0.01) when compared to patients with cABI. Rates of infrapopliteal disease were similar between the two groups (p=0.10), though patients with ncABI had lower rates of iliac (p=0.004) or femoropopliteal stenosis (p=0.003). Infrapopliteal vessels had smaller diameters (p=0.01) with longer lesions (p=0.05) among patients with ncABIs. After 3 years of follow-up, ncABIs were associated with increased rates of mortality (HR 1.75, 95% CI: 1.12-2.78), MACE (HR 2.04, 95% CI: 1.35-3.03) and major amputation (HR 1.96, 95% CI: 1.11-3.45) when compared to patients with cABIs. In conclusion, ncABIs are associated with higher rates of mortality and adverse events among those undergoing endovascular therapy for CLI. [ABSTRACT FROM AUTHOR]

Both open surgery and endovascular peripheral interventions have been shown to effectively improve outcomes in patients with peripheral artery disease, but minimal data exist comparing outcomes performed at and below the knee. The purpose of this study was to compare outcomes following infrageniculate lower extremity open bypass (LEB) versus peripheral vascular intervention (PVI) in patients with critical limb ischemia. Using data from the 2008–2014 Vascular Quality Initiative, 1-year primary patency, major amputation, and mortality were compared among all patients undergoing LEB versus PVI at or below the knee for rest pain or tissue loss. Overall, 2566 patients were included (LEB=500, PVI=2066). One-year primary patency was significantly worse following LEB (73% vs 81%; p<0.001). One-year major amputation (14% vs 12%; p=0.18) and mortality (4% vs 6%; p=0.15) were similar regardless of revascularization approach. Multivariable analysis adjusting for baseline differences between groups confirmed inferior primary patency following LEB versus PVI (HR 0.74; 95% CI, 0.60–0.90; p=0.004), but no significant differences in 1-year major amputation (HR 1.06; 95% CI, 0.80–1.40; p=0.67) or mortality (HR 0.71; 95% CI, 0.44–1.14; p=0.16). Based on these data, we conclude that endovascular revascularization is a viable treatment approach for critical limb ischemia resulting from infrageniculate arterial occlusive disease. [ABSTRACT FROM AUTHOR]

Critical limb ischemia (CLI) is the most severe form of peripheral arterial disease (PAD) which induces extremity rest pain, extremity gangrene or ulcers that mostly might lead to limb loss. One of the most common criteria of CLI is 50 mmHg or less systolic ankle arterial pressure. In this study, a custom made three-lumen catheter (9 Fr) including a distal inflatable balloon in between the inflow and outflow lumen holes was designed and fabricated based on the patented design of Hyper Perfusion Catheter. The proposed catheter design aims to increase ankle systolic pressure to 60 mmHg or more to promote healing and/or alleviating severe pain due to intractable ischemia for patients with CLI. To simulate the blood circulation of related anatomy, in vitro CLI model phantom was designed and constructed by using a modified hemodialysis circuit, a hemodialysis pump and a tube set for cardio-pulmonary bypass surgery. A blood mimicking fluid (BMF) with dynamic viscosity of 4.1 mPa.s was used at 22 ºC to prime the phantom. The data was collected by a custom-made circuit design in real time and all measurements were verified with commercial certificated medical devices. The results of in vitro CLI model phantom experiments have shown that it is feasible to elevate the pressure distal to the occlusion (representing ankle pressure) above 80 mmHg without affecting the systemic pressure. • With current methods untreatable CLI results in amputation of the limb 5. • Ankle systolic pressure is most important determinant in the viability of the limb 6. • The proposed catheter design aims to increase ankle pressure to 60 mmHg or more 7. • A phantom model is created to simulate compromised arterial circulation 8. • The target ankle systolic pressure (>60 mmHg) is achieved in the phantom model experiments 9. [ABSTRACT FROM AUTHOR]

Endovascular therapy has been increasingly utilized for the treatment of lower extremity peripheral artery disease (PAD) given its shorter recovery time, overall safety, and non-inferiority compared to surgical repair.[1] After endovascular interventions, antiplatelet therapy (anti-PLT) is frequently prescribed. Thus, further prospective real-world studies are necessary to determine the efficacy of DAPT/antithrombotic therapy after different revascularization techniques in specific high-risk populations (e.g. elderly patients, patients with cardiovascular comorbidities, etc.). A structured review of antithrombotic therapy in peripheral artery disease with a focus on revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) initiative. [Extracted from the article]

The author reflects on high stakes of limb salvage with skin perfusion pressure (SPP) which is a non-invasive test of regional perfusion able to assess the severity of tissue ischemia. It mentions SPP is unaffected by medial arterial calcification, making the measure particularly suitable among patients with complex peripheral artery disease (PAD). It also mentions Doppler SPP serves as a reasonable surrogate for toe systolic pressure.

Peripheral arterial diseases (PAD) had a great attention owing to devastating consequences of disability and cardiovascular morbidity and mortality. Yet, current therapeutic options are limited to surgical revascularization with no effective pharmacotherapy available. Excessive activity of Rho-associated coiled-coil protein kinase (ROCK) is implicated with several vascular diseases, rendering ROCK inhibition as a potential therapeutic strategy for patients suffering vascular disorders. The current study was dedicated to investigating the vascular protective potential of Fasudil, a ROCK inhibitor, on an experimentally induced unilateral critical limb ischemia (CLI) model in mice and demonstrated the possible underlying mechanisms. Unilateral CLI was induced by ligation and excision of femoral artery followed by daily i.p. injection of Fasudil (10 mg/kg or 25 mg/kg) up to two weeks post-surgery. Mice underwent CLI showed decreased antioxidant capacity and increased inflammatory signal, evident by elevation of ERK1/2 in both serum and GC muscles that coincided with increases in VEGFA, HIF-1α and CD34+ cells of GC muscles. CLI resulted in structural damage of GC muscle fibers, with marked apoptosis, declined proliferation and deteriorated peripheral limb function. Treatment with Fasudil restored antioxidant capacity and attenuated VEGFA, HIF-1α, CD34+ cells and inflammatory markers in ischemic limbs. Furthermore, Fasudil preserved histological integrity of ischemic GC muscles, with amelioration of apoptosis, preserved proliferation rate and improvement in peripheral limb function. Fasudil could protect against experimentally induced unilateral CLI, in a dose-dependent manner, which could pave the way for future clinical application of Fasudil in patients suffering PAD. • Patients with PAD experience serious consequences of disability, with surgical intervention as the only therapeutic option. • Ischemic vascular diseases including PAD involves excessive activity of ROCK; Rho-associated coiled-coil protein kinase. • Fasudil protected against PAD by preserving anti-oxidant capacity, decreasing inflammation and pathological angiogenesis. • Fasudil preserved structural integrity of gastrocnemius muscle and peripheral limb function, deteriorated in PAD. [ABSTRACT FROM AUTHOR]