Compound Danshen Dripping Pills pretreatment protects the heart from ischemia/reperfusion injury by enhancing autophagic flux

Abstract Compound Danshen Dripping Pills (CDDPs) have been used in clinical treatment to protect the heart from ischemia/reperfusion (IR) injury for many years. However, the underlying mechanism implicated in the protective effects remains to be explored. Here, we determined the effects of CDDPs in Sprague-Dawley rats with the IR model. Cardiac function in vivo was assessed by echocardiography. Transmission electron microscopy, histological and immunohistochemical techniques, Western blotting and recombinant adeno-associated virus 9 transfection were used to illustrate the effects of CDDPs on IR and autophagy. Our results showed that pretreatment with CDDPs decreased the level of serum myocardial enzymes and infarct size in rats after IR. Apoptosis evaluation showed that CDDPs significantly ameliorated the cardiac apoptosis level after IR. Meanwhile, CDDPs pretreatment increased myocardial autophagic flux, with upregulation of LC3B, downregulation of p62, and increased autophagosomes and autolysosomes. Moreover, the autophagic flux inhibitor chloroquine could increase IR injury, while CDDPs could partially reverse the effects. Furthermore, our results showed that the activation of AMPK/mTOR was involved in the cardioprotective effect exerted by CDDPs. Herein, we suggest that CDDPs partially protect the heart from IR injury by enhancing autophagic flux through the activation of AMPK/mTOR.

Nephroprotective effects of Lippia sidoides ethanolic extract against ischemia/reperfusion-induced acute kidney injury

Abstract Ischemia/reperfusion injury (I/R) is commonly related to acute kidney injury (AKI) and oxidative stress. Antioxidant agents are used to treat this condition. Lippia sidoides is a brazillian shrub with anti-inflammatory and anti-oxidative properties. Thus, the aim of this study is to evaluate the effect of Lippia sidoides ethanolic extract (LSEE) on in vivo and in vitro models of AKI induced by I/R. Male Wistar rats were submitted to unilateral nephrectomy and ischemia on contralateral kidney for 60 min via clamping followed by reperfusion for 48 h. They were divided into four groups: Sham, LSEE (sham-operated rats pre-treated with LSEE), I/R (rats submitted to ischemia) and I/R-LSEE (rats treated with LSEE before ischemia). Kidney tissues homogenates were used to determine stress parameters and nephrin expression. Plasma and urine samples were collected for biochemical analysis. I/R in vitro assays were evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and flow cytometry assays in Rhesus Monkey Kidney Epithelial Cells (LLC-MK2). The LSEE treatment prevented biochemical and nephrin expression alterations, as well as oxidative stress parameters. In the in vitro assay, LSEE protected against cell death, reduced the reactive oxygen species and increased mitochondrial transmembrane potential. LSEE showed biotechnological potential for a new phytomedicine as a nephroprotective agent.

GLASS (Global Limb Anatomic Staging System): a critical appraisal.

BACKGROUND: THE Global Vascular Guidelines (GVGs) propose a new Global Anatomic Staging System (GLASS) resulting in three stages of complexity for intervention. The aim of this study was to retrospectively classify a large cohort of CLTI patients according to the GLASS, evaluating its distribution in a real-world setting. METHODS: Retrospective, single center, observational study enrolling all consecutive CLTI patients submitted to infra-inguinal endovascular revascularization in our institution, between June 2014 and September 2019. Patients were categorized according to the GLASS for femoro-popliteal (FP), infra-popliteal (IP) and infra-malleolar grading. FP and IP grades were merged to get the final GLASS stage for each limb. RESULTS: The study included 1995 CLTI patients who underwent 2850 endovascular procedures in which 6009 arterial lesions were successfully treated. The FP segment was classified as: 1292 (45.3%) grade 0, 475 (16.6%) grade 1, 159 (5.6%) grade 2, 209 (7.4%) grade 3, and 715 (25.1%) grade 4. The IP segment was classified as: 1529 (53.6%) grade 0, 183 (6.4%) grade 1, 80 (2.8%) grade 2, 207 (7.3%) grade 3, and 851 (29.9%) grade 4. The combination of FP and IP grading led to GLASS stages: 922 (32.3%) stage 1, 375 (13.2%) stage 2, 1472 (51.6%) stage 3. CONCLUSIONS: The distribution of the FP, IP and final GLASS grading was mainly grouped at the two extremes, letting the intermediate grades rather scarce. The majority of patients present with an absent or severely diseased pedal arch, stressing the need to incorporate infra-malleolar disease into the GLASS.

A classification system and treatment algorithm for mastectomy flap ischemia in alloplastic breast reconstruction.

BACKGROUND: Mastectomy flap necrosis remains a major cause of failed breast reconstruction with an associated significant financial/psychological burden. Language describing ischemic mastectomy flaps is imprecise as ischemia can result from many causes and can manifest in different ways. Similarly, management of mastectomy flap ischemia varies depending on its etiology. Intraoperative near-infrared imaging (NIR) with indocyanine green (ICG) is an established modality for evaluation of mastectomy flap perfusion. Herein, we define the types of flap ischemia demonstrated via NIR imaging and propose an algorithm for its management. METHOD: A retrospective review was performed of patients who underwent mastectomy and NIR imaging of mastectomy flaps from 2014 to 2017. Patient characteristics, operative details, and outcomes were recorded. Following retrospective review, distinct patterns of ischemia were identified, and a classification system and treatment algorithm were developed. RESULT: Type A; diffuse hypoperfusion can be caused by a number of factors (hypotension, vasoconstrictive agents, etc.). It is best treated with delayed reconstruction. Type B; geographic hypoperfusion may be caused by electro-cautery burn, inaccurate dissection, or retractor injury. It can be treated by resection/primary closure or delayed reconstruction. Type C; marginal/incisional hypoperfusion is best treated with debridement. Type D; diffuse marginal perfusion is seen with overfilled tissue-expanders or an oversized implant within a smaller skin envelope. Management includes deflation/downsizing. An algorithm was developed for treatment of the four ischemia types. CONCLUSION: NIR imaging aides in delineating the type of ischemic injury. Classification of mastectomy flap ischemia allows precise communication between providers and provides a framework for decision-making.

Editor's Choice - The Prognostic Value of the WIfI Classification in Patients with Chronic Limb Threatening Ischaemia: A Systematic Review and Meta-Analysis.

OBJECTIVES: The Society for Vascular Surgery has proposed the Wound, Ischaemia, and foot Infection (WIfI) classification system as a prognostic tool for the one year amputation risk and the added value of revascularisation in patients with chronic limb threatening ischaemia (CLTI). This systematic review summarises the current evidence on the prognostic value of the WIfI classification system in clinical practice. DESIGN: Systematic review and meta-analysis following the PRISMA guidelines. MATERIALS: The Embase, MEDLINE, and Cochrane databases were searched up to June 2018. METHODS: All studies using the WIfI classification for patients with CLTI were eligible. Outcomes of interest were major amputation, limb salvage, and amputation free survival in relation to WIfI clinical stage. The methodological quality of studies was appraised with the Quality in Prognosis Studies (QUIPS) tool. If possible, data were pooled and analysed using a random effects model. Study selection, quality assessment, and data extraction were carried out by two authors independently. RESULTS: The search yielded 12 studies comprising 2669 patients, most of whom underwent endovascular or open revascularisation. Overall study quality was moderate. All but one were retrospective studies, including a variety of subpopulations of patients with CLTI, such as only haemodialysis dependent, diabetic or non-diabetic patients. The WIfI classification was derived from chart data or prospectively maintained databases, both documented before the WIfI classification was published. Estimated one year major amputation rates from four studies comprising 569 patients were 0%, 8% (95% CI 3-21%), 11% (95% CI 6-18%) and 38% (95% CI 21-58%), for WIfI stages I-IV, respectively. CONCLUSIONS: The likelihood of an amputation after one year in patients with CLTI increases with higher WIfI stages, which is important prognostic information. Prospective evaluations are needed to determine its role in clinical practice.

Guideline-Oriented Therapy of Lower Extremity Peripheral Artery Disease (PAD) - Current Data and Perspectives. / Leitliniengerechte Therapie der PAVK ­ Aktuelle Studienlage und Ausblick.

BACKGROUND: Because of the demographic change, lower extremity peripheral artery disease (PAD) is becoming increasingly relevant with respect to health economics. PAD patients often suffer from multiple diseases. Consequently, therapy is commonly complex and requires an interdisciplinary approach. Because of rapid technical developments, interventional endovascular therapy regimens play an increasingly important role. METHOD: Review and literature search on the basis of the current German S3 guidelines on the therapy of PAD as well as international guidelines. In terms of state-of-the-art therapies, relevant current studies were considered. RESULTS: Knowledge of existing guidelines and recommendations as well as new therapeutic approaches is essential for the adequate therapy of PAD patients. A close cooperation between the interventional radiologist and the vascular surgeon is the key to success. In addition to established conservative approaches and invasive bypass surgery, the endovascular approach has been a mainstay in the TASC A and B environment for years. It has recently shown promising results in advanced PAD conditions, such as TASC C and D. An endovascular-first strategy is defined in most guidelines. CONCLUSION: A primarily endovascular-first strategy has become the standard in the majority of even complex lesions of the lower extremity arterial system. Regarding the crural segment, a decrease in mortality compared to bypass surgery has been demonstrated. Further evidence can be expected from ongoing randomized multicenter trials. KEY POINTS: · Adequate diagnostic examination is essential for the classification and strategy of therapy in PAD. · Therapeutic decisions are ideally made in an interdisciplinary conference. · Interventional therapy of intermittent claudication after exhaustion of conservative and medicamentous therapy. · Endovascular-first approach in supra- and infrainguinal lesions. · Additional evidence expected from future randomized trials. CITATION FORMAT: · Kersting J, Kamper L, Das M et al. Guideline-Oriented Therapy of Lower Extremity Peripheral Artery Disease (PAD) - Current Data and Perspectives. Fortschr Röntgenstr 2019; 191: 311 - 322.

Prognostic value of the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification in patients with no-option chronic limb-threatening ischemia.

OBJECTIVE: The Wound, Ischemia, and foot Infection (WIfI) classification was developed to assess amputation risk and hence to aid in clinical decision-making in patients with chronic limb-threatening ischemia (CLTI). WIfI has been validated in multiple CLTI cohorts worldwide. In this study, we examined the relationship between WIfI stage and clinical outcomes in a well-defined subpopulation of CLTI patients considered not eligible for conventional revascularization. The aim of this study was to assess the prognostic value of the WIfI classification for clinical outcomes in a "no-option" CLTI population. METHODS: The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial was a single-center, double-blinded, randomized placebo-controlled trial studying the effects of autologous bone marrow mononuclear cells in no-option CLTI patients (N = 160). We conducted a retrospective analysis incorporating baseline and follow-up data from the JUVENTAS trial. All wounds were photographed and described at the start and end of the trial to allow WIfI staging. Two independent researchers retrospectively classified all limbs according to the WIfI scheme, which was then related to prospectively collected trial data. Outcomes including wound healing, clinical improvement, minor and major amputation rate, amputation-free survival, and mortality were assessed using Kaplan-Meier analyses. RESULTS: Of the 160 patients, 150 could be included in this study. Most patients had been classified as Rutherford stage 4 (34%) and stage 5 (61%), with corresponding WIfI stage 2 (33%), stage 3 (21%), or stage 4 (35%). Diabetes, impaired renal function, and ankle-brachial index were independently associated with WIfI stage. On univariate analysis, WIfI stage was strongly associated with wound healing (P = .001), improvement of Rutherford stage (P = .009), amputation rate (P < .001), and long-term mortality (median follow-up, 21.1 months; P = .025). Of note, WIfI stage 2 patients had a worse 6-month major amputation rate compared with stage 3. Of the seven amputated stage 2 patients, six were in WIfI category W0-I3-fI0 and scored a maximum grade 3 on ischemia. Reclassification of ischemic rest pain (W0-I3-fI0) to stage 3 improved and reordered the discrimination of outcomes by WIfI stage in this cohort. CONCLUSIONS: This is the first study to demonstrate that WIfI classification is associated with important clinical outcomes in a no-option CLTI population. Our data suggest that limb prognosis is poor in patients with classic ischemic rest pain, without wounds or infection (W0-I3-fI0), when they lack revascularization options. Further studies are needed to determine whether reassignment of this population from WIfI stage 2 to WIfI stage 3 may be appropriate to reflect amputation risk in the absence of successful revascularization for patients suffering from ischemic rest pain in general.

Outcomes of reintervention for recurrent symptomatic disease after tibial endovascular intervention.

OBJECTIVE: Tibial interventions for critical limb ischemia are now commonplace. Restenosis and occlusion remain barriers to durability after intervention. The aim of this study was to examine the patient-centered outcomes of open and endovascular reintervention for symptomatic recurrent disease after a primary isolated tibial endovascular intervention. METHODS: A database of patients undergoing isolated primary lower extremity tibial endovascular interventions between 2006 and 2016 was retrospectively queried. Patients with recurrent critical ischemia (Rutherford 4 and 5) were identified. Outcomes in this cohort were analyzed, and three groups were defined: endovascular reintervention (ie, a repeated tibial or pedal endovascular intervention), bypass (bypass to a tibial or pedal vessel), and primary amputation (ie, above- or below-knee amputation) on the ipsilateral leg. Patient-oriented outcomes of clinical efficacy (absence of recurrent signs or symptoms of critical ischemia, maintenance of ambulation, and absence of major amputation), amputation-free survival (survival without major amputation), and freedom from major adverse limb events (above-ankle amputation of the index limb or major reintervention, such as new bypass graft or jump or interposition graft revision) were evaluated after the reintervention. RESULTS: There were 1134 patients (56% male; average age, 59 years) who underwent primary tibial intervention for critical ischemia, and 54% presented with symptomatic restenosis and occlusion. Of the 513 patients with recurrent disease, 58% presented with rest pain and the remainder with ulceration. A repeated tibial endovascular intervention was performed in 64%, open bypass in 19%, and below-knee amputation in 17%. Bypass was employed in patients with a good target vessel, venous conduit, and good pedal runoff. Patient-centered outcomes were better in the bypass group compared with the reintervention group (amputation-free survival, 45% ± 9% vs 27% ± 9% [P < .01]; major adverse limb events, 50% ± 9% vs 31% ± 9% [P < .05]; clinical efficacy, 60% ± 7% vs 30% ± 9% [P < .01], mean ± standard error of the mean at 5 years). CONCLUSIONS: Tibial interventions for critical ischemia are associated with a high rate of reintervention. In patients with good target vessel, venous conduit, and good pedal runoff, bypass appears more durable than repeated tibial endovascular intervention.

Clinical Analysis of Classification and Prognosis of Ischemia-Type Biliary Lesions After Liver Transplantation.

BACKGROUND The aim of this study was to classify ischemia-type biliary lesions after liver transplantation according to their imaging findings and severity of clinical manifestations and to analyze the relationship between such classification and prognosis. MATERIAL AND METHODS We collected clinical data of patients with ischemia-type biliary lesions (ITBL) after liver transplantation in the Organ Transplantation Center, the First Central Hospital of Tianjin, from August 2012 to July 2013; all patients were classified according to their imaging findings and relevant clinical data to analyze the relationship between their classification and prognosis. RESULTS The mean postoperative survival time, as well as the 1-, 3-, and 5-year survival rate, in Group ITBL showed statistical significance when compared with those in Group NITBL (log rank=12.13, P<0.001), but the mean postoperative survival times among the mild, moderate, and severe ITBL cases showed no statistical significance. The incidence rates of 1-, 3-, and 5-year adverse prognosis in Group ITBL showed statistical significance when compared with Group NITBL with <2% patients who had anastomotic biliary obstruction (log rank=277.06, P<0.001), among which the difference in the incidence rate of adverse prognosis between severe and moderate ITBL cases showed no statistical significance. The difference in the incidence rate of adverse prognosis between mild and moderate ITBL cases showed statistical significance (log rank=6.01, P=0.014), and the difference in the incidence rate of adverse prognosis between mild and severe ITBL cases showed statistical significance (log rank=10.98, P=0.001). CONCLUSIONS ITBL classification based on the severity of biliary imaging and bilirubin level can predict the prognosis of ITBL.

Chronic Total Occlusion Crossing Approach Based on Plaque Cap Morphology: The CTOP Classification.

PURPOSE: To present the chronic total occlusion (CTO) crossing approach based on plaque cap morphology (CTOP) classification system and assess its ability to predict successful lesion crossing. METHODS: A retrospective analysis was conducted of imaging and procedure data from 114 consecutive symptomatic patients (mean age 69±11 years; 84 men) with claudication (Rutherford category 3) or critical limb ischemia (Rutherford category 4-6) who underwent endovascular interventions for 142 CTOs. CTO cap morphology was determined from a review of angiography and duplex ultrasonography and classified into 4 types (I, II, III, or IV) based on the concave or convex shape of the proximal and distal caps. RESULTS: Statistically significant differences among groups were found in patients with rest pain, lesion length, and severe calcification. CTOP type II CTOs were most common and type III lesions the least common. Type I CTOs were most likely to be crossed antegrade and had a lower incidence of severe calcification. Type IV lesions were more likely to be crossed retrograde from a tibiopedal approach. CTOP type IV was least likely to be crossed in an antegrade fashion. Access conversion, or need for an alternate access, was commonly seen in types II, III, and IV lesions. Distinctive predictors of access conversion were CTO types II and III, lesion length, and severe calcification. CONCLUSION: CTOP type I lesions were easiest to cross in antegrade fashion and type IV the most difficult. Lesion length >10 cm, severe calcification, and CTO types II, III, and IV benefited from the addition of retrograde tibiopedal access.

Importance of postprocedural Wound, Ischemia, and foot Infection (WIfI) restaging in predicting limb salvage.

OBJECTIVE: The Wound, Ischemia, and foot Infection (WIfI) classification system was created to encompass demographic changes and expanding techniques of revascularization to perform meaningful analyses of outcomes in the treatment of the threatened limb. The WIfI index is intended to be analogous to the TNM staging system for cancer, with restaging to be done after control of infection and after revascularization. Our goal was to evaluate the effectiveness of WIfI restaging after therapy in the prediction of limb outcomes. METHODS: Preoperative WIfI scoring was performed prospectively for all critical limb ischemia patients who underwent revascularization from January 2014 to June 2015. WIfI restaging and assessment of outcomes were performed retrospectively through August 2016. WIfI classification was determined at the following intervals: preoperatively, immediately postoperatively, and 1 month and 6 months after intervention. Amputation-free survival (AFS) was the primary end point. Kaplan-Meier plot analysis and comparisons of preoperative grades with respective postoperative grades were performed using paired t-test, χ2 test, and correlation analyses. RESULTS: A total of 180 limbs and 172 critical limb ischemia patients underwent revascularization, of which 29 limbs had major amputations (16%). Wound grades generally improved after surgery across the entire cohort. Major amputation was associated with preoperative wound grade and remained associated with wound grade at postoperative restaging at 1 month and beyond on the basis of amputation frequency analysis (preoperatively, 1 month, and 6 months, P = .03, < .001, and < .001, respectively). Wound grade was significantly associated with AFS at 1 month and 6 months after intervention (log-rank, P < .001 for restaging intervals). Ischemia grades improved initially with a slight decline across the cohort at 6 months. Ischemia grade at 1 month postoperatively was associated with AFS (log-rank, P = .03). Foot infection grades also improved at each time interval. Foot infection grade was associated with AFS at 1 month postoperatively (log-rank, P < .001) and at 6 months (log-rank, P = .017). CONCLUSIONS: WIfI restaging is an important tool for predicting limb loss and assessing adequacy of intervention, more so than baseline WIfI alone. The 1- and 6-month postoperative ischemia grade correlated with AFS, whereas preoperative grade did not. The 1- and 6-month postoperative wound and foot infection grades additionally correlated with AFS. WIfI restaging at 1 month and 6 months postoperatively may help identify a cohort that remains at higher risk for limb loss and may merit more expeditious reintervention.

Use of the Wound, Ischemia, foot Infection classification system in hemodialysis patients after endovascular treatment for critical limb ischemia.

OBJECTIVE: The Wound, Ischemia, foot Infection (WIfI) classification system is used to predict the amputation risk in patients with critical limb ischemia (CLI). The validity of the WIfI classification system for hemodialysis (HD) patients with CLI is still unknown. This single-center study evaluated the prognostic value of WIfI stages in HD patients with CLI who had been treated with endovascular therapy (EVT). METHODS: A retrospective analysis was performed of collected data on CLI patients treated with EVT between April 2007 and December 2015. All patients were classified according to their wound status, ischemia index, and extent of foot infection into the following four groups: very low risk, low risk, moderate risk, and high risk. Comorbidities and vascular lesions in each group were analyzed. The prognostic value of the WIfI classification was analyzed on the basis of the wound healing rate and amputation-free survival at 1 year. RESULTS: This study included 163 consecutive CLI patients who underwent HD and successful endovascular intervention. The rate of the high-risk group (36%) was the highest among the four groups, and the proportions of very-low-risk, low-risk, and moderate-risk patients were 10%, 18%, and 34%, respectively. The mean follow-up duration was 784 ± 650 days. The wound healing rates at 1 year were 92%, 70%, 75%, and 42% in the very-low-risk, low-risk, moderate-risk, and high-risk groups, respectively (P <.01). A similar trend was observed for the 1-year amputation-free survival among the groups (76%, 58%, 61%, and 46%, respectively; P = .02). CONCLUSIONS: The WIfI classification system predicted the wound healing and amputation risks in a highly selected group of HD patients with CLI treated with EVT, with a statistically significant difference between high-risk patients and other patients.

[Intermittent claudication and critical limb ischemia : from diagnosis to management]. / Patient claudicant et ischémie critique : du diagnostic à la prise en charge.

In case of atheromatous disease, the practitioner should be part of a multidisciplinary decision due to the associated comorbities. The angiologic assessment is of paramount importance in the diagnosis of peripheral artery disease even when the diagnosis seems clear. Unfortunately the patient is very often straightforward sent to radiological investigations who are faster. In all stages of peripheral artery disease, the medical treatment should be tried first except in case of critical limb ischemia where an invasive approach must be performed for revascularisation. In case of lifestyle-limiting symptoms and only after failure of medical treatment a revascularisation strategy is then indicated.

Chez le patient athéromateux, le médecin traitant est souvent au centre d'une prise en charge qui doit être pluridisciplinaire en raison des comorbidités associées. L'examen angiologique est d'une importance primordiale dans le diagnostic de l'insuffisance artérielle des membres inférieurs, même lorsque le diagnostic semble évident. Le patient est malheureusement trop souvent adressé à tort directement en radiologie pour bénéficier d'examens plus rapides. Quel que soit le stade de l'insuffisance artérielle des membres inférieurs, le traitement est toujours médical en première intention sauf au stade d'ischémie critique où un geste invasif de revascularisation est indiqué d'emblée. En cas de symptômes altérants la qualité de vie et seulement après l'échec d'un traitement médical, un geste de revascularisation pourra être proposé.

The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification system predicts wound healing but not major amputation in patients with diabetic foot ulcers treated in a multidisciplinary setting.

OBJECTIVE: The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) threatened limb classification has been shown to correlate well with risk of major amputation and time to wound healing in heterogeneous diabetic and nondiabetic populations. Major amputation continues to plague the most severe stage 4 WIfI patients, with 1-year amputation rates of 20% to 64%. Our aim was to determine the association between WIfI stage and wound healing and major amputation among patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting. METHODS: All patients presenting to our multidisciplinary DFU clinic from July 2012 to December 2015 were enrolled in a prospective database. Wound healing and major amputation were compared for patients stratified by WIfI classification. RESULTS: There were 217 DFU patients with 439 wounds (mean age, 58.3 ± 0.8 years; 58% male, 63% black) enrolled, including 28% WIfI stage 1, 11% stage 2, 33% stage 3, and 28% stage 4. Peripheral arterial disease and dialysis were more common in patients with advanced (stage 3 or 4) wounds (P ≤ .05). Demographics of the patients, socioeconomic status, and comorbidities were otherwise similar between groups. There was a significant increase in the number of active wounds per limb at presentation with increasing WIfI stage (stage 1, 1.1 ± 0.1; stage 4, 1.4 ± 0.1; P = .03). Mean wound area (stage 1, 2.6 ± 0.6 cm2; stage 4, 15.3 ± 2.8 cm2) and depth (stage 1, 0.2 ± 0.0 cm; stage 4, 0.8 ± 0.1 cm) also increased progressively with increasing wound stage (P < .001). Minor amputations (stage 1, 18%; stage 4, 56%) and revascularizations (stage 1, 6%; stage 4, 55%) were more common with increasing WIfI stage (P < .001). On Kaplan-Meier analysis, WIfI classification was predictive of wound healing (P < .001) but not of major amputation (P = .99). For stage 4 wounds, the mean wound healing time was 190 ± 17 days, and risk of major amputation at 1 year was 5.7% ± 3.2%. CONCLUSIONS: Among patients with DFU, the WIfI classification system correlated well with wound healing but was not associated with risk of major amputation at 1 year. Although further prospective research is warranted, our results suggest that use of a multidisciplinary approach for DFUs may augment healing time and reduce amputation risk compared with previously published historical controls of standard wound care among patients with advanced stage 4 disease.