Development and evaluation of a prediction model for peripheral artery disease-related major adverse limb events using novel biomarker data.

OBJECTIVE: Prognostic tools for individuals with peripheral artery disease (PAD) remain limited. We developed prediction models for 3-year PAD-related major adverse limb events (MALE) using demographic, clinical, and biomarker data previously validated by our group. METHODS: We performed a prognostic study using a prospectively recruited cohort of patients with PAD (n = 569). Demographic/clinical data were recorded including sex, age, comorbidities, previous procedures, and medications. Plasma concentrations of three biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], fatty acid binding protein 3 [FABP3], and FABP4) were measured at baseline. The cohort was followed for 3 years. MALE was the primary outcome (composite of open/endovascular vascular intervention or major amputation). We trained three machine learning models with 10-fold cross-validation using demographic, clinical, and biomarker data (random forest, decision trees, and Extreme Gradient Boosting [XGBoost]) to predict 3-year MALE in patients. Area under the receiver operating characteristic curve (AUROC) was the primary model evaluation metric. RESULTS: Three-year MALE was observed in 162 patients (29%). XGBoost was the top-performing predictive model for 3-year MALE, achieving the following performance metrics: AUROC = 0.88 (95% confidence interval [CI], 0.84-0.94); sensitivity, 88%; specificity, 84%; positive predictive value, 83%; and negative predictive value, 91% on test set data. On an independent validation cohort of patients with PAD, XGBoost attained an AUROC of 0.87 (95% CI, 0.82-0.90). The 10 most important predictors of 3-year MALE consisted of: (1) FABP3; (2) FABP4; (3) age; (4) NT-proBNP; (5) active smoking; (6) diabetes; (7) hypertension; (8) dyslipidemia; (9) coronary artery disease; and (10) sex. CONCLUSIONS: We built robust machine learning algorithms that accurately predict 3-year MALE in patients with PAD using demographic, clinical, and novel biomarker data. Our algorithms can support risk stratification of patients with PAD for additional vascular evaluation and early aggressive medical management, thereby improving outcomes. Further validation of our models for clinical implementation is warranted.

Fatty acid binding protein 4 has prognostic value in peripheral artery disease.

OBJECTIVE: Peripheral artery disease (PAD) remains undertreated, despite its association with major amputation and mortality. This is partly due to a lack of available disease biomarkers. The intracellular protein fatty acid binding protein 4 (FABP4) is implicated in diabetes, obesity, and metabolic syndrome. Given that these risk factors are strong contributors to vascular disease, we assessed the prognostic ability of FABP4 in predicting PAD-related adverse limb events. METHODS: This was a prospective case-control study with 3 years of follow-up. Baseline serum FABP4 concentrations were measured in patients with PAD (n = 569) and without PAD (n = 279). The primary outcome was major adverse limb event (MALE; defined as a composite of vascular intervention or major amputation). The secondary outcome was worsening PAD status (drop in ankle-brachial index ≥0.15). Kaplan-Meier and Cox proportional hazards analyses adjusted for baseline characteristics were conducted to assess the ability of FABP4 to predict MALE and worsening PAD status. RESULTS: Patients with PAD were older and more likely to have cardiovascular risk factors compared with those without PAD. Over the study period, MALE and worsening PAD status occurred in 162 (19%) and 92 (11%) patients, respectively. Higher FABP4 levels were significantly associated with 3-year MALE (unadjusted hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.04-1.27; adjusted HR, 1.18; 95% CI, 1.03-1.27; P = .022) and worsening PAD status (unadjusted HR, 1.18; 95% CI, 1.13-1.31; adjusted HR, 1.17; 95% CI, 1.12-1.28; P < .001). Three-year Kaplan-Meier survival analysis demonstrated that patients with high FABP4 levels had a decreased freedom from MALE (75% vs 88%; log rank = 22.6; P < .001), vascular intervention (77% vs 89%; log rank = 20.8; P < .001), and worsening PAD status (87% vs 91%; log rank = 6.16; P = .013). CONCLUSIONS: Individuals with higher serum concentrations of FABP4 are more likely to develop PAD-related adverse limb events. FABP4 has prognostic value in risk-stratifying patients for further vascular evaluation and management.

A novel Canadian multidisciplinary acute care pathway for people hospitalised with a diabetic foot ulcer.

This manuscript describes the implementation and initial evaluation of a novel Canadian acute care pathway for people with a diabetic foot ulcer (DFU). A multidisciplinary team developed and implemented an acute care pathway for patients with a DFU who presented to the emergency department (ED) and required hospitalisation at a tertiary care hospital in Canada. Processes of care, length of stay (LOS), and hospitalisation costs were considered through retrospective cohort study of all DFU hospitalizations from pathway launch in December 2018 to December 2020. There were 82 DFU-related hospital admissions through the ED of which 55 required invasive intervention: 28 (34.1%) minor amputations, 16 (19.5%) abscess drainage and debridement, 6 (7.3%) lower extremity revascularisations, 5 (6.1%) major amputations. Mean hospital LOS was 8.8 ± 4.9 days. Mean hospitalisation cost was $20 569 (±14 143): $25 901 (±15 965) when surgical intervention was required and $9279 (±7106) when it was not. LOS and hospitalisation costs compared favourably to historical data. An acute care DFU pathway can support the efficient evaluation and management of patients hospitalised with a DFU. A dedicated multidisciplinary DFU care team is a valuable resource for hospitals in Canada.

Aspirin Resistance in Vascular Disease: A Review Highlighting the Critical Need for Improved Point-of-Care Testing and Personalized Therapy.

Aspirin resistance describes a phenomenon where patients receiving aspirin therapy do not respond favorably to treatment, and is categorized by continued incidence of adverse cardiovascular events and/or the lack of reduced platelet reactivity. Studies demonstrate that one in four patients with vascular disease are resistant to aspirin therapy, placing them at an almost four-fold increased risk of major adverse limb and adverse cardiovascular events. Despite the increased cardiovascular risk incurred by aspirin resistant patients, strategies to diagnose or overcome this resistance are yet to be clinically validated and integrated. Currently, five unique laboratory assays have shown promise for aspirin resistance testing: Light transmission aggregometry, Platelet Function Analyzer-100, Thromboelastography, Verify Now, and Platelet Works. Newer antiplatelet therapies such as Plavix and Ticagrelor have been tested as an alternative to overcome aspirin resistance (used both in combination with aspirin and alone) but have not proven to be superior to aspirin alone. A recent breakthrough discovery has demonstrated that rivaroxaban, an anticoagulant which functions by inhibiting active Factor X when taken in combination with aspirin, improves outcomes in patients with vascular disease. Current studies are determining how this new regime may benefit those who are considered aspirin resistant.

ICD-10 Diagnostic Coding for Identifying Hospitalizations Related to a Diabetic Foot Ulcer.

PURPOSE: To estimate the positive predictive value (PPV) of Canadian ICD-10 diagnostic coding for the identification of hospitalization related to a diabetic foot ulcer (DFU). METHODS: Hospitalizations related to a neuropathic and/or ischemic DFU were identified from the Discharge Abstract Database (DAD) records of a single Canadian tertiary care hospital between April 1, 2002 and March 31, 2019. The first coding approach required a most responsible diagnosis (MRDx) code for diabetes-specific foot ulceration or gangrene (DSFUG group). Three alternative coding approaches were also considered: MRDx code for lower-limb osteomyelitis (osteomyelitis group); lower-limb ulceration (LLU group); or lower-limb atherosclerotic gangrene (atherosclerosis group)-each in conjunction with a non-MRDx DSFUG code on the same DAD record. From all eligible DAD records, random samples were drawn for each coding group. DAD records were independently compared by a masked reviewer who manually abstracted data from the entire hospital record (reference standard). The PPV and 95% CI were generated. RESULTS: Out of 1,460 hospitalizations, a total of 300, 50, 33 and seven records were included from the DSFUG, osteomyelitis, LLU and atherosclerosis samples, respectively. Compared to the reference standard, the PPV for all 390 records was 88.5% (95% CI 84.9 to 91.5). The DSFUG group had the highest PPV (90.0%, 95% CI 86.0 to 93.2), followed by the atherosclerosis (85.7%, 95% CI 42.1 to 99.6), LLU (84.9%, 95% CI 68.1 to 94.9) and osteomyelitis (82.0%, 95% CI 68.6 to 91.4) groups. CONCLUSION: Based on data from a Canadian tertiary care hospital, the specified coding algorithms can be used to identify and study the management and outcomes of people hospitalized with a DFU in Ontario.

Management of a Mycotic Aneurysm in a Patient with COVID-19: A Case Report.

The aim of this paper is to share our experience in managing a patient with Klebsiella pneumoniae mycotic abdominal aortic aneurysm who was also infected with COVID-19. A 69-year-old male was transferred to our hospital for the management of an infra-renal mycotic abdominal aortic aneurysm. During his hospital course, the patient contracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He was intubated due to respiratory distress. Over a short period, his mycotic aneurysm increased in size from 2.5 cm to 3.9 cm. An emergency repair of his expanding aneurysm was achieved using our previously described protocol of coating endovascular stents with rifampin. The patient was managed with a rifampin-coated endovascular stent graft without any major complications. Postoperatively, the patient did not demonstrate any neurological deficits nor any vascular compromise. He remained afebrile during his postoperative course and was extubated sometime thereafter. He was then transferred to the ward for additional monitoring prior to his discharge to a rehab hospital while being on long-term antibiotics. During his hospital stay, he was monitored with serial ultrasounds to ensure the absence of abscess formation, aortic aneurysm growth or graft endoleak. At 6 weeks after stent graft placement, he underwent a CT scan, which showed a patent stent graft, with a residual sac size of 2.5 cm without any evidence of abscess or endoleak. Over a follow-up period of 180 days, the patient remained asymptomatic while remaining on long-term antibiotics. Thus, in patients whose surgical risk is prohibitive, endovascular stent grafts can be used as a bridge to definitive surgical management.

A systematic review and meta-analysis of plain versus drug-eluting balloon angioplasty in the treatment of juxta-anastomotic hemodialysis arteriovenous fistula stenosis.

OBJECTIVE: Owing to the lack of comparative evidence between the endovascular technologies for arteriovenous fistula (AVF) stenosis treatments, we sought to summarize the reported data comparing the effectiveness of different endovascular approaches for the treatment of AVF stenoses at the juxta-anastomotic site. METHODS: We performed a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases were searched from inception to June 12, 2018 for observational and randomized studies that had examined the effectiveness of AVF stenosis treatment using plain percutaneous balloon angioplasty (PTA), cutting balloon angioplasty, drug-eluting balloon (DEB) angioplasty, high-pressure balloon angioplasty, and stenting. Bias was assessed using the Newcastle-Ottawa scale for observational studies and the Cochrane Collaboration tool for randomized studies. Article screening, full-text review, assessment of bias, and data collection were conducted in duplicate, with a third reviewer to reconcile any discrepancies. We conducted a qualitative synthesis of the available evidence and a quantitative meta-analysis for the primary assisted patency outcome. The meta-analysis was conducted using Review Manager, version 5.3, using random effects models, with the I2 statistic used to assess heterogeneity. Statistical significance was set at P < .05. RESULTS: Our search yielded 3683 reports. Of these, three randomized trials and three observational studies were included. Three studies with 342 patients had described the effectiveness of high-pressure balloon angioplasty, conventional PTA, and stenting and had analyzed the data qualitatively. Three studies with 141 patients had investigated native AVF patency after DEB angioplasty and conventional PTA and were included in the meta-analysis. DEB angioplasty showed significantly greater primary assisted patency rates at 12 months after treatment compared with PTA (odds ratio, 3.66; 95% confidence interval, 1.32-10.14; I2 = 49%). No statistically significant differences were found in 6-month primary assisted patency among the treatment groups (odds ratio, 2.03; 95% confidence interval, 0.64-6.45; I2 = 50%). A total of 58 of 72 AVFs remained patent 6 months after DEB angioplasty compared with 45 of 69 at 6 months after PTA. At 12 months after treatment, 48 of 72 AVFs remained patent after DEB angioplasty compared with 23 of 69 AVFs after PTA. CONCLUSIONS: Our findings suggest DEB angioplasty is a more effective treatment option for AVF stenosis at the juxta-anastomotic site compared with PTA. Although DEB angioplasty might provide longer term patency than other endovascular treatments, further high-quality data are needed to confirm this finding.

The economic burden of inpatient diabetic foot ulcers in Toronto, Canada.

OBJECTIVE: Diabetic foot ulcer, which often leads to lower limb amputation, is a devastating complication of diabetes that is a major burden on patients and the healthcare system. The main objective of this study is to determine the economic burden of diabetic foot ulcer-related care. METHODS: We conducted a multicenter study of all diabetic foot ulcer patients admitted to general internal medicine wards at seven hospitals in the Greater Toronto Area, Canada from 2010 to 2015, using the GEMINI database. We compared the mean costs of care per patient for diabetic foot ulcer-related admissions, admissions for other diabetes-related complications, and admissions for the top five most costly general internal medicine conditions, using the Ontario Case Costing Initiative. Regression models were used to determine adjusted estimates of cost per patient. Propensity-score matched analyses were performed as sensitivity analyses. RESULTS: Our study cohort comprised of 557 diabetic foot ulcer patients; 2939 non-diabetic foot ulcer diabetes patients; and 23,656 patients with the top 5 most costly general internal medicine conditions. Diabetic foot ulcer admissions incurred the highest mean cost per patient ($22,754) when compared to admissions with non-diabetic foot ulcer diabetes ($8,350) and the top five most costly conditions ($10,169). Using adjusted linear regression, diabetic foot ulcer admissions demonstrated a 49.6% greater mean cost of care than non-diabetic foot ulcer-related diabetes admissions (95% CI 1.14-1.58), and a 25.6% greater mean cost than the top five most costly conditions (95% CI 1.17-1.34). Propensity-scored matched analyses confirmed these results. CONCLUSION: Diabetic foot ulcer patients incur significantly higher costs of care when compared to admissions with non-diabetic foot ulcer-related diabetes patients, and the top five most costly general internal medicine conditions.

Altered coagulation profile in peripheral artery disease patients.

OBJECTIVE: Peripheral artery disease patients have been shown to be more susceptible to thrombotic events compared to non-peripheral artery disease patients. Therefore, the aim of this study was to investigate the coagulation profile in peripheral artery disease patients with chronic limb threatening ischemia, moderate peripheral artery disease patients with claudication, and non-peripheral artery disease controls. METHODS: Chronic limb threatening ischemia patients were matched to peripheral artery disease patients with claudication and non-peripheral artery disease controls in a 1:1:1 ratio. Each patient had their cytokines, markers of thrombin generation, coagulation factors, natural anti-coagulants, fibrinolysis, and endothelial injury markers assessed. RESULTS: Markers of thrombin activation, thrombin Fragments F1 + 2 (Frag 1 + 2), and thrombin-anti-thrombin complex were found to be significantly elevated in all peripheral artery disease and chronic limb threatening ischemia patients relative to non-peripheral artery disease controls. Similarly, relative to non-peripheral artery disease controls, inflammatory markers including C-reactive protein, soluble platelet factor 4, and neutrophil gelatinase-associated lipocalin were also found to be significantly upregulated in chronic limb threatening ischemia patients, but not in peripheral artery disease patients with claudication. Furthermore, our data demonstrated significant increases in markers of endothelial injury in chronic limb threatening ischemia patients relative to non-peripheral artery disease controls. Finally, decreases in natural anti-coagulants (protein C and protein S) and coagulation factors FIX, FXI, and FXII were also observed in chronic limb threatening ischemia patients when compared with non-peripheral artery disease controls. CONCLUSIONS: Our data suggest that in relation to non-peripheral artery disease controls, chronic limb threatening ischemia patients are more hypercoagulable. However, peripheral artery disease patients with claudication appear to have similar levels of circulating procoagulant markers as non-peripheral artery disease patients. This may explain the increased risk of thrombotic events observed in chronic limb threatening ischemia patients.

Knowledge gap of peripheral artery disease starts in medical school.

OBJECTIVE: Previous data suggest that physicians have suboptimal knowledge about peripheral artery disease (PAD). Our aim was to evaluate Canadian medical students' knowledge of PAD to determine if this knowledge gap exists early in medical training. METHODS: We conducted a descriptive, cross-sectional, interview-based study of graduating medical students at the University of Toronto. We used a standardized questionnaire to evaluate students' knowledge of PAD and coronary artery disease (CAD) in the following domains: clinical presentation, risk factors, preventative measures, treatment, and complications. We calculated mean (standard deviation [SD]) scores for each CAD and PAD knowledge domain and examined for differences in PAD vs CAD scores. RESULTS: Seventy-two graduating medical students participated in this study, of which females accounted for 58%. Nearly all participants reported being exposed to PAD (89%) and CAD (92%) through their medical school curriculum. Overall, medical students scored better in identifying CAD characteristics (mean [SD] score, 16.4 [2.7]) compared with PAD (mean [SD] score, 14.6 [3.2]) (P < .0001). This difference was driven by the inferior performance of students in identifying risk factors (P < .0001), preventative measures (P = .049), and complications (P < .0001) of PAD compared with CAD. Out-of-class exposure (eg, clinical rotation, research experience) had a positive impact on students knowledge of both PAD and CAD. CONCLUSIONS: Our results demonstrate suboptimal knowledge of medical graduates of both CAD and PAD. Although they share common atherosclerotic risk factors and cardiovascular complications, medical students were less likely to associate these with PAD than CAD. We recommend a comprehensive module that incorporates all presentations of atherosclerotic disorders to enhance students' understanding of these pathologies in medical schools.

Thirty-day hospital readmission and emergency department visits after vascular surgery: a Canadian prospective cohort study.

BACKGROUND: Rates of hospital readmission following surgery can serve as a marker for quality of care. The aim of this study was to establish the rates and causes of readmission and emergency department visits after vascular surgery and to understand how these patients are managed. METHODS: We conducted a prospective observational cohort study including all inpatients who underwent major vascular surgery between September 2015 and June 2016 at a tertiary vascular care centre in Toronto. Patients were followed at 30 days after discharge via telephone interview. RESULTS: We enrolled 133 patients (94 men [70.7%] and 39 women [29.3%] with a mean age of 65.3 years). The most common index admission diagnosis was peripheral artery disease (67 patients [50.4%]). At 30 days, 19 patients (14.8%) had been readmitted or had visited the emergency department, most commonly after lower extremity revascularization (19.4%). Ten patients were readmitted a mean of 16.8 days following discharge; surgical site infection was the most common cause for readmission (3 patients). The most common treatment was antimicrobial therapy (4 patients). The mean hospital length of stay was 14.4 days. Nine patients presented to the emergency department a mean of 10.6 days after discharge; 6 reported a wound issue, and most (6 of 9) were managed with oral antibiotic treatment. CONCLUSION: Early readmission/emergency department visits after lower extremity revascularization surgery in patients with peripheral artery disease are common and are often due to surgical site infection or wound-related issues. Follow-up within 7-10 days and a specialized wound care team may help reduce the occurrence of these events.

CONTEXTE: Les taux de réadmission à l'hôpital après une chirurgie peuvent servir d'indicateur de la qualité des soins. L'étude visait à déterminer les taux et les causes de réadmissions et de visites à l'urgence chez les patients ayant subi une chirurgie vasculaire et à étudier la façon dont ces patients étaient pris en charge. MÉTHODES: Nous avons mené une étude de cohorte observationnelle prospective portant sur tous les patients qui ont été hospitalisés pour une importante chirurgie vasculaire entre septembre 2015 et juin 2016 dans un centre de soins tertiaires vasculaires à Toronto. Nous avons fait un suivi téléphonique auprès de ces patients 30 jours après leur congé. RÉSULTATS: Nous avons recruté 133 patients (94 hommes [70,7 %] et 39 femmes [29,3 %] dont l'âge moyen était de 65,3 ans). Le diagnostic le plus courant à l'admission initiale était la maladie artérielle périphérique (67 patients [50,4 %]). À 30 jours, 19 patients (14,8 %) avaient été réhospitalisés ou s'étaient présentés à l'urgence; la plupart avaient initialement subi une revascularisation des membres inférieurs (19,4 %). Dix patients ont été réhospitalisés en moyenne 16,8 jours après leur congé; l'infection du site opératoire était la cause la plus courante de réadmission (3 patients). Le traitement le plus courant chez les patients réhospitalisés était le traitement antimicrobien (4 patients). La durée médiane des séjours à l'hôpital était de 14,4 jours. Neuf patients se sont présentés à l'urgence en moyenne 10,6 jours après leur congé; 6 ont signalé un problème avec leur plaie, et la majorité (6 des 9 patients) ont reçu une antibiothérapie orale. CONCLUSION: Les réadmissions ou les visites à l'urgence de patients atteints d'une maladie artérielle périphérique peu après une chirurgie de revascularisation des membres inférieurs sont courantes et souvent attribuables à une infection du site opératoire ou à des problèmes associés à la plaie. Un suivi après 7 à 10 jours ainsi que les services d'une équipe spécialisée en soin des plaies pourraient contribuer à réduire la fréquence de ce type d'événement.

Thirty-day hospital readmission and emergency department visits after vascular surgery: a Canadian prospective cohort study.

BACKGROUND: Rates of hospital readmission following surgery can serve as a marker for quality of care. The aim of this study was to establish the rates and causes of readmission and emergency department visits after vascular surgery and to understand how these patients are managed. METHODS: We conducted a prospective observational cohort study including all inpatients who underwent major vascular surgery between September 2015 and June 2016 at a tertiary vascular care centre in Toronto. Patients were followed at 30 days after discharge via telephone interview. RESULTS: We enrolled 133 patients (94 men [70.7%] and 39 women [29.3%] with a mean age of 65.3 years). The most common index admission diagnosis was peripheral artery disease (67 patients [50.4%]). At 30 days, 19 patients (14.8%) had been readmitted or had visited the emergency department, most commonly after lower extremity revascularization (19.4%). Ten patients were readmitted a mean of 16.8 days following discharge; surgical site infection was the most common cause for readmission (3 patients). The most common treatment was antimicrobial therapy (4 patients). The mean hospital length of stay was 14.4 days. Nine patients presented to the emergency department a mean of 10.6 days after discharge; 6 reported a wound issue, and most (6 of 9) were managed with oral antibiotic treatment. CONCLUSION: Early readmission/emergency department visits after lower extremity revascularization surgery in patients with peripheral artery disease are common and are often due to surgical site infection or wound-related issues. Follow-up within 7-10 days and a specialized wound care team may help reduce the occurrence of these events.

CONTEXTE: Les taux de réadmission à l'hôpital après une chirurgie peuvent servir d'indicateur de la qualité des soins. L'étude visait à déterminer les taux et les causes de réadmissions et de visites à l'urgence chez les patients ayant subi une chirurgie vasculaire et à étudier la façon dont ces patients étaient pris en charge. MÉTHODES: Nous avons mené une étude de cohorte observationnelle prospective portant sur tous les patients qui ont été hospitalisés pour une importante chirurgie vasculaire entre septembre 2015 et juin 2016 dans un centre de soins tertiaires vasculaires à Toronto. Nous avons fait un suivi téléphonique auprès de ces patients 30 jours après leur congé. RÉSULTATS: Nous avons recruté 133 patients (94 hommes [70,7 %] et 39 femmes [29,3 %] dont l'âge moyen était de 65,3 ans). Le diagnostic le plus courant à l'admission initiale était la maladie artérielle périphérique (67 patients [50,4 %]). À 30 jours, 19 patients (14,8 %) avaient été réhospitalisés ou s'étaient présentés à l'urgence; la plupart avaient initialement subi une revascularisation des membres inférieurs (19,4 %). Dix patients ont été réhospitalisés en moyenne 16,8 jours après leur congé; l'infection du site opératoire était la cause la plus courante de réadmission (3 patients). Le traitement le plus courant chez les patients réhospitalisés était le traitement antimicrobien (4 patients). La durée médiane des séjours à l'hôpital était de 14,4 jours. Neuf patients se sont présentés à l'urgence en moyenne 10,6 jours après leur congé; 6 ont signalé un problème avec leur plaie, et la majorité (6 des 9 patients) ont reçu une antibiothérapie orale. CONCLUSION: Les réadmissions ou les visites à l'urgence de patients atteints d'une maladie artérielle périphérique peu après une chirurgie de revascularisation des membres inférieurs sont courantes et souvent attribuables à une infection du site opératoire ou à des problèmes associés à la plaie. Un suivi après 7 à 10 jours ainsi que les services d'une équipe spécialisée en soin des plaies pourraient contribuer à réduire la fréquence de ce type d'événement.

The Identification and Evaluation of Interleukin-7 as a Myokine Biomarker for Peripheral Artery Disease Prognosis.

Background/Objectives: Myokines have been demonstrated to be associated with cardiovascular diseases; however, they have not been studied as biomarkers for peripheral artery disease (PAD). We identified interleukin-7 (IL-7) as a prognostic biomarker for PAD from a panel of myokines and developed predictive models for 2-year major adverse limb events (MALEs) using clinical features and plasma IL-7 levels. Methods: A prognostic study was conducted with a cohort of 476 patients (312 with PAD and 164 without PAD) that were recruited prospectively. Their plasma concentrations of five circulating myokines were measured at recruitment, and the patients were followed for two years. The outcome of interest was two-year MALEs (composite of major amputation, vascular intervention, or acute limb ischemia). Cox proportional hazards analysis was performed to identify IL-7 as the only myokine that was associated with 2-year MALEs. The data were randomly divided into training (70%) and test sets (30%). A random forest model was trained using clinical characteristics (demographics, comorbidities, and medications) and plasma IL-7 levels with 10-fold cross-validation. The primary model evaluation metric was the F1 score. The prognostic model was used to classify patients into low vs. high risk of developing adverse limb events based on the Youden Index. Freedom from MALEs over 2 years was compared between the risk-stratified groups using Cox proportional hazards analysis. Results: Two-year MALEs occurred in 28 (9%) of patients with PAD. IL-7 was the only myokine that was statistically significantly correlated with two-year MALE (HR 1.56 [95% CI 1.12-1.88], p = 0.007). For the prognosis of 2-year MALEs, our model achieved an F1 score of 0.829 using plasma IL-7 levels in combination with clinical features. Patients classified as high-risk by the predictive model were significantly more likely to develop MALEs over a 2-year period (HR 1.66 [95% CI 1.22-1.98], p = 0.006). Conclusions: From a panel of myokines, IL-7 was identified as a prognostic biomarker for PAD. Using a combination of clinical characteristics and plasma IL-7 levels, we propose an accurate predictive model for 2-year MALEs in patients with PAD. Our model may support PAD risk stratification, guiding clinical decisions on additional vascular evaluation, specialist referrals, and medical/surgical management, thereby improving outcomes.

A machine learning algorithm for peripheral artery disease prognosis using biomarker data.

Peripheral artery disease (PAD) biomarkers have been studied in isolation; however, an algorithm that considers a protein panel to inform PAD prognosis may improve predictive accuracy. Biomarker-based prediction models were developed and evaluated using a model development (n = 270) and prospective validation cohort (n = 277). Plasma concentrations of 37 proteins were measured at baseline and the patients were followed for 2 years. The primary outcome was 2-year major adverse limb event (MALE; composite of vascular intervention or major amputation). Of the 37 proteins tested, 6 were differentially expressed in patients with vs. without PAD (ADAMTS13, ICAM-1, ANGPTL3, Alpha 1-microglobulin, GDF15, and endostatin). Using 10-fold cross-validation, we developed a random forest machine learning model that accurately predicts 2-year MALE in a prospective validation cohort of PAD patients using a 6-protein panel (AUROC 0.84). This algorithm can support PAD risk stratification, informing clinical decisions on further vascular evaluation and management.

Increasing Awareness for Peripheral Artery Disease through the Identification of Novel Biomarkers.

Peripheral artery disease (PAD) is a chronic atherosclerotic disorder that involves the lower extremity arteries, manifesting in claudication, rest pain, and tissue loss [...].

Current Biomarkers for Carotid Artery Stenosis: A Comprehensive Review of the Literature.

Carotid artery stenosis (CAS), an atherosclerotic disease of the carotid artery, is one of the leading causes of transient ischemic attacks (TIA) and cerebrovascular attacks (CVA). The atherogenic process of CAS affects a wide range of physiological processes, such as inflammation, endothelial cell function, smooth muscle cell migration and many more. The current gold-standard test for CAS is Doppler ultrasound; however, there is yet to be determined a strong, clinically validated biomarker in the blood that can diagnose patients with CAS and/or predict adverse outcomes in such patients. In this comprehensive literature review, we evaluated all of the current research on plasma and serum proteins that are current contenders for biomarkers for CAS. In this literature review, 36 proteins found as potential biomarkers for CAS were categorized in to the following nine categories based on protein function: (1) Inflammation and Immunity, (2) Lipid Metabolism, (3) Haemostasis, (4) Cardiovascular Markers, (5) Markers of Kidney Function, (6) Bone Health, (7) Cellular Structure, (8) Growth Factors, and (9) Hormones. This literature review is the most up-to-date and current comprehensive review of research on biomarkers of CAS, and the only review that demonstrated the several pathways that contribute to the initiation and progression of the disease. With this review, future studies can determine if any new markers, or a panel of the proteins explored in this study, may be contenders as diagnostic or prognostic markers for CAS.

Angiogenesis-related proteins as biomarkers for peripheral artery disease.

Background: Angiogenesis plays an important role in peripheral artery disease (PAD) and angiogenesis-related proteins may act as prognostic biomarkers. This study assesses the potential for angiogenesis-related proteins to predict adverse events associated with PAD. Methods: This was a case-control study. Patients with PAD (n = 250) and without PAD (n = 125) provided blood samples and were followed prospectively for three years. Concentrations of 17 angiogenesis-related proteins were measured in plasma. The incidence of major adverse limb event (MALE), defined as a composite of major amputation or vascular intervention, was the primary outcome. Worsening PAD status, defined as a drop in ankle brachial index ≥ 0.15, was the secondary outcome. Multivariable regression adjusted for baseline characteristics was conducted to determine the prognostication value of angiogenesis-related proteins in predicting MALE. Findings: Relative to patients without PAD, 8 proteins related to angiogenesis were expressed differentially in PAD patients. Worsening PAD status and MALE were observed in 52 (14%) and 83 (22%) patients, respectively. Hepatocyte growth factor (HGF) was the most reliable predictor of MALE (adjusted HR 0.79, 95% CI 0.15-0.86). Compared to individuals with high HGF, patients with low HGF had a decreased three-year freedom from MALE [66% vs 88%, p = 0.001], major amputation [93% vs 98%, p = 0.023], vascular intervention [68% vs 88%, p = 0.001], and worsening PAD status [81% vs 91%, p = 0.006]. Interpretation: Measuring plasma levels of HGF in individuals with PAD can assist in identifying patients at elevated risk of adverse events related to PAD who may benefit from additional evaluation or treatment.

Validating fatty acid binding protein 3 as a diagnostic and prognostic biomarker for peripheral arterial disease: A three-year prospective follow-up study.

Background: Patients with peripheral arterial disease (PAD) often remain undiagnosed and therefore suboptimally managed. Here, we investigated the diagnostic and prognostic potential of fatty acid binding protein 3 (FABP3) in patients with PAD. Methods: In the discovery phase, 374 PAD and 184 non-PAD patients were recruited from vascular surgery ambulatory clinics at St. Michael's Hospital (Toronto, Ontario, Canada) between October 4, 2017 to October 29, 2018. The diagnostic ability of baseline FABP3 level was investigated through receiver operator characteristic (ROC) curves to determine two cutoff points: 1) an exclusionary "rule out" cutoff point, and 2) a confirmatory "rule in" cutoff point. Next, these cutoff points were confirmed in the external validation phase using a separate cohort of 312 patients (180 PAD and 132 non-PAD) recruited from ambulatory vascular surgery clinics at St. Michael's Hospital (Canada) between November 6, 2018-July 30, 2019. Cox regression analyses were used to explore the independent association between FABP3 and major adverse limb events (MALE - defined as need for arterial revascularization or major amputation) and decrease in ankle-brachial index (ABI -defined as drop ≥0.15) during 3 years of follow-up. Findings: In the discovery phase, FABP3 levels were significantly elevated in patients with PAD compared to non-PAD patients. ROC analysis demonstrated that FABP3 had an AUC of 0.83 (95% CI: 0.81-0.86, p-value < 0.001). FABP3 exclusionary cutoff was <1.55 ng/ml (sensitivity = 96%; specificity = 40%), whereas FABP3 confirmatory cutoff was >3.55 ng/ml (sensitivity = 43%; specificity = 95%) - values that were confirmed in the external validation phase. Cox regression analysis demonstrated FABP3 to be an independent predictor of increase in MALE [HR = 1.14 (1.03-1.29); p-value = 0.010] and worsening PAD status (drop in ABI >0.15 [HR = 1.11 (1.02-1.19); p-value = 0.009]). Interpretation: Our findings suggested that FABP3 levels can be used as both a diagnostic and prognostic biomarker for PAD, and may facilitate risk stratification in select individuals for purposes of vascular evaluation or intensive medical management. Funding: Funding for this study was provided by the Bill and Vicky Blair Foundation.

The predictive value of interarm systolic blood pressure differences in patients with vascular disease: Sub-analysis of the COMPASS trial.

BACKGROUND AND AIMS: Systolic blood pressure interarm difference (IAD) predicts cardiovascular morbidity and mortality in primary prevention populations. We examined the predictive value of IAD and the effects of treatment with the combination of rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily versus aspirin 100 mg once daily according to IAD in patients with chronic coronary artery disease or peripheral artery disease. METHODS: COMPASS trial patients with IAD <15 mmHg and IAD >15 mmHg were compared with respect to thirty-month incidence risk of: 1) composite of stroke, myocardial infarction, or cardiovascular death (MACE), 2) composite of acute limb-ischemia or vascular amputation (MALE), 3) composite of MACE or MALE, and 4) effects of treatment with the combination versus aspirin alone on these outcomes. RESULTS: 24,539 patients had IAD<15 mmHg and 2,776 had IAD ≥15 mmHg. Relative to patients with IAD ≥15 mm Hg, those with IAD<15 mmHg had similar incidence rates for all measured outcomes including the composite of MACE or MALE (HR 1.12 [95% CI: 0.95 to 1.31], p = 0.19), with the exception of stroke (HR 1.38 [95% CI: 1.02 to 1.88], p = 0.04). Compared to aspirin alone, the combination consistently reduced the composite of MACE or MALE in both IAD <15 mmHg (HR 0.74 [95% CI: 0.65-0.85], p < 0.0001, ARR = -23.1) and IAD>15 mmHg (HR 0.65 [95% CI: 0.44-0.96], p = 0.03; ARR = -32.6, p interaction = 0.53) groups. CONCLUSIONS: Unlike primary prevention populations, measuring IAD for risk stratification purposes does not appear to be useful in patients with established vascular disease.

Urinary neutrophil gelatinase-associated lipocalin (NGAL) can potentially predict vascular complications and reliably risk stratify patients with peripheral arterial disease.

Neutrophil gelatinase-associated lipocalin (NGAL) is expressed in atherosclerotic plaques and implicated in the development of cardiovascular diseases. Peripheral arterial disease (PAD) is an atherosclerotic disease that often results in major cardiovascular events. This study aimed to prospectively examine the potential of urine NGAL (uNGAL) in predicting worsening PAD status and major adverse limb events (MALE). Baseline urine NGAL (uNGAL) and urine creatinine (uCr) concentrations were measured in PAD (n = 121) and non-PAD (n = 77) patients. Levels of uNGAL were normalized for urine creatinine (uNGAL/uCr). Outcomes included worsening PAD status, which was defined as a drop in ankle brachial index (ABI) > 0.15, and major adverse limb events (MALE), which was defined as a need for surgical revascularization or amputations. PAD patients had 2.30-fold higher levels of uNGAL/uCr [median (IQR) 31.8 (17.0-62.5) µg/g] in comparison to non-PAD patients [median (IQR) 73.3 (37.5-154.7) µg/g] (P = 0.011). Multivariate cox analysis showed that uNGAL/uCr levels were independently associated with predicting worsening PAD status and MALE outcomes. Cumulative survival analysis, over follow up period, demonstrated a direct correlation between elevated uNGAL/uCr levels and PAD disease progression and MALE outcomes. These data demonstrate an association between elevated uNGAL/uCr levels and worsening PAD disease status and MALE outcomes, indicating its potential for risk-stratification of PAD patients.