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Ben Li,1– 4,* Farah Shaikh,2,* Abdelrahman Zamzam,2 Ravel Raphael,2 Muzammil H Syed,2 Houssam K Younes,5 Rawand Abdin,6 Mohammad Qadura1– 3,7 1Department of Surgery, University of Toronto, Toronto, Ontario, Canada; 2Division of Vascular Surgery, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada; 3Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; 4Temerty Centre for Artificial Intelligence Research and Education in Medicine (T-CAIREM), University of Toronto, Toronto, Ontario, Canada; 5Heart, Vascular, & Thoracic Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; 6Department of Medicine, McMaster University, Hamilton, Ontario, Canada; 7Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Unity Health Toronto, University of Toronto, Toronto, Ontario, Canada*These authors contributed equally to this workCorrespondence: Mohammad Qadura, University of Toronto, Division of Vascular Surgery, St. Michael’s Hospital, Unity Health Toronto, 30 Bond Street, Suite 7-076, Toronto, Ontario, M5B 1W8, Canada, Tel +1 416-864-5154, Email mohammad.qadura@utoronto.caPurpose: Inflammatory biomarkers associated with peripheral artery disease (PAD) have been examined separately; however, an algorithm that includes a panel of inflammatory proteins to inform prognosis of PAD could improve predictive accuracy. We developed predictive models for 2-year PAD-related major adverse limb events (MALE) using clinical/inflammatory biomarker data.Methods: We conducted a prognostic study using 2 phases (discovery/validation models). The discovery cohort included 100 PAD patients that were propensity-score matched to 100 non-PAD patients. The validation cohort included 365 patients with PAD and 144 patients without PAD (non-matched). Plasma concentrations of 29 inflammatory proteins were determined at recruitment and the cohorts were followed for 2 years. The outcome of interest was 2-year MALE (composite of major amputation, vascular intervention, or acute limb ischemia). A random forest model was trained with 10-fold cross-validation to predict 2-year MALE using the following input features: 1) clinical characteristics, 2) inflammatory biomarkers that were expressed differentially in PAD vs non-PAD patients, and 3) clinical characteristics and inflammatory biomarkers.Results: The model discovery cohort was well-matched on age, sex, and comorbidities. Of the 29 proteins tested, 5 were elevated in PAD vs non-PAD patients (MMP-7, MMP-10, IL-6, CCL2/MCP-1, and TFPI). For prognosis of 2-year MALE on the validation cohort, our model achieved AUROC 0.63 using clinical features alone and adding inflammatory biomarker levels improved performance to AUROC 0.84.Conclusion: Using clinical characteristics and inflammatory biomarker data, we developed an accurate predictive model for PAD prognosis.Plain Language Summary: Inflammatory biomarkers associated with peripheral artery disease (PAD) have been examined separately; however, an algorithm that includes an inflammatory protein panel to inform prognosis of PAD may improve predictive accuracy. We developed predictive models for 2-year major adverse limb events (MALE) using clinical characteristics (demographics, comorbidities, and medications) and a panel of 5 PAD-specific inflammatory biomarkers (MMP-7, MMP-10, IL-6, CCL2/MCP-1, and TFPI) that achieved excellent performance on an independent validation cohort (AUROC 0.84). The models developed through this study may support PAD risk-stratification and targeted management strategies.Keywords: inflammatory biomarkers, predictive model, prognosis, peripheral artery disease

Soluble interleukin 1 receptor-like 1 (ST2) is a circulating protein demonstrated to be associated with cardiovascular diseases; however, it has not been studied as a biomarker for peripheral artery disease (PAD). Using a prospectively recruited cohort of 476 patients (312 with PAD and 164 without PAD), we conducted a prognostic study of PAD using clinical/biomarker data. Plasma concentrations of three circulating proteins [ST2, cytokine-responsive gene-2 (CRG-2), vascular endothelial growth factor (VEGF)] were measured at baseline and the cohort was followed for 2 years. The outcome of interest was a 2-year major adverse limb event (MALE; composite of major amputation, vascular intervention, or acute limb ischemia). Using 10-fold cross-validation, a random forest model was trained using clinical characteristics and plasma ST2 levels. The primary model evaluation metric was the F1 score. Out of the three circulating proteins analyzed, ST2 was the only one that was statistically significantly higher in individuals with PAD compared to patients without PAD (mean concentration in plasma of 9.57 [SD 5.86] vs. 11.39 [SD 6.43] pg/mL, p < 0.001). Over a 2-year period, 28 (9%) patients with PAD experienced MALE. Our predictive model, incorporating clinical features and plasma ST2 levels, achieved an F1 score of 0.713 for forecasting 2-year MALE outcomes. Patients identified as high-risk by this model showed a significantly increased likelihood of developing MALE (HR 1.06, 95% CI 1.02-1.13, p = 0.003). By combining clinical characteristics and plasma ST2 levels, our proposed predictive model offers accurate risk assessment for 2-year MALE in PAD patients. This algorithm supports risk stratification in PAD, guiding clinical decisions regarding further vascular evaluation, specialist referrals, and appropriate medical or surgical interventions, thereby potentially enhancing patient outcomes.

Cytokine-induced neutrophil chemoattractant 1 (CINC-1), a cluster of differentiation 95 (CD95), fractalkine, and T-cell immunoglobulin and mucin domain 1 (TIM-1) are circulating proteins known to be involved in inflammation. While their roles have been studied in neurological conditions and cardiovascular diseases, their potential as peripheral artery disease (PAD) biomarkers remain unexplored. We conducted a cross-sectional diagnostic study using data from 476 recruited patients (164 without PAD and 312 with PAD). Plasma levels of CINC-1, CD95, fractalkine, and TIM-1 were measured at baseline. A PAD diagnosis was established at recruitment based on clinical exams and investigations, defined as an ankle-brachial index < 0.9 or toe-brachial index < 0.67 with absent/diminished pedal pulses. Using 10-fold cross-validation, we trained a random forest algorithm, incorporating clinical characteristics and biomarkers that showed differential expression in PAD versus non-PAD patients to predict a PAD diagnosis. Among the proteins tested, CINC-1, CD95, and fractalkine were elevated in PAD vs. non-PAD patients, forming a 3-biomarker panel. Our predictive model achieved an AUROC of 0.85 for a PAD diagnosis using clinical features and this 3-biomarker panel. By combining the clinical characteristics with these biomarkers, we developed an accurate predictive model for a PAD diagnosis. This algorithm can assist in PAD screening, risk stratification, and guiding clinical decisions regarding further vascular assessment, referrals, and medical/surgical management to potentially improve patient outcomes.

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., Competing Interests: Disclosures None., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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.

Background and Objectives: Inflammatory proteins and their prognostic value in patients with carotid artery stenosis (CAS) have not been adequately studied. Herein, we identified CAS-specific biomarkers from a large pool of inflammatory proteins and assessed the ability of these biomarkers to predict adverse events in individuals with CAS. Materials and Methods: Samples of blood were prospectively obtained from 336 individuals (290 with CAS and 46 without CAS). Plasma concentrations of 29 inflammatory proteins were determined at recruitment, and the patients were followed for 24 months. The outcome of interest was a major adverse cardiovascular event (MACE; composite of stroke, myocardial infarction, or death). The differences in plasma protein concentrations between patients with vs. without a 2-year MACE were determined using the independent t -test or Mann-Whitney U test to identify CAS-specific prognostic biomarkers. Kaplan-Meier and Cox proportional hazards analyses with adjustment for baseline demographic and clinical characteristics were performed to assess the prognostic value of differentially expressed inflammatory proteins in predicting a 2-year MACE in patients with CAS. Results: The mean age of the cohort was 68.8 (SD 10.2) years and 39% were female. The plasma concentrations of two inflammatory proteins were significantly higher in individuals with a 2-year MACE relative to those without a 2-year MACE: IL-6 (5.07 (SD 4.66) vs. 3.36 (SD 4.04) pg/mL, p = 0.03) and CD163 (233.825 (SD 230.306) vs. 159.673 (SD 175.669) pg/mL, p = 0.033). Over a follow-up period of 2 years, individuals with elevated levels of IL-6 were more likely to develop MACE (HR 1.269 (95% CI 1.122-1.639), p = 0.042). Similarly, over a 2-year period, patients with high levels of CD163 were more likely to develop MACE (HR 1.413 (95% CI 1.022-1.954), p = 0.036). Conclusions: The plasma levels of inflammatory proteins IL-6 and CD163 are independently associated with adverse outcomes in individuals with CAS. These CAS-specific prognostic biomarkers may assist in the risk stratification of patients at an elevated risk of a MACE and subsequently guide further vascular evaluation, specialist referrals, and aggressive medical/surgical management, thereby improving outcomes for patients with CAS.

Background: Carotid stenosis (CS) is an atherosclerotic disease of the carotid artery that can lead to devastating cardiovascular outcomes such as stroke, disability, and death. The currently available treatment for CS is medical management through risk reduction, including control of hypertension, diabetes, and/or hypercholesterolemia. Surgical interventions are currently suggested for patients with symptomatic disease with stenosis >50%, where patients have suffered from a carotid-related event such as a cerebrovascular accident, or asymptomatic disease with stenosis >60% if the long-term risk of death is <3%. There is a lack of current plasma protein biomarkers available to predict patients at risk of such adverse events. Methods: In this study, we investigated several growth factors and biomarkers of inflammation as potential biomarkers for adverse CS events such as stroke, need for surgical intervention, myocardial infarction, and cardiovascular-related death. In this pilot study, we use a support vector machine (SVM), random forest models, and the following four significantly elevated biomarkers: C-X-C Motif Chemokine Ligand 6 (CXCL6); Interleukin-2 (IL-2); Galectin-9; and angiopoietin-like protein (ANGPTL4). Results: Our SVM model best predicted carotid cerebrovascular events with an area under the curve (AUC) of >0.8 and an accuracy of 0.88, demonstrating strong prognostic capability. Conclusions : Our SVM model may be used for risk stratification of patients with CS to determine those who may benefit from surgical intervention.

Introduction: Blood-based biomarkers for abdominal aortic aneurysm (AAA) have been studied individually; however, we considered a panel of proteins to investigate AAA prognosis and its potential to improve predictive accuracy., Materials and Methods: Using a prospectively recruited cohort of patients with/without AAA ( n = 452), we conducted a prognostic study to develop a model that accurately predicts AAA outcomes using clinical features and circulating biomarker levels. Serum concentrations of 9 biomarkers were measured at baseline, and the cohort was followed for 2 years. The primary outcome was major adverse aortic event (MAAE; composite of rapid AAA expansion [>0.5 cm/6 months or >1 cm/12 months], AAA intervention, or AAA rupture). Using 10-fold cross-validation, we trained a random forest model to predict 2 year MAAE using (1) clinical characteristics, (2) biomarkers, and (3) clinical characteristics and biomarkers., Results: Two-year MAAE occurred in 114 (25%) patients. Two proteins were significantly elevated in patients with AAA compared with those without AAA (angiopoietin-2 and aggrecan), composing the protein panel. For predicting 2 year MAAE, our random forest model achieved area under the receiver operating characteristic curve (AUROC) 0.74 using clinical features alone, and the addition of the 2-protein panel improved performance to AUROC 0.86., Conclusions: Using a combination of clinical/biomarker data, we developed a model that accurately predicts 2 year MAAE.

Abdominal aortic aneurysm (AAA) is a progressive dilatation of the aorta that can lead to aortic rupture. The pathophysiology of the disease is not well characterized but is known to be caused by the general breakdown of the extracellular matrix within the aortic wall. In this comprehensive literature review, all current research on proteins that have been investigated for their potential prognostic capabilities in patients with AAA was included. A total of 45 proteins were found to be potential prognostic biomarkers for AAA, predicting incidence of AAA, AAA rupture, AAA growth, endoleak, and post-surgical mortality. The 45 proteins fell into the following seven general categories based on their primary function: (1) cardiovascular health, (2) hemostasis, (3) transport proteins, (4) inflammation and immunity, (5) kidney function, (6) cellular structure, (7) and hormones and growth factors. This is the most up-to-date literature review on current prognostic markers for AAA and their functions. This review outlines the wide pathophysiological processes that are implicated in AAA disease progression.

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., Competing Interests: All authors declare no competing interests., (© 2024 The Authors.)

Background: Peripheral artery disease (PAD) involves atherosclerosis of the lower extremity arteries and is a major contributor to limb loss and death worldwide. Several studies have demonstrated that interleukins (ILs) play an important role in the development and progression of PAD; however, a comprehensive literature review has not been performed. Methods: A systematic review was conducted and reported according to PRISMA guidelines. MEDLINE was searched from inception to 5 December 2022, and all studies assessing the association between ILs and PAD were included. Results: We included 17 studies from a pool of 771 unique articles. Five pro-inflammatory ILs (IL-1β, IL-2, IL-5, IL-6, and IL-8) and one pro-atherogenic IL (IL-12) were positively correlated with PAD diagnosis and progression. In contrast, two anti-inflammatory ILs (IL-4 and IL-10) were protective against PAD diagnosis and adverse limb events. Specifically, IL-6 and IL-8 were the most strongly associated with PAD and can act as potential disease biomarkers to support the identification and treatment of PAD. Conclusions: Ongoing work to identify and validate diagnostic/prognostic inflammatory biomarkers for PAD has the potential to assist clinicians in identifying high-risk patients for further evaluation and management which could reduce the risk of adverse cardiovascular and limb events.

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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

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., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

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.

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Connolly reports personal fees from BMS, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Portola during the conduct of the study. k. Dr Bosch reported receiving honararium and salary support for conducting research from Bayer. Dr. Eikelboom reports honoraria and grant support from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi-Sankyo, GlaxoSmithKline, Janssen, Sanofi Aventis, and Eli Lilly as well as a personnel award from the Heart and Stroke Foundation. Dr. Anand, receiving lecture fees from Bayer and Janssen. Dr Muehlhofer, being employed by Bayer. Dr Aboyans reports grants and/or honoraria for speaking and consulting from Bayer, Bristol Myers Squibb, Novartis, and Pfizer and personal fees from Boehringer Ingelheim, Amgen, and Bristol Myers Squibb/Pfizer Alliance. Dr. Yusuf reported grants and personal fees from and has received research grants and honoraria and travel reimbursement for speaking from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, AstraZeneca, Cadila Pharmaceuticals, and Sanofi Aventis., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

A man in his 60s who underwent endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm 4 years ago presents with 1 week of abdominal pain, fever and leucocytosis. CT angiogram demonstrated an enlarged aneurysm sac with intraluminal gas and periaortic stranding consistent with infected EVAR. He was clinically unfit for an open surgical intervention due to his significant cardiac comorbidities, including hypertension, dyslipidaemia, type 2 diabetes, recent coronary artery bypass grafting and congestive heart failure secondary to ischaemic cardiomyopathy with an ejection fraction of 30%. Therefore, due to this significant surgical risk, he was treated with percutaneous drainage for the aortic collection and lifelong antibiotics. The patient is well 8 months following presentation with no signs of ongoing endograft infection, residual aneurysm sac enlargement, endoleak or haemodynamic instability., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Circulating fatty acid-binding protein 3 (FABP3) is an effective biomarker of myocardial injury and peripheral artery disease (PAD). The endothelium, which forms the inner most layer of every blood vessel, is exposed to higher levels of FABP3 in PAD or following myocardial injury, but the pathophysiological role of endothelial FABP3, the effect of FABP3 exposure on endothelial cells, and related mechanisms are unknown. Here, we aimed to evaluate the pathophysiological role of endothelial FABP3 and related mechanisms in vitro. Our molecular and functional in vitro analyses show that (1) FABP3 is basally expressed in endothelial cells; (2) inflammatory stress in the form of lipopolysaccharide (LPS) upregulated endothelial FABP3 expression; (3) loss of endogenous FABP3 protected endothelial cells against LPS-induced endothelial dysfunction; however, exogenous FABP3 exposure exacerbated LPS-induced inflammation; (4) loss of endogenous FABP3 protected against LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling pathways. Together, these findings suggest that gain-of endothelial FABP3 exacerbates, whereas loss-of endothelial FABP3 inhibits LPS-induced endothelial dysfunction by promoting cell survival and anti-inflammatory and pro-angiogenic signaling. We propose that an increased circulating FABP3 in myocardial injury or PAD patients may be detrimental to endothelial function, and therefore, therapies aimed at inhibiting FABP3 may improve endothelial function in diseased states., Competing Interests: Conflict of interest The authors declare no conflict of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Dr. John Eikelboom reports consulting fees/honoraria and/or grant support from 10.13039/100004325AstraZeneca, Bayer Boehringer-Ingelheim, Bristol-Myer-Squibb/10.13039/100004319Pfizer, 10.13039/501100002973Daiichi-Sankyo, 10.13039/100004312Eli Lilly & Co, 10.13039/100004330GlaxoSmithKline, 10.13039/100004319Pfizer, 10.13039/100005565Janssen, 10.13039/100004339sanofi-aventis, 10.13039/501100011725Servier. The remaining authors have nothing to disclose., (© 2022 The Authors.)

Background: Levels of inflammatory proteins and their prognostic potential have been inadequately studied in patients with peripheral artery disease (PAD). In this study, we quantified and assessed the ability of inflammatory proteins in predicting PAD-related adverse events., Methods: In this prospective case-control study, blood samples were collected from patients without PAD ( n = 202) and patients with PAD ( n = 275). The PAD cohort was stratified by disease severity based on ankle brachial index (ABI): mild ( n = 49), moderate ( n = 164), and severe ( n = 62). Patients were followed for 2 years. Plasma concentrations of 5 inflammatory proteins were measured: Alpha-2-Macroglobulin (A2M), Fetuin A, Alpha-1-Acid Glycoprotein (AGP), Serum Amyloid P component (SAP), and Adipsin. The primary outcome of our study was major adverse limb event (MALE), defined as the need for vascular intervention (open or endovascular revascularization) or major amputation. The secondary outcome was worsening PAD status, defined as a drop in ABI greater than or equal to 0.15 over the study period. Multivariable logistic regression was performed to assess the prognostic value of inflammatory proteins in predicting MALE, adjusting for confounding variables., Results: Compared to patients without PAD, three inflammatory proteins were differentially expressed in patients with PAD (AGP, Fetuin A, and SAP). The primary outcome (MALE) and secondary outcome (worsening PAD) status were noted in 69 (25%) and 60 (22%) patients, respectively. PAD-related adverse events occurred more frequently in severe PAD patients. Based on our data, the inflammatory protein AGP was the most reliable predictor of primary and secondary outcomes. On multivariable analysis, there was a significant association between AGP and MALE in all PAD disease states [mild: adjusted HR 1.13 (95% CI 1.05-1.47), moderate: adjusted HR 1.23 (95% CI 1.16-1.73), severe: adjusted HR 1.37 (95% CI 1.25-1.85)]. High levels of AGP were associated with lower 2-year MALE-free survival in all PAD disease states [mild (64% vs. 100%, p = 0.02), moderate (64% vs. 85%, p = 0.02), severe (55% vs. 88%, p = 0.02), all PAD (62% vs. 88%, p = 0.01)]., Conclusion: Levels of inflammatory protein AGP may help in risk stratifying PAD patients at high risk of MALE and worsening PAD status and subsequently facilitate further vascular evaluation and initiation of aggressive medical/surgical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Djahanpour, Zamzam, Syed, Jain, Arfan, Abdin and Qadura.)

Blood-based adjunctive measures that can reliably predict abdominal aortic aneurysm (AAA)-related complications hold promise for mitigating the AAA disease burden. In this pilot study, we sought to evaluate the prognostic performance of complement factors in predicting AAA-related clinical outcomes. We recruited consecutive AAA patients (n = 75) and non-AAA patients (n = 75) presenting to St. Michael's Hospital. Plasma levels of complement proteins were assessed at baseline, as well as prospectively measured regularly over a period of 2 years. The primary outcome was the incidence of rapidly progressing AAA (i.e. aortic expansion), defined as change in AAA diameter by either 0.5 cm in 6 months, or 1 cm in 12 months. Secondary outcomes included incidence of major adverse aortic events (MAAE) and major adverse cardiovascular events (MACE). All study outcomes (AAA diameter, MACE and MAAE) were obtained during follow-up. Multivariable adjusted Cox regression analyses were performed to assess the prognostic value of plasma C2 levels in patients with AAA regarding rapid aortic expansion and MAAE and MACE. Event-free survival rates of both groups were also compared. Compared to non-AAA patients, patients with AAA demonstrated significantly higher plasma concentrations of C1q, C4, Factor B, Factor H and Factor D, and significantly lower plasma concentrations of C2, C3, and C4b (p = 0.001). After a median of 24 months from initial baseline measurements, C2 was determined as the strongest predictor of rapid aortic expansion (HR 0.10, p = 0.040), MAAE (HR 0.09, p = 0.001) and MACE (HR 0.14, p = 0.011). Based on the data from the survival analysis, higher levels of C2 at admission in patients with AAA predicted greater risk for rapid aortic expansion and MAAE (not MACE). Plasma C2 has the potential to be a biomarker for predicting rapid aortic expansion, MAAE, and the eventual need for an aortic intervention in AAA patients., (© 2022. The Author(s).)

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.

Fatty acid binding proteins (FABPs) are proteins found in the cytosol that contribute to disorders related to the cardiovascular system, including atherosclerosis and metabolic syndrome. Functionally, FABPs serve as intracellular lipid chaperones, interacting with hydrophobic ligands and mediating their transportation to sites of lipid metabolism. To date, nine unique members of the FABP family (FABP 1-9) have been identified and classified according to the tissue in which they are most highly expressed. In the literature, FABP3 has been shown to be a promising clinical biomarker for coronary and peripheral artery disease. Given the rising incidence of cardiovascular disease and its associated morbidity/mortality, identifying biomarkers for early diagnosis and treatment is critical. In this review, we highlight key discoveries and recent studies on the role of FABP3 in cardiovascular disorders, with a particular focus on its clinical relevance as a biomarker for peripheral artery disease.

Approximately 20% of vascular patients treated with acetyl salicylic acid (i.e., aspirin) demonstrate less than expected platelet inhibition - putting them at a four-fold increased risk of adverse cardiovascular events. Low-dose rivaroxaban (2.5 mg twice daily) in combination with low-dose aspirin has been shown to reduce adverse cardiovascular and limb events when compared to aspirin alone. In this study, light transmission aggregometry was used to measure arachidonic acid-induced platelet aggregation to evaluate the potential of combining low-dose rivaroxaban and aspirin in attenuating or overcoming aspirin non-sensitivity. In the discovery phase, 83 patients with peripheral arterial disease (PAD) taking 81 mg aspirin daily were recruited from the outpatient vascular surgery clinic at St Michael's Hospital between January to September 2021. 19 (23%) were determined to be non-sensitive to aspirin. After ex-vivo addition of 2.5 mg dosage equivalent of rivaroxaban, aspirin non-sensitivity was overcome in 11 (58%) of these 19 patients. In the validation phase, 58 patients with cardiovascular risk factors who were not previously prescribed aspirin were recruited. In this group, ex-vivo addition of 2.5 mg dosage equivalent of rivaroxaban significantly reduced arachidonic acid-induced platelet aggregation in the presence of aspirin. These results demonstrate the potential for low-dose rivaroxaban to overcome aspirin non-sensitivity in patients with PAD. Further studies are needed to evaluate and confirm these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Khan, Popkov, Jain, Djahanpour, Syed, Rand, Eikelboom, Mazer, Al-Omran, Abdin and Qadura.)

Objective: Angiotensin II (Ang II)-induced endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases such as systemic hypertension, cardiac hypertrophy and atherosclerosis. Recently, long noncoding RNAs (lncRNAs) have been shown to play an essential role in the pathobiology of cardiovascular diseases; however, the effect of Ang II on lncRNAs and coding RNAs expression in endothelial cells has not been evaluated. Accordingly, we sought to evaluate the expression profiles of lncRNAs and coding RNAs in endothelial cells following treatment with Ang II., Methods: Human umbilical vein endothelial cells (HUVECs) were cultured and treated with Ang II (10-6 mol/l) for 24 h. The cells were then profiled for the expression of lncRNAs and mRNAs using the Arraystar Human lncRNA Expression Microarray V3.0., Results: In HUVECs following Ang II treatment, from a total of 30 584 lncRNA targets screened, 25 targets were significantly upregulated, while 69 were downregulated. In the same HUVECs samples, from 26 106 mRNA targets screened, 28 targets were significantly upregulated and 67 were downregulated. Of the differentially expressed lncRNAs, RP11-354P11.2 and RP11-360F5.1 were the most upregulated (11-fold) and downregulated (three-fold) lncRNAs, respectively. Assigning the differentially regulated genes into functional groups using bioinformatics reveals numerous genes involved in the nucleotide excision repair and ECM-receptor interaction., Conclusion: This is the first study to profile the Ang II-induced differentially expressed lncRNAs and mRNAs in human endothelial cells. Our results reveal novel targets and substantially extend the list of potential candidate genes involved in Ang II-induced endothelial dysfunction and cardiovascular diseases., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Despite its association with adverse outcomes, peripheral artery disease (PAD) remains undertreated. Cystatin C is elevated in patients with renal disease and may be a marker of cardiovascular disease. We examined the prognostic ability of urinary Cystatin C (uCystatinC) in predicting adverse PAD-related events. In this prospective case-control study, urine samples were collected from patients with PAD ( n = 121) and without PAD ( n = 77). The cohort was followed for 2 years. uCystatinC was normalized to urinary creatinine (uCr) (uCystatinC/uCr; μg/g). The primary outcome was major adverse limb event (MALE; composite of vascular intervention (open or endovascular) or major limb amputation). The secondary outcome was worsening PAD status (drop in ABI ≥ 0.15). Multivariable Cox regression and Kaplan-Meier analyses were performed to assess the prognostic value of uCystatinC/uCr with regards to predicting MALE and worsening PAD status. Our analysis demonstrated that patients with PAD had significantly higher median [IQR] uCystatinC/uCr levels (24.9 μg/g [14.2-32.9] vs. 20.9 μg/g [11.1-27.8], p = 0.018). Worsening PAD status and MALE were observed in 39 (20%) and 34 (17%) patients, respectively. uCystatinC/uCr predicted worsening PAD status with a hazard ratio (HR) of 1.78 (95% CI 1.12-2.83, p = 0.015), which persisted after controlling for baseline demographic and clinical characteristics (adjusted HR 1.79 [95% CI 1.11-2.87], p = 0.017). Patients with high uCystatinC/uCr had a lower 2-year freedom from MALE (77% vs. 89%, p = 0.025) and worsening PAD status (63% vs. 87%, p = 0.001). Based on these data, higher uCystatinC/uCr levels are associated with adverse PAD-related events and have prognostic value in risk-stratifying individuals for further diagnostic vascular evaluation or aggressive medical management.

Background: Despite its significant association with limb loss and death, peripheral artery disease (PAD) remains underdiagnosed and undertreated. The current accepted gold-standard for PAD screening, the ankle brachial index (ABI), is limited by operator dependence, erroneous interpretation, and unreliability in patients with diabetes. Fatty acid binding protein 3 (FABP3) is an intracellular protein that becomes released into circulation and excreted into urine following skeletal muscle injury. We examined the prognostic ability of urinary FABP3 (uFABP3) in predicting adverse PAD-related events., Methods: In this prospective case-control study, urine samples were collected from patients with PAD ( n = 142) and without PAD ( n = 72). The cohort was followed for 2 years. uFABP3 was normalized to urinary creatinine (uCr) (uFABP3/uCr). The primary outcome was major adverse limb event (MALE; composite of vascular intervention [open or endovascular] or major limb amputation). The secondary outcome was worsening PAD status (drop in ABI≥0.15). Cox regression analyses with multivariable adjustment for baseline demographic and clinical variables were performed to assess the prognostic value of uFABP3/uCr with regards to predicting MALE and worsening PAD status., Results: Patients with PAD had significantly higher median [IQR] uFABP3/uCr levels (3.46 [2.45-6.90] vs. 2.61 [1.98-4.62], p = 0.001). MALE and worsening PAD status were observed in 21 (10%) and 28 (14%) patients, respectively. uFABP3/uCr predicted MALE and worsening PAD status with adjusted hazard ratios (HR) of 1.28 (1.16-1.41, p = 0.001) and 1.16 (1.02-1.27, p = 0.021), respectively. Patients with high uFABP3/uCr had a lower 2-year freedom from MALE (86 vs. 96%, p = 0.047) and worsening PAD status (78 vs. 99%, p = 0.001). There was good discriminatory ability for uFABP3/uCr in predicting the primary outcome of MALE, with an area under the receiver operating characteristics curve (AUROC) of 0.78., Conclusions: Measuring uFABP3/uCr levels in patients with PAD can help identify those at high risk of adverse PAD-related events. This study highlights the prognostic value of uFABP3 in risk-stratifying individuals for further diagnostic vascular evaluation or aggressive medical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zamzam, Syed, Jahanpour, Jain, Abdin and Qadura.)

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., (© 2022. The Author(s).)

A woman in her 50s presented with uncontrolled hypertension, chest/back pain, paraplegia, right lower limb ischaemia and acute kidney injury. A CT angiogram demonstrated a type B aortic dissection originating distal to the left subclavian artery to bilateral common iliac arteries complicated by occlusion of the right renal artery and right common iliac artery. She was started on intravenous antihypertensive therapy and transferred to our institution for emergent thoracic endovascular aortic repair. Due to bleeding risk from coagulopathy, a spinal drain was not placed immediately post-operatively but instead was inserted after 24 hours while maintaining a mean arterial pressure of 80-100 mm Hg. Postoperatively, her right lower extremity perfusion was re-established, and her renal function recovered following temporary dialysis. At discharge on postoperative day 13, she regained full neurological function., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

D-dimer and prothrombin fragment (F1+2) levels are elevated in patients with peripheral artery disease (PAD). We examined their prognostic potential in predicting decreasing ABI and major adverse limb events (MALE). A total of 206 patients were recruited from St. Michael’s Hospital and followed for two years. Baseline plasma concentrations of D-dimer and F1+2 were recorded. Pearson’s correlation was used to assess the correlation between the biomarkers and ABI at year 2. During follow-up, multivariable Cox proportional hazard analysis was performed to investigate their role in predicting decreasing ABI (defined as change in ABI > −0.15) and MALE (defined as the need for arterial intervention or major limb amputation). Cumulative survival was assessed using Kaplan−Meier analysis. Baseline D-dimer and F1+2 levels were elevated in PAD patients (median (IQR) 1.34 (0.80−2.20) for D-dimer and 3.60 (2.30−4.74) for F1+2; p = 0.001) compared to non-PAD controls (median (IQR) 0.69 (0.29−1.20) for D-dimer and 1.84 (1.17−3.09) for F1+2; p = 0.001). Both markers were negatively correlated with ABI at year 2 (r = −0.231 for D-dimer, r = −0.49 for F1+2; p = 0.001). Cox analysis demonstrated F1+2 and D-dimer to be independent predictors of PAD status (HR = 1.27, 95% CI = 1.15−1.54; p = 0.013 for D-dimer and HR = 1.28, 95% CI = 1.14−1.58; p = 0.019 for F1+2). Elevated baseline concentrations of D-dimer and F1+2 were associated with high incidence of decreasing ABI and 1- and 2-year event-free survival (62% and 86%, respectively). Combined analysis of D-dimer and F1+2 provides important prognostic information that facilitates risk stratification for future disease progression and MALE outcomes in patients with PAD.

A 63-year-old man presented to an outside hospital with presyncope, back pain, hypotension and inferior ST segment elevations. He received aspirin, ticagrelor and heparin and was transferred to our institution as a Code STEMI (ST-segment elevation myocardial infarction). A coronary angiogram demonstrated multivessel disease but no occlusive lesion for acute intervention. The following day, he developed worsening abdominal/back pain. A CT angiogram (CTA) showed a ruptured infrarenal abdominal aortic aneurysm. He underwent urgent percutaneous endovascular aneurysm repair. CTA on postoperative day (POD) 10 demonstrated a patent stent graft with no endoleak. The patient was discharged on POD 12 in stable condition., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Aspirin is a key antiplatelet therapy for the prevention of thrombotic events in patients with cardiovascular disease. Studies suggest that ≈20% of patients with cardiac disease suffer from aspirin nonsensitivity, a phenomenon characterized by the inability of 81 mg aspirin to inhibit platelet aggregation and/or prevent adverse cardiovascular events., Objectives: To investigate aspirin nonsensitivity in patients with vascular disease and assess the consequences of aspirin nonsensitivity., Methods: One hundred fifty patients presenting to St. Michael's Hospital's outpatient clinics with evidence of vascular disease (peripheral arterial disease or carotid artery stenosis) and a previous prescription of 81 mg of aspirin were recruited in this study. Light transmission aggregometry with arachidonic acid induction was used to determine sensitivity to aspirin. Patients with a maximum aggregation ≥20% in response to arachidonic acid were considered aspirin nonsensitive, as per previous studies., Results: Of the 150 patients recruited, 36 patients (24%) were nonsensitive to 81 mg of aspirin. Of these 36 nonsensitive patients, 30 patients provided a urine sample for urine salicyluric acid analysis (a major metabolite of aspirin). Urine analysis demonstrated that 14 patients were compliant and 16 were noncompliant with their aspirin therapy. Major adverse cardiovascular events and major adverse limb events were significantly higher in the nonsensitive patients compared to sensitive patients (hazard ratio, 3.68; P  < 0.001)., Conclusion: These data highlight the high prevalence of aspirin nonsensitivity and noncompliance in patients with vascular disease and emphasizes the urgent need for improved medical management options for this patient population., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Surgical departments commonly rely on third-party quality improvement registries. As electronic health data become increasingly integrated and accessible within an institution, alternatives to these platforms arise. We present the conceptualization and implementation of an in-house quality improvement platform that provides real-time reports, is less onerous on clinicians and is tailored to an institution's priorities of care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

(1) Introduction: The ankle-brachial index (ABI) is the most widely used method of diagnosing peripheral arterial disease (PAD). However, the uptake of ABIs has been reported to be low in primary care settings across different various healthcare settings; however, this is yet to be investigated within the Canadian context. (2) Objective: Therefore, we sought to assess the rates of ABI usage as well as perceived barriers among primary care practitioners (PCPs) in Toronto, Canada. (3) Methods: A modified questionnaire was electronically sent to 257 PCPs in the Greater Toronto Area (GTA). Questions pertained to frequency, feasibility, utility, and barriers associated with ABI usage in clinical practice. Responses were collected and tallied. (4) Results: A total of 52 PCPs completed the questionnaire. 79% of PCPs did not routinely perform ABIs within their clinical practice, and 56% deemed ABI usage as unfeasible. Constraints in time and staff personnel, as well as complexity of ABI result interpretation, were cited as the major perceived barriers to ABI usage. The overwhelming majority of PCPs viewed alternative forms of diagnosis, such as a blood test for PAD, as being preferable to ABI, as such an approach would enhance diagnostic simplicity and efficiency. (5) Conclusion: ABI usage rates are poor within primary care practices in Toronto, Canada. Alternative approaches for diagnosing PAD may result in greater adoption rates among PCPs and therefore improve the identification of patients with PAD.

Aspirin (ASA) therapy is proven to be effective in preventing adverse cardiovascular events; however, up to 30% of patients are non-sensitive to their prescribed ASA dosage. In this pilot study, we demonstrated, for the first time, how ASA non-sensitivity can be diagnosed using Plateletworks ® , a point-of-care platelet function test. Patients prescribed 81 mg of ASA were recruited in a series of two successive phases-a discovery phase and a validation phase. In the discovery phase, a total of 60 patients were recruited to establish a cut-off point (COP) for ASA non-sensitivity using Plateletworks ® . Each sample was simultaneously cross-referenced with a light transmission aggregometer (LTA). Our findings demonstrated that >52% maximal platelet aggregation using Plateletworks ® had a sensitivity, specificity, and likelihood ratio of 80%, 70%, and 2.67, respectively, in predicting ASA non-sensitivity. This COP was validated in a secondary cohort of 40 patients prescribed 81 mg of ASA using Plateletworks ® and LTA. Our data demonstrated that our established COP had a 91% sensitivity and 69% specificity in identifying ASA non-sensitivity using Plateletworks ® . In summary, Plateletworks ® is a point-of-care platelet function test that can appropriately diagnose ASA non-sensitive patients with a sensitivity exceeding 80%.

N-terminal pro B-type natriuretic peptide (NT-proBNP), a cardiac disease biomarker, has been demonstrated to be a strong independent predictor of cardiovascular events in patients without heart failure. Patients with peripheral arterial disease (PAD) are at high risk of cardiovascular events and death. In this study, we investigated levels of NT-proBNP in patients with PAD compared to non-PAD controls. A total of 355 patients were recruited from outpatient clinics at a tertiary care hospital network. Plasma NT-proBNP levels were quantified using protein multiplex. There were 279 patients with both clinical and diagnostic features of PAD and 76 control patients without PAD (non-PAD cohort). Compared with non-PAD patients, median (IQR) NT-proBNP levels in PAD patients were significantly higher (225 ng/L (120-363) vs 285 ng/L (188-425), p- value = 0.001, respectively). Regression analysis demonstrated that NT-proBNP remained significantly higher in patients with PAD relative to non-PAD despite adjusting for age, sex, hypercholesterolemia, smoking and hypertension [odds ratio = 1.28 (1.07-1.54), p-value <0.05]. Subgroup analysis showed elevated NT-proBNP levels in patients with PAD regardless of prior history of CHF, CAD, diabetes and hypercholesteremia (p-value <0.05). Finally, spearmen's correlation analysis demonstrated a negative correlation between NT-proBNP and ABI (ρ = -0.242; p-value < 0.001). In conclusion, our data shows that patients with PAD in an ambulatory care setting have elevated levels of NT-proBNP compared to non-PAD patients in the absence of cardiac symptoms., Competing Interests: Lastly, Dr. John Eikelboom reports consulting fees/honoraria and/or grant support from Astra-Zeneca, Bayer Boehringer-Ingelheim, Bristol-Myer-Squibb/Pfizer, Daiichi-Sankyo, Eli-Lilly, Glaxo-Smith-Kline, Pfizer, Janssen, Sanofi-Aventis, Servier. The funders also had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. All other authors declare no competing interests. Please note that this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Plasma levels of fatty acid binding protein 3 (pFABP3) are elevated in patients with peripheral artery disease (PAD). Since the kidney filters FABP3 from circulation, we investigated whether urinary fatty acid binding protein 3 (uFABP3) is associated with PAD, and also explored its potential as a diagnostic biomarker for this disease state. A total of 130 patients were recruited from outpatient clinics at St. Michael's Hospital, comprising of 65 patients with PAD and 65 patients without PAD (non-PAD). Levels of uFABP3 normalized for urine creatinine (uFABP3/uCr) were 1.7-folds higher in patients with PAD [median (IQR) 4.41 (2.79-8.08)] compared with non-PAD controls [median (IQR) 2.49 (1.78-3.12), p-value = 0.001]. Subgroup analysis demonstrated no significant effect of cardiovascular risk factors (age, sex, hypertension, hypercholesteremia, diabetes and smoking) on uFABP3/uCr in both PAD and non-PAD patients. Spearmen correlation studies demonstrated a significant negative correlation between uFABP3/uCr and ABI (ρ = - 0.436; p-value = 0.001). Regression analysis demonstrated that uFABP3/Cr levels were associated with PAD independently of age, sex, hypercholesterolemia, smoking, prior history of coronary arterial disease and Estimated Glomerular Filtration rate (eGFR) [odds ratio: 2.34 (95% confidence interval: 1.47-3.75) p-value < 0.001]. Lastly, receiver operator curve (ROC) analysis demonstrated unadjusted area under the curve (AUC) for uFABP3/Cr of 0.79, which improved to 0.86 after adjusting for eGFR, age, hypercholesteremia, smoking and diabetes. In conclusion, our results demonstrate a strong association between uFABP3/Cr and PAD and suggest the potential of uFABP3/Cr in identifying patients with PAD.