Predictors of bleeding complications during catHeter-dirEcted thrombolysis for peripheral arterial occlusions (POCHET).

INTRODUCTION: The risk of major bleeding complications in catheter directed thrombolysis (CDT) for acute limb ischemia (ALI) remains high, with reported major bleeding complication rates in up to 1 in every 10 treated patients. Fibrinogen was the only predictive marker used for bleeding complications in CDT, despite the lack of high quality evidence to support this. Therefore, recent international guidelines recommend against the use of fibrinogen during CDT. However, no alternative biomarkers exist to effectively predict CDT-related bleeding complications. The aim of the POCHET biobank is to prospectively assess the rate and etiology of bleeding complications during CDT and to provide a biobank of blood samples to investigate potential novel biomarkers to predict bleeding complications during CDT. METHODS: The POCHET biobank is a multicentre prospective biobank. After informed consent, all consecutive patients with lower extremity ALI eligible for CDT are included. All patients are treated according to a predefined standard operating procedure which is aligned in all participating centres. Baseline and follow-up data are collected. Prior to CDT and subsequently every six hours, venous blood samples are obtained and stored in the biobank for future analyses. The primary outcome is the occurrence of non-access related major bleeding complications, which is assessed by an independent adjudication committee. Secondary outcomes are non-major bleeding complications and other CDT related complications. Proposed biomarkers to be investigated include fibrinogen, to end the debate on its usefulness, anti-plasmin and D-Dimer. DISCUSSION AND CONCLUSION: The POCHET biobank provides contemporary data and outcomes of patients during CDT for ALI, coupled with their blood samples taken prior and during CDT. Thereby, the POCHET biobank is a real world monitor on biomarkers during CDT, supporting a broad spectrum of future research for the identification of patients at high risk for bleeding complications during CDT and to identify new biomarkers to enhance safety in CDT treatment.

A systematic review of the neutrophil to lymphocyte and platelet to lymphocyte ratios in patients with lower extremity arterial disease.

Lower extremity arterial disease (LEAD) is caused by atherosclerotic plaque in the arterial supply to the lower limbs. The neutrophil to lymphocyte and platelet to lymphocyte ratios (NLR, PLR) are established markers of systemic inflammation which are related to inferior outcomes in multiple clinical conditions, though remain poorly described in patients with LEAD. This review was carried out in accordance with PRISMA guidelines. The MEDLINE database was interrogated for relevant studies. Primary outcome was the prognostic effect of NLR and PLR on clinical outcomes following treatment, and secondary outcomes were the prognostic effect of NLR and PLR on disease severity and technical success following revascularisation. There were 34 studies included in the final review reporting outcomes on a total of 19870 patients. NLR was investigated in 21 studies, PLR was investigated in two studies, and both NLR & PLR were investigated in 11 studies. Relating to increased levels of systemic inflammation, 20 studies (100%) reported inferior clinical outcomes, 13 (92.9%) studies reported increased disease severity, and seven (87.5%) studies reported inferior technical results from revascularisation. The studies included in this review support the role of elevated NLR and PLR as key components influencing the clinical outcomes, severity, and success of treatment in patients with LEAD. The use of these easily accessible, cost effective and routinely available markers is supported by the present review.

Sex differences in the purinergic 2 receptor-mediated blood pressure response to treadmill exercise in rats with simulated peripheral artery disease.

We investigated the role played by ATP-sensitive purinergic 2 (P2) receptors in evoking the pressor response to treadmill exercise in male and female rats with and without femoral arteries that were ligated for ∼72 h to induce simulated peripheral artery disease (PAD). We hypothesized that PPADS (P2 receptor antagonist, 10 mg iv) would reduce the pressor response to 4 min of treadmill exercise (15 m·min-1, 1° incline) and steady-state exercise plasma norepinephrine (NE) values in male and female rats, and that the magnitude of effect of PPADS would be greater in rats with simulated PAD ("ligated") than in sham-operated rats. In males, PPADS significantly reduced the difference between steady-state exercise and baseline mean arterial pressure (ΔMAP) response to treadmill exercise in sham (n = 8; pre-PPADS: 12 ± 2, post-PPADS: 1 ± 5 mmHg; P = 0.037) and ligated (n = 4; pre-PPADS: 20 ± 2, post-PPADS: 11 ± 3 mmHg; P = 0.028) rats with a similar magnitude of effect observed between groups (P = 0.720). In females, PPADS had no effect on the ΔMAP response to treadmill exercise in sham (n = 6; pre-PPADS: 9 ± 2, post-PPADS: 7 ± 2 mmHg; P = 0.448) or ligated (n = 6; pre-PPADS: 15 ± 2, post-PPADS: 16 ± 3 mmHg; P = 0.684) rats. When NE values were grouped by sex independent of ligation/sham status, PPADS significantly reduced plasma NE in male (P = 0.016) and female (P = 0.027) rats. The data indicate that P2 receptors contribute to the sympathetic response to exercise in both male and female rats but that the sympathoexcitatory role for P2 receptors translates into an obligatory role in the blood pressure response to exercise in male but not in female rats.NEW & NOTEWORTHY Here, we demonstrate that purinergic 2 (P2) receptors contribute significantly to the blood pressure response to treadmill exercise in male rats both with and without simulated PAD induced by femoral artery ligation. We found no role for P2 receptors in the blood pressure response to treadmill exercise in female rats, thus revealing clear sex differences in P2 receptor-mediated blood pressure control during exercise.

Evaluation of Plasma Biomarkers for Causal Association With Peripheral Artery Disease.

BACKGROUND: Hundreds of biomarkers for peripheral artery disease (PAD) have been reported in the literature; however, the observational nature of these studies limits causal inference due to the potential of reverse causality and residual confounding. We sought to evaluate the potential causal impact of putative PAD biomarkers identified in human observational studies through genetic causal inference methods. METHODS: Putative circulating PAD biomarkers were identified from human observational studies through a comprehensive literature search based on terms related to PAD using PubMed, Cochrane, and Embase. Genetic instruments were generated from publicly available genome-wide association studies of circulating biomarkers. Two-sample Mendelian randomization was used to test the association of genetically determined biomarker levels with PAD using summary statistics from a genome-wide association study of 31 307 individuals with and 211 753 individuals without PAD in the Veterans Affairs Million Veteran Program and replicated in data from FinnGen comprised of 11 924 individuals with and 288 638 individuals without PAD. RESULTS: We identified 204 unique circulating biomarkers for PAD from the observational literature, of which 173 were genetically instrumented using genome-wide association study results. After accounting for multiple testing (false discovery rate, <0.05), 10 of 173 (5.8%) biomarkers had significant associations with PAD. These 10 biomarkers represented categories including plasma lipoprotein regulation, lipid homeostasis, and protein-lipid complex remodeling. Observational literature highlighted different pathways including inflammatory response, negative regulation of multicellular organismal processes, and regulation of response to external stimuli. CONCLUSIONS: Integrating human observational studies and genetic causal inference highlights several key pathways in PAD pathophysiology. This work demonstrates that a substantial portion of biomarkers identified in observational studies are not well supported by human genetic evidence and emphasizes the importance of triangulating evidence to understand PAD pathophysiology. Although the identified biomarkers offer insights into atherosclerotic development in the lower limb, their specificity to PAD compared with more widespread atherosclerosis requires further study.

Remnant Cholesterol, Not LDL Cholesterol, Explains Peripheral Artery Disease Risk Conferred by apoB: A Cohort Study.

BACKGROUND: Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction. METHODS: apoB, remnant cholesterol, and LDL cholesterol were measured in 93 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25 347 of the individuals. Results were replicated in 302 167 individuals without statin use from the UK Biobank (2004-2010). RESULTS: In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings. CONCLUSIONS: PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.

Impact of lipoprotein(a) levels on primary patency after endovascular therapy for femoropopliteal lesions.

Lipoprotein(a) [Lp(a)] is a risk factor for peripheral artery disease (PAD). However, the relationship between Lp(a) levels and clinical events after endovascular therapy (EVT) for the femoropopliteal artery in PAD patients remains unclear. Thus, this study aimed to assess the impact of Lp(a) levels on primary patency after EVT for de novo femoropopliteal lesions in PAD patients. A retrospective analysis was conducted on 109 patients who underwent EVT for de novo femoropopliteal lesions, and Lp(a) levels were measured before EVT between June 2016 and December 2019. Patients were divided into low Lp(a) [Lp(a) < 30 mg/dL; 78 patients] and high Lp(a) [Lp(a) ≥ 30 mg/dL; 31 patients] groups. The main outcome was primary patency following EVT. Loss of primary patency was defined as a peak systolic velocity ratio > 2.4 on a duplex scan or > 50% stenosis on angiography. Cox proportional hazards analysis was performed to determine whether high Lp(a) levels were independently associated with loss of primary patency. The mean follow-up duration was 28 months. The rates of primary patency were 83 and 76% at 1 year and 75 and 58% at 2 years in the low and high Lp(a) groups, respectively (P = 0.02). After multivariate analysis, High Lp(a)[Lp(a) ≥ 30 mg/dL] (hazard ratio 2.44; 95% CI 1.10-5.44; P = 0.03) and female sex (hazard ratio 2.65; 95% CI 1.27-5.51; P < 0.01) were independent predictors of loss of primary patency. Lp(a) levels might be associated with primary patency after EVT for de novo femoropopliteal lesions.

Implications of fasting plasma glucose variability on the risk of incident peripheral artery disease in a population without diabetes: a nationwide population-based cohort study.

BACKGROUND: Diabetes have been known as a traditional risk factor of developing peripheral artery disease (PAD). However, the study evaluating the impact of long-term glycemic variability on the risk of developing PAD is limited, especially in a general population without diabetes. METHODS: We included 152,931 individuals without diabetes from the Korean National Health Insurance Service-Health Screening Cohort. Fasting plasma glucose (FPG) variability was measured using coefficient variance (FPG-CV), standard deviation (FPG-SD), and variability independent of the mean (FPG-VIM). RESULTS: A total of 16,863 (11.0%) incident cases of PAD were identified during a median follow-up of 8.3 years. Kaplan-Meier curves showed a progressively increasing risk of PAD in the higher quartile group of FPG variability than in the lowest quartile group (log rank P < 0.001). Multivariable Cox proportional hazard analysis showed the hazard ratio for PAD prevalence as 1.11 (95% CI 1.07-1.16, P < 0.001) in the highest FPG-CV quartile than in the lowest FPG-CV quartile after adjusting for confounding variables, including mean FPG. Similar degree of association was shown in the FPG-SD and FPG-VIM. In sensitivity analysis, the association between FPG variability and the risk of developing PAD persisted even after the participants were excluded based on previously diagnosed diseases, including stroke, coronary artery disease, congestive heart failure, chronic kidney disease, or current smokers or drinkers. Subgroup analysis demonstrated that the effects of FPG variability on the risk of PAD were more powerful in subgroups of younger age, regular exercisers, and those with higher income. CONCLUSIONS: Increased long-term glycemic variability may have a significant prognostic effect for incident PAD in individuals without diabetes.

Serum Legumain Is Associated with Peripheral Artery Disease in Patients with Type 2 Diabetes.

BACKGROUND: Legumain is related to carotid atherosclerotic plaques and may be a new biomarker of carotid atherosclerosis. However, the association between legumain and peripheral artery disease (PAD) of lower extremity has been less studied. This study is aimed at exploring the potential link between legumain and PAD in patients with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional study was conducted on 483 hospitalized T2DM patients. The serum legumain level was measured by a sandwich enzyme-linked immunosorbent assay. PAD was evaluated by color Doppler sonography. The association between legumain and PAD was tested by logistic regression. The predictive power of legumain for PAD was evaluated with the receiver-operating-characteristic (ROC) curve. RESULTS: Overall, 201 (41.6%) patients suffered from PAD. Patients with PAD had significantly higher serum legumain level than those without PAD [11.9 (6.3, 17.9) µg/L vs. 7.6 (3.2, 14.2) µg/L, p < 0.001]. Logistic regression showed that a higher serum legumain level was independently associated with a greater risk of PAD in T2DM patients [adjusted odds ratio (aOR): 1.03; 95% confidence interval (CI): 1.01-1.06]. The area under the ROC curve was 0.634 (95% CI, 0.585 to 0.684). CONCLUSION: High serum legumain level was significantly correlated with an increased risk of PAD in T2DM patients.

Peripheral Artery Disease on The Prognosis Value of Patients with Stable Coronary Artery Disease Undergoing Percutaneous Coronary Intervention: A Retrospective, Single-Center Cohort Study.

OBJECTIVE: The purpose of this investigation aimed to clarify the impact of peripheral artery disease (PAD) on the prognosis value of patients with stable coronary artery disease (CAD) who underwent percutaneous coronary intervention (PCI). METHODS: The SPSS 16 software was used for secondary analysis of DRYAD database data. A total of 204 patients were enrolled from Shinonoi General Hospital for newly diagnosed stable CAD and received PCI performance between October 2014 and October 2017. Patients with old myocardial infarction (MI) were excluded. We divided patients into two groups with PAD and without PAD. The primary endpoints were major adverse cardiac events (MACE, defined as all-cause death, non-fatal MI, and non-fatal stroke) and cardiovascular events (defined as cardiovascular death, non-fatal MI, and non-fatal stroke). The secondary outcomes were the individual components of the composite primary outcomes. The median follow-up time was 783 days. RESULTS: No statistical difference was found between PAD and non-PAD patients of lesional characteristics. Spearman's rank correlations indicate diabetes mellitus (DM) (P = 0.019) and HbA1c (P = 0.009) are positively correlated with PAD. In Kaplan-Meier analysis, patients with PAD predicted poor prognosis in MACE (P < 0.05) and cardiovascular events (P < 0.05). In Multivariable Cox proportional hazards analysis, patients with PAD independently predicted MACE and cardiovascular events. CONCLUSIONS: PAD is a significant mediator for the prognosis of patients with stable CAD who underwent PCI treatment.

The prognostic role of RBP-4 and adiponectin in patients with peripheral arterial disease undergoing lower limb endovascular revascularization.

BACKGROUND: RBP4 is an adipokine with an established role in atherosclerosis, while adiponectin has unique anti-inflammatory properties. We investigated the association of RBP4 and adiponectin with the presence of symptomatic peripheral artery disease (PAD) and their possible prognostic role in major adverse cardiovascular events (MACE). METHODS: We enrolled 168 consecutive patients with symptomatic, established PAD, requiring revascularization by endovascular means of any or both of their lower limbs. 88 age- and sex-matched subjects with less than 2 classical cardiovascular risk factors served as controls. Clinical parameters, glycemic and lipid profile, RBP4 and adiponectin levels were assayed. The occurrence of MACE was recorded during the 6-month follow-up and patients were assigned to MACE and non-MACE subgroups. RESULTS: The presence of symptomatic PAD was significantly correlated with age, diabetes, hsCRP, RBP4 and low adiponectin levels (p < 0.05). After adjustment for age, RBP4 (ß = 0.498, p < 0.001), and adiponectin (ß = -0.288, p < 0.001) levels remained as independent predictors of PAD presence in the whole study cohort. At baseline, MACE subgroup appeared with higher RBP-4 and hsCRP serum levels than non-MACE subgroup (p < 0.001), but no differences were detected for adiponectin (p = 0.758). Serum RBP4 levels remained independent predictor of MACE (ß = 0.455, p < 0.001) after adjustment for traditional cardiovascular risk factors. CONCLUSIONS: High RBP4 and low adiponectin serum levels are independently associated with PAD presence. In addition, RBP4 is an independent predictor of MACE incidence in symptomatic PAD patients.

COVID-19 and acute limb ischemia: a systematic review.

INTRODUCTION: The main goal of this systematic review was to analyze the outcomes of acute limb ischemia (ALI) in patients suffering from the novel Coronavirus: COVID-19 (SARS-CoV-2). EVIDENCE ACQUISITION: A systematic review on Medline and Embase was conducted up to May 15, 2021. All papers were sorted by abstract and full text by two independent authors. Systematic reviews, commentaries, and studies that did not distinguish status of COVID-19 infection were excluded from review. Patient demographics were recorded along with modality of treatment (endovascular and/or surgical). We analyzed 30-day outcomes, including mortality. Primary outcome was to evaluate clinical characteristic of ALI in patients affected by SARS-CoV-2 in term of location of ischemia, treatment options and 30-day outcomes. EVINDENCE SYNTHESIS: We selected 36 articles with a total of 194 patients. Most patients were male (80%) with a median age of 60 years old. The treatment most used was thromboembolectomy (31% of all surgical interventions). A total of 32 patients (19%) were not submitted to revascularization due to critical status. The rate of technical success was low (68%), and mortality rate was high (35%). CONCLUSIONS: This review confirms that SARS-CoV-2 is associated with a high risk of ALI. Further studies are needed to investigate the association and elucidate potential mechanisms, which may include a hypercoagulable state and hyperactivation of the immune response. Furthermore, management of ALI is not standardized and depends on patient condition and extension of the thrombosed segment. ALI in COVID-19 patients is associated with high risk of failure of revascularization and perioperative mortality.

Risk stratification and mortality prediction in octo- and nonagenarians with peripheral artery disease: a retrospective analysis.

OBJECTIVES: Among changes in demographics, aging is the most relevant cardiovascular risk factor. The prevalence of peripheral artery disease (PAD) is high in elderly patients and is associated with a worse prognosis. Despite optimal treatments, mortality in the high-risk population of octo- and nonagenarians with PAD remains excessive, and predictive factors need to be identified. The objective of this study was to investigate predictors of mortality in octo- and nonagenarians with PAD. METHODS: Cases of treated octo- and nonagenarians, including the clinical characteristics and markers of myocardial injury and heart failure, were studied retrospectively with respect to all-cause mortality. Hazard ratios [HR] were calculated and survival was analyzed by Kaplan-Meyer curves and receiver operating characteristic curved were assessed for troponin-ultra and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and chronic limb-threatening ischemia (CLTI). RESULTS: A total of 123 octo- and nonagenarians admitted for PAD were eligible. The troponin level was the major predictor of all-cause mortality (HR: 4.6, 95% confidence interval [CI]: 1.4-15.3), followed by the NT-proBNP level (HR: 3.9, 95% CI 1.8-8.8) and CLTI (HR: 3.1, 95% CI 1.6-5.9). Multivariate regression revealed that each increment of 1 standard deviation in log troponin and log NT-proBNP was associated with a 2.7-fold (95% CI 1.8-4.1) and a 1.9-fold (95% CI 1.2-2.9) increased risk of all-cause death. Receiver operating characteristic curve analysis using a combination of all predictors yielded an improved area under the curve of 0.888. In a control group of an equal number of younger individuals, only NT-proBNP (HR: 4.2, 95% CI 1.2-14.1) and CLTI (HR: 6.1, 95% CI 1.6-23.4) were predictive of mortality. CONCLUSION: Our study demonstrates that cardiovascular biomarkers and CLTI are the primary predictors of increased mortality in elderly PAD patients. Further risk stratification through biomarkers in this high-risk population of octo- and nonagenarians with PAD is necessary.

Lipid profiles of patients with manifest coronary versus peripheral atherosclerosis - Is there a difference?

AIM: Peripheral arterial disease (PAD) and coronary artery disease (CAD) are both caused by atherosclerosis. Serum lipids and lipoproteins are predictive of the development of atherosclerosis but it is not clear if they differ in the two manifestations, PAD and CAD. We tested whether a more detailed characterization of the lipid and lipoprotein patterns of PAD and CAD allows a clear differentiation between the two atherosclerotic phenotypes. METHODS: A cohort of 274 statin-naïve patients with either newly diagnosed imaging proven PAD (n = 89) or stable CAD (n = 185) was characterized using nuclear magnetic resonance- and liquid chromatography-tandem mass spectrometry-based advanced lipid and lipoprotein analysis. An independent cohort of 1239 patients with PAD and CAD was used for validation. RESULTS: We found a significant difference in markers of inflammation as well as ceramide and phosphatidylcholine levels between patients with PAD and CAD. In contrast, basic lipid markers including total cholesterol, LDL cholesterol, HDL cholesterol, lipoprotein(a) or detailed lipoprotein profiles did not differ significantly between patients with PAD and CAD. Applying ratios and scores derived from ceramides and phosphatidylcholines further improved the discrimination between PAD and CAD. These significant differences were independent of body composition, from the status of smoking or type 2 diabetes mellitus, and also from apolipoprotein C-III and other inflammatory parameters which were different between CAD and PAD. CONCLUSION: The present study clearly suggests that PAD and CAD differ in terms of their ceramide- and phosphatidylcholine-based lipid patterns but not in lipoprotein characteristics.

Feasibility of Photo-Optical Transcutaneous Oxygen Tension Measurement During Revascularization of the Lower Extremity.

OBJECTIVES: A novel approach in the evaluation of peripheral arterial disease is the photo-optical oxygen tension measurement (pTCpO2). This modality is suggested to be more practical in use in comparison to standard electro-chemical oxygen tension measurement. Hence, pTCpO2 might be of added value to evaluate revascularization of the lower extremities peri-procedural. We conducted a preliminary feasibility study to analyze the potential of pTCpO2 during revascularization. METHODS: Ten patients scheduled for revascularization of the lower extremities were enrolled. pTCpO2 values of the affected lower extremity were measured pre-operatively, during revascularization and after revascularization. Results were compared to the pre- and postoperative ankle-brachial index (ABI) and to perioperative angiography. Primary endpoint was the feasibility of perioperative pTCpO2 measurement. Secondary endpoints were concordance between pTCpO2, ABI, angiography and clinical outcome. RESULTS: Two out of twelve measurements were unsuccessful. Eight out of ten patients experienced significant clinical improvement and pTCpO2 increase. Two patients that did not experience clinical improvement corresponded with no changes in intraoperative angiography and without increase in ABI or pTCpO2. A significant and strong correlation was found between prior and after revascularization ABI and pTCpO2 measurements (r = 0.82 P = 0.04). CONCLUSIONS: Photo-optical transcutaneous oxygen tension measurement may serve as an intraoperative tool to evaluate the success of revascularization. pTCpO2 could be an alternative for the ABI to determine the success of lower extremity revascularization.

Diagnostic Validation Study. Relationship Between Optical Spectroscopy and Ankle Brachial Index Tests for Peripheral Artery Disease.

INTRODUCTION: Ankle brachial index (ABI) is an essential diagnostic test for peripheral artery disease. It has some important limitations so it can´t always be performed. In those cases, tissue oximetry based on near-infrared spectrum could overcome these limitations. OBJECTIVES: Assessment of the relationship between ABI and tissue oximetry tests and the ability of the oximetry to detect postoperative improvement. METHOD AND MATERIALS: Prospective observational study. Several measures were made by both, ankle pressure and tissue oximetry tests, in lower limbs. Absolute values were collected at foot level (anterior and posterior tibial arteries) and the indexes were calculated in relation to a control (upper limbs for ABI and left infraclavicular region for tissue oximetry). In order to evaluate the correlation between ankle pressure and tissue oximetry values, Pearson correlation coefficient and linear regression analyses were applied. T-Student and ROC curve analysis were made to evaluate the postoperative improvement detected by both ankle pressure and tissue oximetry tests. RESULTS: 60 patients with peripheral artery disease were included. Ankle pressure and tissue oximetry were measured in 70 lower limbs, in 45 of them before and after revascularization. Compared to ankle pressure, tissue oximetry was able to detect improvement in absolute values and indexes after revascularization. This indexes improvement was parallel (P=0.234 for anterior tibial artery and P=0.356 for posterior tibial artery). We weren´t able to determine a cutoff point between both tests (ROC curve analysis). We observed a significative positive correlation in absolute values of both tests (Pearson correlation coefficient, r = 0,281; P < 0.001). CONCLUSION: Tissue oximetry is able to detect improvement after revascularization of lower limbs.

Comparison of Photo-optical Transcutaneous Oxygen Tension Measurement with Electro-chemical Transcutaneous Oxygen Tension Measurement in Patients with Arterial Claudication.

PURPOSE: Photo-optical TCpO2 (pTCpO2) has been proposed as a new method to determine the partial oxygen pressure of the lower extremity in patients with peripheral arterial disease. It is aimed to determine the level of agreement between pTCpO2 and the traditional electro-chemical transcutaneous oxygen tension measurement (eTCpO2). METHODS: Eighteen patients with intermittent claudication underwent simultaneous ankle-brachial index measurement, toe-pressure, pTCpO2 and eTCpO2 tests. Oxygen tension levels were measured on anterior chest and calf prior in rest (T0), during induced ischemia (T1) and after blood flow restoration (T2). TCpO2 agreement was assessed according to the principles of Bland and Altman. RESULTS: Absolute average TCpO2 values differed between eTCpO2 and pTCpO2 for calf in T2 (38,1 mmHg (σ 14,4) vs. 49,8 (σ 22.3) with P = 0.35). The Bland-Altman plots demonstrated eTCpO2 and pTCpO2 bias of 3,7 mmHg (σ 18,8), 11,6 mmHg (σ 17,6) and 6,7 mmHg (σ 23,5) for T0, T1 and T2 for the calf. CONCLUSION: pTCpO2 is in agreement with eTCpO2 in measuring pO2 levels of the lower extremity in rest and during induced ischemia in patients with vascular claudication. The large variability between eTCpO2 and pTCpO2 should be accounted for, while pTCpO2 values have a tendency to demonstrate higher values in comparison to eTCpO2.

High Apolipoprotein E Levels Predict Adverse Limb Events in Patients with Peripheral Artery Disease Due to Peripheral Artery Disease Undergoing Endovascular Treatment and On-Statin Treatment.

Little is known about the association between limb prognosis in peripheral artery disease and apolipoprotein E (apoE). We evaluated the long-term impact of apoE on adverse limb events in patients with intermittent claudication receiving statin treatment.A total of 218 consecutive patients (mean age, 73 ± 8 years; 81% men) with intermittent claudication who underwent their first intervention between 2009 and 2020 were included in this study. All patients had achieved LDL-C < 100 mg/dL on statin treatment and were divided into two groups based on the apoE value (≥ 4.7 or < 4.7 mg/dL). We evaluated the incidence of major adverse limb events (MALEs), including vessel revascularization and limb ischemia development.A total of 39 and 179 patients were allocated to the higher and lower apoE groups, respectively. Compared to the lower apoE group, the higher apoE group had a significantly higher total cholesterol level, triglyceride level, and non-high-density lipoprotein cholesterol level. During the median follow-up period of 3.6 years, 30 patients (13.8%) developed MALEs. Kaplan-Meier analysis revealed that the cumulative incidence of MALEs in the higher apoE group was significantly higher than that in the lower apoE group (44.0% versus 21.6%, log-rank test, P = 0.002). During multivariable Cox hazard analysis, higher apoE level (≥ 4.7 mg/dL) (hazard ratio, 2.61; 95% confidence interval, 1.18-5.70, P = 0.019) was the only strong independent predictor of MALEs.ApoE levels could be a strong predictor and residual risk for long-term limb prognosis in patients with intermittent claudication and achieving LDL-C < 100 mg/dL with statin treatment.

Up and down waves of glycemic control and lower-extremity amputation in diabetes.

Lower extremity amputations (LEA) are associated with a high mortality and medical expenditure. Diabetes accounts for 45% to 70% of LEA and is one of the most potent risk factors for peripheral artery diseases (PAD). The existence of a link between the recent relaxation of glycemic targets and the resurgence of LEA is suggested from the analysis of adult participants in the National Health and Nutrition Examination Survey (NHANES) between 2010 and 2015, when diabetes-related LEA increased by more than 25% associated with a decline in glycemic control. Indeed, in "the perfect wave" of NHANES, including the years 2007-2010, there was the highest number of diabetic people with hemoglobin A1c (HbA1c), non-high-density lipoprotein (HDL) cholesterol and blood pressure levels at their respective targets, associated with the lowest number of LEA. Until now, the ACCORD study, testing the role of aggressive vs conventional glucose control, and the LEADER trial, evaluating the effects of liraglutide versus placebo, have shown a reduced incidence of LEA in people with type 2 diabetes. The results of ongoing clinical trials involving glucagon-like peptide-1 receptor agonists (GLP-1RA, liraglutide or semaglutide) hopefully will tell us whether the wider use of these drugs may provide additional vascular benefits for diabetic people affected by PAD to decrease their risk of LEA.

Elevated plasma levels of NT-proBNP in ambulatory patients with peripheral arterial disease.

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.

Effectiveness of Blood Lipid Management in Patients With Peripheral Artery Disease.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is associated with heightened risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in peripheral artery disease (PAD). Lipid-lowering therapies (LLT) that reduce LDL-C decrease this risk. OBJECTIVES: The authors examined LLT use and actual achieved LDL-C in PAD. METHODS: PAD patients in MarketScan from 2014 to 2018 were identified. Outcomes included LLT use, defined as high-intensity (HI) (high-intensity statin, statin plus ezetimibe, or PCSK9 inhibitor), low-intensity (any other lipid regimen), or no therapy, and follow-up LDL-C. Factors associated with LDL-C <70 mg/dl were identified with multivariable logistic regression. RESULTS: Among 250,103 PAD patients, 20.5% and 39.5% were treated at baseline with HI and low-intensity LLT, respectively; 40.0% were on no LLT. Over a 15-month median follow-up period, HI LLT use increased by 1.5%. Among 18,747 patients with LDL-C data, at baseline, 25.1% were on HI LLT, median LDL-C was 91 mg/dl, and 24.5% had LDL-C <70 mg/dl. Within the HI LLT subgroup, median LDL-C was 81 mg/dl, and 64% had LDL-C ≥70 mg/dl. At follow-up, HI LLT use increased by 3.7%, median LDL-C decreased by 4.0 mg/dl, and an additional 4.1% of patients had LDL-C <70 mg/dl. HI LLT use was greater after follow-up MACE (55.0%) or MALE (41.0%) versus no ischemic event (26.1%). After MACE or MALE, LDL-C was <70 mg/dl in 41.5% and 36.1% of patients, respectively, versus 27.1% in those without an event. Factors associated with follow-up LDL-C <70 mg/dl included smoking, hypertension, diabetes, prior lower extremity revascularization, and prior myocardial infarction but not prior acute or critical limb ischemia. CONCLUSIONS: In PAD, LLT use is suboptimal, LDL-C remains elevated, and LLT intensity is a poor surrogate for achieved LDL-C. Less aggressive lipid management was observed in PAD versus cardiovascular disease, highlighting missed opportunities for implementation of proven therapies in PAD.