Atherosclerotic Plaque Epigenetic Age Acceleration Predicts a Poor Prognosis and Is Associated With Endothelial-to-Mesenchymal Transition in Humans.

BACKGROUND: Epigenetic age estimators (clocks) are predictive of human mortality risk. However, it is not yet known whether the epigenetic age of atherosclerotic plaques is predictive for the risk of cardiovascular events. METHODS: Whole-genome DNA methylation of human carotid atherosclerotic plaques (n=485) and of blood (n=93) from the Athero-Express endarterectomy cohort was used to calculate epigenetic age acceleration (EAA). EAA was linked to clinical characteristics, plaque histology, and future cardiovascular events (n=136). We studied whole-genome DNA methylation and bulk and single-cell transcriptomics to uncover molecular mechanisms of plaque EAA. We experimentally confirmed our in silico findings using in vitro experiments in primary human coronary endothelial cells. RESULTS: Male and female patients with severe atherosclerosis had a median chronological age of 69 years. The median epigenetic age was 65 years in females (median EAA, -2.2 [interquartile range, -4.3 to 2.2] years) and 68 years in males (median EAA, -0.3 [interquartile range, -2.9 to 3.8] years). Patients with diabetes and a high body mass index had higher plaque EAA. Increased EAA of plaque predicted future events in a 3-year follow-up in a Cox regression model (univariate hazard ratio, 1.7; P=0.0034) and adjusted multivariate model (hazard ratio, 1.56; P=0.02). Plaque EAA predicted outcome independent of blood EAA (hazard ratio, 1.3; P=0.018) and of plaque hemorrhage (hazard ratio, 1.7; P=0.02). Single-cell RNA sequencing in plaque samples from 46 patients in the same cohort revealed smooth muscle and endothelial cells as important cell types in plaque EAA. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally confirmed by TGFß-triggered endothelial-to-mesenchymal transition inducing rapid epigenetic aging in coronary endothelial cells. CONCLUSIONS: Plaque EAA is a strong and independent marker of poor outcome in patients with severe atherosclerosis. Plaque EAA was linked to mesenchymal endothelial and smooth muscle cells. Endothelial-to-mesenchymal transition was associated with EAA, which was experimentally validated. Epigenetic aging mechanisms may provide new targets for treatments that reduce atherosclerosis complications.

Rationale and design for the randomized placebo-controlled double-blind trial studying the effect of single antiplatelet therapy (clopidogrel) versus dual antiplatelet therapy (clopidogrel/acetylsalicylic acid) on the occurrence of atherothrombotic events following lower extremity peripheral transluminal angioplasty (CLEAR-PATH).

RATIONALE: Antiplatelet therapy (APT) is the standard of care after endovascular revascularization (EVR) in patients with peripheral artery disease (PAD). APT aims to prevent both major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Nonetheless, the rates of MACE and MALE after EVR remain high. In coronary artery and cerebrovascular disease, dual APT (DAPT)compared to acetylsalicylic acid alone has been proven to reduce MACE without increasing the risk of major bleeding when applied for a restricted number of weeks. However, within the PAD population, insufficient data are available to understand the potential attributable effect of DAPT over single APT (SAPT). Therefore, prospective randomized studies in targeted study populations are warranted. TRIAL DESIGN: CLEAR-PATH is a Dutch multicenter, double-blind, placebo-controlled, randomized trial comparing SAPT (clopidogrel 75 mg plus placebo) with DAPT (clopidogrel 75 mg plus acetylsalicylic acid 80 mg) in patients with PAD undergoing EVR. CLEAR-PATH includes a time-to-event analysis with a follow-up of one year. The primary composite efficacy endpoint consists of all-cause mortality, nonfatal stroke, nonfatal myocardial infarction, severe limb ischemia, (indication for) re-intervention due to any symptomatic restenosis, re-occlusion, or due to acute limb ischemia, and major amputation. The primary safety endpoint contains major bleeding following the Thrombolysis in Myocardial Infarction classification. The enrolment started in August 2022. In total 450 primary efficacy outcome events are required which expectedly amounts to 1696 subjects. Recruitment will take approximately 36 months. CONCLUSION: CLEAR-PATH will assess the efficacy and safety of DAPT compared to SAPT following EVR in PAD patients. TRIAL REGISTRATION NUMBER: NL80009.041.21.

Outcomes following carotid revascularization for stroke stratified by Modified Rankin Scale and time of intervention.

OBJECTIVES: The relationship between baseline Modified Rankin Scale (mRS) in patients with prior stroke and optimal timing of carotid revascularization is unclear. Therefore, we evaluated the timing of transfemoral carotid artery stenting (tfCAS), transcarotid artery revascularization (TCAR), and carotid endarterectomy (CEA) after prior stroke, stratified by preoperative mRS. METHODS: We identified patients with recent stroke who underwent tfCAS, TCAR, or CEA between 2012 and 2021. Patients were stratified by preoperative mRS (0-1, 2, 3-4, or 5) and days from symptom onset to intervention (time to intervention; ≤2 days, 3-14 days, 15-90 days, and 91-180 days). First, we performed univariate analyses comparing in-hospital outcomes between separate mRS or time-to-intervention cohorts for all carotid intervention methods. Afterward, multivariable logistic regression was used to adjust for demographics and comorbidities across groups, and outcomes between the various intervention methods were compared. Primary outcome was the in-hospital stroke/death rate. RESULTS: We identified 4260 patients who underwent tfCAS, 3130 patients who underwent TCAR, and 20,012 patients who underwent CEA. Patients were most likely to have minimal disability (mRS, 0-1 [61%]) and least likely to have severe disability (mRS, 5 [1.5%]). Patients most often underwent revascularization in 3 to 14 days (45%). Across all intervention methods, increasing preoperative mRS was associated with higher procedural in-hospital stroke/death (all P < .03), whereas increasing time to intervention was associated with lower stroke/death rates (all P < .01). After adjustment for demographics and comorbidities, undergoing tfCAS was associated with higher stroke/death compared with undergoing CEA (adjusted odds ratio, 1.6; 95% confidence interval, 1.3-1.9; P < .01) or undergoing TCAR (adjusted odds ratio, 1.3; 95% confidence interval, 1.0-1.8; P = .03). CONCLUSIONS: In patients with preoperative stroke, optimal timing for carotid revascularization varies with stroke severity. Increasing preoperative mRS was associated with higher procedural in-hospital stroke/death rates, whereas increasing time to-intervention was associated with lower stroke/death rates. Overall, patients undergoing CEA were associated with lower in-hospital stroke/deaths. To determine benefit for delayed intervention, these results should be weighed against the risk of recurrent stroke during the interval before intervention.

An international, multispecialty, expert-based Delphi Consensus document on controversial issues in the management of patients with asymptomatic and symptomatic carotid stenosis.

OBJECTIVE: Despite the publication of various national/international guidelines, several questions concerning the management of patients with asymptomatic (AsxCS) and symptomatic (SxCS) carotid stenosis remain unanswered. The aim of this international, multi-specialty, expert-based Delphi Consensus document was to address these issues to help clinicians make decisions when guidelines are unclear. METHODS: Fourteen controversial topics were identified. A three-round Delphi Consensus process was performed including 61 experts. The aim of Round 1 was to investigate the differing views and opinions regarding these unresolved topics. In Round 2, clarifications were asked from each participant. In Round 3, the questionnaire was resent to all participants for their final vote. Consensus was reached when ≥75% of experts agreed on a specific response. RESULTS: Most experts agreed that: (1) the current periprocedural/in-hospital stroke/death thresholds for performing a carotid intervention should be lowered from 6% to 4% in patients with SxCS and from 3% to 2% in patients with AsxCS; (2) the time threshold for a patient being considered "recently symptomatic" should be reduced from the current definition of "6 months" to 3 months or less; (3) 80% to 99% AsxCS carries a higher risk of stroke compared with 60% to 79% AsxCS; (4) factors beyond the grade of stenosis and symptoms should be added to the indications for revascularization in AsxCS patients (eg, plaque features of vulnerability and silent infarctions on brain computed tomography scans); and (5) shunting should be used selectively, rather than always or never. Consensus could not be reached on the remaining topics due to conflicting, inadequate, or controversial evidence. CONCLUSIONS: The present international, multi-specialty expert-based Delphi Consensus document attempted to provide responses to several unanswered/unresolved issues. However, consensus could not be achieved on some topics, highlighting areas requiring future research.

Interleukin-6 Predicts Carotid Plaque Severity, Vulnerability, and Progression.

BACKGROUND: IL-6 (interleukin-6) has important roles in atherosclerosis pathophysiology. To determine if anti-IL-6 therapy warrants evaluation as an adjuvant stroke prevention strategy in patients with carotid atherosclerosis, we tested whether circulating IL-6 levels predict carotid plaque severity, vulnerability, and progression in the prospective population-based CHS (Cardiovascular Health Study). METHODS: Duplex carotid ultrasound was performed at baseline and 5 years. Baseline plaque severity was scored 0 to 5 based on North American Symptomatic Carotid Endarterectomy Trial grade of stenosis. Plaque vulnerability at baseline was the presence of markedly irregular, ulcerated, or echolucent plaques. Plaque progression at 5 years was a ≥1 point increase in stenosis severity. The relationship of baseline plasma IL-6 levels with plaque characteristics was modeled using multivariable linear (severity) or logistic (vulnerability and progression) regression. Risk factors of atherosclerosis were included as independent variables. Stepwise backward elimination was used with P>0.05 for variable removal. To assess model stability, we computed the E-value or minimum strength of association (odds ratio scale) that unmeasured confounders must have with log IL-6 and the outcome to suppress the association. We performed internal validation with 100 bootstrap samples. RESULTS: There were 4334 participants with complete data (58.9% women, mean age: 72.7±5.1 years), including 1267 (29.2%) with vulnerable plaque and 1474 (34.0%) with plaque progression. Log IL-6 predicted plaque severity (ß=0.09, P=1.3×10-3), vulnerability (OR, 1.21 [95% CI, 1.05-1.40]; P=7.4×10-3, E-value=1.71), and progression (OR, 1.44 [95% CI, 1.23-1.69], P=9.1×10-6, E-value 2.24). In participants with >50% predicted probability of progression, mean log IL-6 was 0.54 corresponding to 2.0 pg/mL. Dichotomizing IL-6 levels did not affect the performance of prediction models. CONCLUSIONS: Circulating IL-6 predicts carotid plaque severity, vulnerability, and progression. The 2.0 pg/mL cutoff could facilitate the selection of individuals that would benefit from anti-IL-6 drugs for stroke prevention.

Female Gene Networks Are Expressed in Myofibroblast-Like Smooth Muscle Cells in Vulnerable Atherosclerotic Plaques.

BACKGROUND: Women presenting with coronary artery disease more often present with fibrous atherosclerotic plaques, which are currently understudied. Phenotypically modulated smooth muscle cells (SMCs) contribute to atherosclerosis in women. How these phenotypically modulated SMCs shape female versus male plaques is unknown. METHODS: Gene regulatory networks were created using RNAseq gene expression data from human carotid atherosclerotic plaques. The networks were prioritized based on sex bias, relevance for smooth muscle biology, and coronary artery disease genetic enrichment. Network expression was linked to histologically determined plaque phenotypes. In addition, their expression in plaque cell types was studied at single-cell resolution using single-cell RNAseq. Finally, their relevance for disease progression was studied in female and male Apoe-/- mice fed a Western diet for 18 and 30 weeks. RESULTS: Here, we identify multiple sex-stratified gene regulatory networks from human carotid atherosclerotic plaques. Prioritization of the female networks identified 2 main SMC gene regulatory networks in late-stage atherosclerosis. Single-cell RNA sequencing mapped these female networks to 2 SMC phenotypes: a phenotypically modulated myofibroblast-like SMC network and a contractile SMC network. The myofibroblast-like network was mostly expressed in plaques that were vulnerable in women. Finally, the mice ortholog of key driver gene MFGE8 (milk fat globule EGF and factor V/VIII domain containing) showed retained expression in advanced plaques from female mice but was downregulated in male mice during atherosclerosis progression. CONCLUSIONS: Female atherosclerosis is characterized by gene regulatory networks that are active in fibrous vulnerable plaques rich in myofibroblast-like SMCs.

Surveillance After Surgical and Endovascular Treatment for Peripheral Artery Disease: a Dutch Survey.

OBJECTIVE: At present, there is no clear, optimal approach to surveillance after invasive treatment of peripheral artery disease (PAD) in terms of modality, duration, clinical benefit, and cost effectiveness. The ongoing debate on the clinical benefit and cost effectiveness of standard surveillance creates a clear knowledge gap and may result in overtreatment or undertreatment. In this study, a survey was conducted among vascular surgeons in the Netherlands to assess the currently applied surveillance programmes. METHODS: All vascular surgeons from the Dutch Society for Vascular Surgery received an online survey on follow up after open and endovascular revascularisation in patients with PAD. Surveillance was defined as at least one follow up visit after intervention with or without additional imaging or ankle brachial index (ABI) measurement. Ten types of PAD intervention were surveyed. RESULTS: Surveys were returned by 97 (46.2%) of 210 vascular surgeons, and 76% reported using a routine follow up protocol after an invasive intervention. Clinical follow up only is most commonly performed after femoral endarterectomy (53%). After peripheral bypass surgery, clinical follow up only is applied rarely (4 - 8%). In six of the 10 interventions surveyed, duplex ultrasound (DUS) was the most used imaging modality for follow up. After bypass surgery, 76 - 86% of vascular surgeons perform DUS with or without ABI measurement. After endovascular interventions, 21 - 60% performed DUS surveillance. Lifelong surveillance is most often applied after aortobifemoral bypass (57%). Surveillance frequency and duration vary greatly within the same intervention. Frequencies range from every three or six months to annually. Duration ranges from one time surveillance to lifelong follow up. CONCLUSION: There is significant practice variation in surveillance after surgical and endovascular treatment of patients with PAD in the Netherlands. Prospective studies to evaluate treatment outcomes and to define the clinical need and cost effectiveness of standardised surveillance programmes for patients with PAD are recommended.

Similar long-term outcomes for venous, bovine pericardial, and polyester patches for primary carotid endarterectomy.

BACKGROUND: Currently, the type of patch used for carotid endarterectomy closure depends on the preference of the operating surgeon. Various materials are available, including autologous venous patches, bovine pericardial patches (BPP), and synthetic patches. The purpose of this study was to compare the long-term outcomes. METHODS: All patients who underwent primary carotid endarterectomy with patch angioplasty using a venous, bovine, or polyester patch between 2010 and 2020 at two high-volume medical centers were included in this retrospective analysis on largely prospectively collected data. Study endpoints included long-term ipsilateral transient ischemic attack or cerebrovascular accident, restenosis, reintervention, and all-cause mortality. Cox proportional hazard models were fitted to assess the effect of patch type to each outcome. RESULTS: In total, 1481 CEAs were performed with a follow-up of 32 (13-65) months. Venous patch was used in 309 patients (20.9%), BPP in 1000 patients (67.5%), and polyester patch in 172 patients (11.6%). A preoperative symptomatic carotid artery stenosis of >50% was observed in 91.9% (n = 284) of the patients who received a venous patch, 92.1% (n = 921) of the patients who received BPP, and 90.7% (n = 156) of the patients who received a polyester patch (p = 0.799). Only in selected patients with an asymptomatic stenosis of >70% surgery was considered. Multivariable analyses showed no significant differences between the three patch types regarding long-term outcomes after adjusting for confounders. CONCLUSIONS: In patients undergoing primary carotid endarterectomy, the use of venous, bovine pericardial, or polyester patches seems equally safe and durable in terms of comparability in long-term outcomes.

Long-Term Stroke Risk in Patients With New Ischemic Brain Lesions on MRI After Carotid Revascularization.

BACKGROUND: Carotid artery revascularization can result in new ischemic brain lesions on diffusion-weighted magnetic resonance imaging. This study aimed to investigate the relationship between periprocedural ischemic diffusion-weighted imaging (DWI) lesions after carotid artery revascularization and recurrent long-term cerebrovascular events. METHODS: A secondary observational prospective cohort analysis of existing clinical trial data was performed on 162 patients with symptomatic carotid stenosis that were previously randomized to carotid artery stenting or carotid endarterectomy in the ICSS (International Carotid Stenting Study) and included in the magnetic resonance imaging substudy. Magnetic resonance imagings were performed 1 to 7 days before and 1 to 3 days after treatment. The primary composite clinical outcome was the time to any stroke or transient ischemic attack during follow-up. Patients with new diffusion-weighted imaging (DWI) lesions on posttreatment magnetic resonance imaging scan (DWI+) were compared with patients without new lesions (DWI-). RESULTS: The median time of follow-up was 8.6 years (interquartile range, 5.0-12.5). Kaplan-Meier cumulative incidence for the primary outcome after 12.5-year follow-up was 35.3% (SE, 8.9%) in DWI+ patients and 31.1% (SE, 5.6%) in DWI- patients. Uni- and multivariable regression analyses did not show significant differences (hazard ratio, 1.50 [95% CI, 0.76-2.94] and hazard ratio, 1.30 [95% CI, 0.10-1.02], respectively). Higher event rate of the primary outcome in DWI+ patients in the overall cohort was mainly caused by events in the carotid artery stenting group. CONCLUSIONS: Based on our outcome analysis within the ICSS magnetic resonance imaging substudy, DWI lesions following carotid revascularization did not seem to have a relationship with long-term stroke risk. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: ISRCTN 25337470.

Temporal Trends and Determinants of Stroke Risk in Patients With Medically Treated Asymptomatic Carotid Stenosis.

BACKGROUND: Effectiveness of carotid procedures (surgery and stenting) in patients with asymptomatic carotid artery stenosis (ACAS) depends on the absolute risk reduction that patients might receive from these procedures. We aimed to quantify the risk of ipsilateral ischemic stroke and examined temporal trends and determinants of these risks in patients with ACAS treated conservatively. METHODS: We conducted a systematic review from inception to March 9, 2023, of peer-reviewed trials and cohort studies describing ipsilateral ischemic stroke risk in medically treated patients with ACAS of ≥50%. Risk of bias was assessed with an adapted version of the Quality in Prognosis Studies tool. We calculated the annual incidence rates of ipsilateral ischemic stroke. We explored temporal trends and associations of sex and degree of stenosis with ipsilateral ischemic stroke using Poisson metaregression analysis and incidence rate ratios, respectively. RESULTS: After screening 5915 reports, 73 studies describing ipsilateral ischemic stroke rates of 28 625 patients with midyear of recruitment ranging from 1976 to 2014 were included. The incidence of ipsilateral ischemic stroke was 0.98 (95% CI, 0.93-1.04) per 100 patient-years (median duration of follow-up, 3.3 years). The incidence decreased 24% with every 5 years more recent midyear of recruitment (rate ratio, 0.76 [95% CI, 0.73-0.78]). Incidence rates of ipsilateral ischemic stroke were lower in female patients (rate ratio, 0.74 [95% CI, 0.63-0.87]) and in patients with moderate versus severe stenosis when assessed in cohort studies, with incidence rate ratios of 0.41 ([95% CI, 0.35-0.49] cutoff, 70%) and 0.42 ([95% CI, 0.30-0.59] cutoff, 80%). CONCLUSIONS: Reported risks of ipsilateral ischemic stroke in patients with ACAS have declined 24% every 5 years from mid-1970s onward, further challenging the routine use of carotid procedures. Risks were lower in female patients and more than twice as high with severe compared with moderate ACAS. Inclusion of these findings in individualized risk assessment can help to determine the benefit of carotid procedures in selected individual patients with ACAS. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42021222940.

Patch angioplasty during carotid endarterectomy using different materials has similar clinical outcomes.

OBJECTIVE: Patch angioplasty during carotid endarterectomy (CEA) is commonly used to treat carotid artery stenosis. However, the choice of which patch to use remains a matter of debate. Autologous venous material has disadvantages such as wound-related problems at the harvest site and a prolonged intervention time. These limitations can be bypassed when synthetic or biological patches are used. Both materials have been associated with divergent advantages and disadvantages. Therefore, the aim of our study was to compare the long-term follow-up outcomes in patients who underwent CEA and closure with either a bovine pericardial patch (BPP) or polyester patch. METHODS: A retrospective cohort study was conducted including all patients who underwent primary CEA and closure with a BPP or a polyester patch between January 2010 and December 2020 at our tertiary referral center. In 2015, the BPP was introduced as an alternative for polyester. The primary outcome was the occurrence of transient ischemic attack (TIA) or cerebrovascular accident (CVA) during follow-up and secondary outcomes included restenosis, reintervention, all-cause mortality, and patch infection. Cox proportional hazard models were used and hazard ratios with 95% confidence intervals were used to predict these outcomes. RESULTS: We included 417 CEA patients; 254 patients (61%) received a BPP and 163 received (39%) a polyester patch. The mean age was 70.2 ± 8.7 years and 67% were male. The median follow-up time was 15 months (range, 12-27 months) for BPP and 42 months (range, 16-60 months) for polyester (P < .001). Postoperative hematoma (≤30 days) was significantly lower in the BPP cohort (2% BPP vs 6% polyester; P = .047). No other significant differences on short-term outcomes were found. Univariable Cox regression analyses showed no significant differences between the effect estimates of polyester and BPP on TIA or CVA (P = .106), restenosis (P = .211), reintervention (P = .549), or all-cause mortality (P = .158). No significant differences were found after adjusting for confounders in the multivariable analyses: TIA or CVA (P = .939), restenosis (P = .057), reintervention (P = .193) and all-cause mortality (P = .742). Three patients with a polyester patch had patch infection compared with none of the patients in the group who received a BPP. CONCLUSIONS: This large retrospective study showed comparable safety and durability of both BPP and polyester suggesting that both patch types can be safely applied for CEA with patch angioplasty. Patch infection was rare and was absent in the BPP group.

In-hospital outcomes after carotid endarterectomy for stroke stratified by modified Rankin scale score and time of intervention.

OBJECTIVE: Although the benefits of carotid endarterectomy (CEA) for treating symptomatic carotid stenosis are well known, the optimal timing of intervention after acute stroke and whether the optimal timing will vary with preoperative stroke severity has remained unclear. Therefore, we assessed the effect of stroke severity and timing of the intervention on the postoperative outcomes for patients who had undergone CEA for stroke. METHODS: We identified all patients in the Vascular Quality Initiative who had undergone CEA from 2012 to 2020 for prior stroke. The patients were stratified using the preoperative modified Rankin scale score (mRS score, 0-5) and time to CEA after stroke onset (≤2 days, 3-14 days, 15-90 days, 91-180 days). After univariate comparisons, the patients were stratified into the following mRS cohorts for further analysis: 0 to 1, 2, 3 to 4, and 5. The primary outcome was in-hospital stroke/death. RESULTS: We identified 15,601 patients, of whom 30% had had an mRS score of 0, 34% an mRS score of 1, 17% an mRS score of 2, 11% an mRS score of 3, 8% an mRS score of 4, and 1% an mRS score of 5. Overall, 9.3% of the patients had undergone CEA within ≤2 days, 46% within 3 to 14 days, 36% in 15 to 90 days, and 8.4% within 90 to 180 days. A decreasing mRS score and an increasing time to CEA were associated with lower rates of perioperative stroke/death (Ptrend < .01). After risk adjustment, with CEA at 3 to 14 days as the comparator group, the mRS score 0 to 1 group had had a higher incidence of stroke/death after CEA within ≤2 days (3.6% vs 2.0%; odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.7). The mRS score 2 group had had a similar incidence of stroke/death after CEA within ≤2 days (4.4% vs 3.9%; OR, 1.2; 95% CI, 0.6-2.3) but a lower incidence after CEA at 15 to 90 days (2.1% vs 3.9%; OR 0.5; 95% CI, 0.3-0.96). The mRS score 3 to 4 group had had a higher incidence of stroke/death after CEA within ≤2 days (8.0% vs 3.8%; OR, 2.4; 95% CI, 1.5-3.9) but a similar incidence of stroke/death after CEA at 15 to 90 days (3.0% vs 3.8%; OR, 0.8; 95% CI, 0.5-1.3). For the mRS score 5 group, the stroke/death rates were ≥6.5% across all the time to CEA groups. However, the low sample size limited meaningful comparisons. CONCLUSIONS: Patients with minimal disability after stroke (mRS score, 0-1) seemed to benefit from CEA within 3 to 14 days. However, those with severe disability (mRS score 5) have a very high risk from CEA at any time point given the poor outcomes. In contrast to the current guidelines, patients with mild disability (mRS score 2) could benefit from delaying CEA to 15 to 90 days, and those with moderate disability (mRS score 3-4) might benefit from CEA within 3 to 90 days given the acceptable in-hospital outcomes. These data should be considered within the context of the clinical situation in the weeks after index event to determine the net benefit of delayed CEA.

Postprocedural Management in Patients After Percutaneous Deep Venous Arterialization: An Expert Opinion.

CLINICAL IMPACT: After percutaneous deep venous arterialization (pDVA), the created arteriovenous circuit needs time to develop. Postprocedural care in patients after pDVA is essential in order to create optimal conditions for maturation of the circuit, and thus save the limb. However, current literature mainly focusses on the procedure itself, making postprocedural care an underexposed topic. Therefore, this study presents an overview of the available literature of postprocedural care of pDVA patients and provides recommendations based on expert opinion when current knowledge is limited.

Multicenter Case Series and Literature Review on Durability of Stents in the Thoracic Outlet.

PURPOSE: The aim of this paper was to report our experience with arterial and venous endovascular stent placement in the thoracic outlet (TO) and review available literature. METHODS: All patients that underwent arterial or venous stent placement in the TO between 2013 and 2020 in 5 Dutch vascular teaching-hospitals were retrospectively identified. Primary endpoint was symptomatic stent failure due to stenosis, chronic or posture dependent compression, fracture, or occlusion of the stent. Secondary endpoints were symptoms at last follow-up and re-interventions. For the literature review, we searched studies reporting on stenting in the TO. RESULTS: Twenty-six patients were included with 11 arterial and 15 venous stents implanted to treat angioplasty resistant stenosis in arterial or venous TO syndrome, iatrogenic or traumatic vascular injury, radiotherapy fibrosis, or arterial dissection. Median follow-up was 19 and 14 months in the arterial and venous-group, respectively. Eight (73%) patients in the arterial, and 9 (60%) in the venous-group suffered symptomatic stent failure. Seven (64%) patients in the arterial, and 9 (60%) in the venous-group required at least 1 re-intervention. When comparing all patients with stent placement after TO decompression (TOD) to patients without, there were substantially more symptomatic stent failures and re-interventions required in the patients without TOD. Six patients (54%) in the arterial-group and 11 (73%) in the venous-group were symptom-free at last follow-up. Five articles describing 51 patients with arterial and 6 articles describing 81 patients with venous stents were included in the literature review. In the arterial-group, no TOD prior to stent placement was performed, while in the venous-group all but 1 article performed TOD prior to stent placement. Results showed comparable rates of symptomatic stent failure (24% vs 30%), and patients requiring re-interventions (29% vs 21%) between groups. CONCLUSION: Based on our multicenter series and review, stents in the TO have a considerable risk of failure, both in the venous and the arterial territory. Especially in patients without TOD: the need for re-interventions is high and half the patients eventually undergo TOD. Based on the currently available data, stenting in the TO should be applied cautiously while TOD should be considered.

A Delphi Consensus Study on Undergoing Carotid Endarterectomy: Patient Reported Outcome Measures.

OBJECTIVE: Currently, evidence is lacking for disease specific patient reported outcome measures (PROMs) for use in atherosclerotic carotid artery stenosis (either symptomatic or asymptomatic) submitted to carotid endarterectomy (CEA). This study aimed to obtain expert consensus on the most important items to include in a PROM designed to capture the impact of atherosclerotic carotid artery stenosis and its treatment on health related quality of life. METHODS: A three round modified Delphi consensus study was performed. A mixed expert Delphi panel of doctors (international panel of dedicated vascular surgeons and neurologists) and patients (either symptomatic or asymptomatic patients meeting criteria for carotid artery revascularisation) was implemented. The aim was to obtain pre-defined consensus on items in four pre-defined domains: generic, quality of life, symptom related, and treatment related. Consensus was reached in rounds two and three with > 70% overall expert agreement. RESULTS: The experts agreed on 23 items (out of 49) which were distributed as follows: five in the generic, six in the quality of life, six in the symptom, and six in the treatment related domain. Interestingly, comparing the items that reached consensus in this study, with the generic and disease specific PROMs previously used in carotid artery disease investigation, the only constant items were "difficulty with walking" and "ability to perform daily activities" included in the symptom domain. Considering the items that reached expert consensus in the additional domains, emphasis was given to the impact of the diagnosis, treatment and follow up, and to fear or concern "about the future" and "about severe stroke". In the treatment domain emphasis was also attained on the side effects, long term patient satisfaction, and on the information provided regarding treatment options. DISCUSSION: As hard clinical outcomes become increasingly rare, assessment of the impact of CEA becomes increasingly difficult. The consensus reached provides a newly defined disease specific PROM that warrants independent validation in specific populations in the future.

Peripheral Interventions in Patients with Pseudoxanthoma Elasticum (PXE).

OBJECTIVE: Pseudoxanthoma elasticum (PXE) is an autosomal recessive metabolic disorder that may be associated with a high prevalence of peripheral artery disease (PAD) and related symptoms. However, the evidence supporting this association is weak, as only small cohort studies are available. Furthermore, limited data are available on the outcome of lower limb peripheral arterial interventions (PAI) in patients with PXE. It was the aim of this study to clarify the prevalence of PAD, and the occurrence and outcome of PAI in patients with PXE. METHODS: This was a retrospective review of prospectively collected data from the Dutch Expertise Centre for PXE database. Clinical data of consecutive patients with a definitive diagnosis of PXE were examined. The primary endpoint was the prevalence of PAD (defined as an ankle brachial index of < 0.9). The secondary endpoint was to report an overview of PAI and target lesion revascularisations. RESULTS: In 285 PXE patients (median age 58 years), 50.9% of patients (n = 145) met the criteria for PAD. Seventeen patients underwent a PAI, mostly for intermittent claudication, at a median age of 51 years. The incidence of PAI was 2.25 per 1 000 patient years in patients with PAD and PXE. A total of 58 interventions was recorded, of which 35 were target lesion revascularisations in nine patients. Twenty one revascularisations were performed within a year following the primary intervention, in 16 cases due to an acute occlusion. CONCLUSION: Within a well phenotyped and large PXE cohort, the diagnosis of PAD was prevalent in one in two patients. The observed rate of peripheral interventions was low, while the re-intervention rate was unfavourable after endovascular or bypass surgical procedures, with over half of these re-interventions indicated within a year.

Plasma Extracellular Vesicle Serpin G1 and CD14 Levels are Associated with Major Adverse Cardiovascular Events and Major Adverse Limb Events in Patients Undergoing Femoral Endarterectomy.

OBJECTIVE: Plasma extracellular vesicles (EV) are an emerging source of biomarkers for diagnosis and prognosis of cardiovascular disease (CVD). Risk stratification for common adverse events such as major adverse limb events (MALE) and major adverse cardiovascular events (MACE) by an EV blood sample could improve healthcare management by individualising drug therapy or improving informed decision making regarding revascularisations in patients with peripheral artery disease (PAD). As such, this study investigated the associations between plasma EV proteins and prospectively registered MALE and MACE in consecutive patients undergoing femoral endarterectomy. METHODS: Using the Athero-Express biobank study, four EV proteins (Cystatin C, CD14, Serpin C1, and Serpin G1) were measured in the high density lipoprotein subfraction isolated from plasma of 317 PAD patients undergoing arterial revascularisation. Multivariable Cox proportional hazard regression was used to investigate the association between plasma EV protein levels and MACE and MALE in the three year post-operative period. RESULTS: Most patients were treated for claudication (Fontaine II, 52.8%), although rest pain (Fontaine III, 30.1%) and ischaemic wounds (Fontaine IV, 17.1%) were common in this cohort. Within three years 51 patients died, amongst whom 25 deaths were due to CVD, 39 patients experienced a MACE, and 125 patients experienced a MALE. Multivariable regression models, based on statistically proven covariables and literature, showed a significant association of Serpin G1 (HR 1.49; 95% CI 1.08 - 2.06; p = .016) and CD14 (HR 1.40; 1.03 - 1.90; p = .029) with MACE, and of Serpin G1 (HR 1.29; 1.07 - 1.57; p = .009) with MALE. CONCLUSION: Serpin G1 and CD14 plasma EV protein levels are associated with future MACE and MALE in patients with severe PAD.

Plasma Lipoprotein Lipase Is Associated with Risk of Future Major Adverse Cardiovascular Events in Patients Following Carotid Endarterectomy.

INTRODUCTION: Carotid plaque intraplaque haemorrhage (IPH) is associated with future cardiovascular events. It was hypothesised that plasma proteins associated with carotid plaque IPH are also likely to be associated with major adverse cardiovascular events (MACE) after carotid endarterectomy (CEA). METHODS: In pre-operative blood samples from patients undergoing CEA within the Athero-Express biobank, proteins involved in cardiovascular disease were measured using three OLINK proteomics immunoassays. The association between proteins and IPH was analysed using logistic regression analyses. Subsequently, the association between the IPH associated plasma proteins and the three year post-operative risk of MACE (including stroke, myocardial infarction, or cardiovascular death) was analysed. RESULTS: Within the three year follow up, 130 patients (18.9%) of 688 symptomatic and asymptomatic patients undergoing CEA developed MACE. Six of 276 plasma proteins were found to be significantly associated with IPH, from which only lipoprotein lipase (LPL) was associated with the post-operative risk of MACE undergoing CEA. Within the 30 day peri-operative period, high plasma LPL was independently associated with an increased risk of MACE (adjusted hazard ratio [HR] per standard deviation [SD] 1.60, 1.10 - 2.30), p = .014). From 30 days to three years, however, high LPL was associated with a lower risk of MACE (adjusted HR per SD 0.80, 0.65 - 0.99, p= .036). CONCLUSION: High LPL concentrations were found to be associated with a higher risk of MACE in the first 30 post-operative days but with a lower risk MACE between 30 days and three years, meaning that LPL has different hazards at different time points.

Systematic Review on Botulinum Toxin Injections as Diagnostic or Therapeutic Tool in Thoracic Outlet Syndrome.

BACKGROUND: The optimal diagnostic and treatment algorithm for patients with suspected thoracic outlet syndrome (TOS) remains challenging. Botulinum toxin (BTX) muscle injections have been suggested to shrink muscles in the thoracic outlet reducing neurovascular compression. This systematic review evaluates the diagnostic and therapeutic value of BTX injections in TOS. METHODS: A systematic review of studies reporting BTX as a diagnostic or therapeutic tool in TOS (or pectoralis minor syndrome as TOS subtype) was conducted in PubMed, Embase, and CENTRAL databases on May 26, 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was followed. Primary end point was symptom reduction after primary procedure. Secondary end points were symptom reduction after repeated procedures, the degree of symptom reduction, complications, and duration of clinical effect. RESULTS: Eight studies (1 randomized controlled trial [RCT], 1 prospective cohort study, and 6 retrospective cohort studies) were included reporting 716 procedures in at least 497 patients (at minimum 350 primary and 25 repeated procedures, residual unclear) diagnosed with presumably only neurogenic TOS. Except for the RCT, the methodological quality was fair to poor. All studies were designed on an intention to treat basis, one also investigated BTX as a diagnostic tool to differentiate pectoralis minor syndrome from costoclavicular compression. Reduction of symptoms was reported in 46-63% of primary procedures; no significant difference was found in the RCT. The effect of repeated procedures could not be determined. Degree of symptom reduction was reported by up to 30-42% on the Short-form McGill Pain scale and up to 40 mm on a visual analog scale. Complication rates varied among studies, no major complications were reported. Symptom relief ranged from 1 to 6 months. CONCLUSIONS: Based on limited quality evidence, BTX may provide short-lasting symptom relief in some neurogenic TOS patients but remains overall undecided. The role of BTX for treatment of vascular TOS and as a diagnostic tool in TOS is currently unexploited.

External Validation of Risk Prediction Models to Improve Selection of Patients for Carotid Endarterectomy.

BACKGROUND AND PURPOSE: The net benefit of carotid endarterectomy (CEA) is determined partly by the risk of procedural stroke or death. Current guidelines recommend CEA if 30-day risks are <6% for symptomatic stenosis and <3% for asymptomatic stenosis. We aimed to identify prediction models for procedural stroke or death after CEA and to externally validate these models in a large registry of patients from the United States. METHODS: We conducted a systematic search in MEDLINE and EMBASE for prediction models of procedural outcomes after CEA. We validated these models with data from patients who underwent CEA in the American College of Surgeons National Surgical Quality Improvement Program (2011-2017). We assessed discrimination using C statistics and calibration graphically. We determined the number of patients with predicted risks that exceeded recommended thresholds of procedural risks to perform CEA. RESULTS: After screening 788 reports, 15 studies describing 17 prediction models were included. Nine were developed in populations including both asymptomatic and symptomatic patients, 2 in symptomatic and 5 in asymptomatic populations. In the external validation cohort of 26 293 patients who underwent CEA, 702 (2.7%) developed a stroke or died within 30-days. C statistics varied between 0.52 and 0.64 using all patients, between 0.51 and 0.59 using symptomatic patients, and between 0.49 to 0.58 using asymptomatic patients. The Ontario Carotid Endarterectomy Registry model that included symptomatic status, diabetes, heart failure, and contralateral occlusion as predictors, had C statistic of 0.64 and the best concordance between predicted and observed risks. This model identified 4.5% of symptomatic and 2.1% of asymptomatic patients with procedural risks that exceeded recommended thresholds. CONCLUSIONS: Of the 17 externally validated prediction models, the Ontario Carotid Endarterectomy Registry risk model had most reliable predictions of procedural stroke or death after CEA and can inform patients about procedural hazards and help focus CEA toward patients who would benefit most from it.