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.

Cardiometabolic Risk, Peripheral Arterial Disease and Cardiovascular Events in Polycystic Ovary Syndrome: Time to Implement Systematic Screening and Update the Management.

Polycystic ovary syndrome (PCOS) is a highly prevalent endocrine disorder in women of reproductive age. It presents with gynaecologic, metabolic, and psychologic manifestations. The dominant drivers of pathophysiology are hyperandrogenism and insulin resistance. Both conditions are related to cardiometabolic risk factors, such as obesity, hypertension, dyslipidaemia, hyperglycaemia, type 2 and gestational diabetes, nonalcoholic fatty liver disease and obstructive sleep apnoea. Women with PCOS of reproductive age consistently demonstrated an elevated risk of subclinical atherosclerosis, as indicated by different measurement methods, while findings for menopausal age groups exhibited mixed results. Translation of subclinical atherosclerosis into the increased incidence of peripheral arterial disease and major cardiovascular (CV) events is less clear. Although several expert groups have advised screening, the CV risk assessment and prevention of CV events are frequently underdiagnosed and overlooked aspects of the management of PCOS. A combination of lifestyle management and pharmacotherapy, including the promising new era of anti-obesity medicine, can lead to improvements in cardiometabolic health.

Testosterone and Peripheral Arterial Disease.

Testosterone levels in men begin declining in the early years of adulthood, with a 1-2% reduction/year. Low testosterone levels in men are associated with obesity, metabolic syndrome, diabetes mellitus, dyslipidaemia, hypertension and increased cardiovascular mortality. However, observational studies of testosterone levels in males and their relationship with peripheral arterial disease (PAD) have yielded mixed results; only some cohorts show a clear association with low free testosterone levels. This discrepancy may, in part, be due to methodological issues with estimating free testosterone but also to different effects of testosterone on the vessel wall and metabolism. While testosterone improves glycaemic control, has anti-obesity effects and induces vasodilation, it also stimulates platelet aggregation and increases the haematocrit. Androgen deprivation treatment for advanced prostate cancer may be associated with elevated cardiovascular risk, as is testosterone abuse for performance enhancement. On the other hand, judicious treatment of male hypogonadism or testosterone treatment of trans-men appears to be safe.

Why do guidelines recommend screening for abdominal aortic aneurysms, but not for asymptomatic carotid stenosis? A plea for a randomized controlled trial.

BACKGROUND: Current guidelines do not recommend screening for asymptomatic carotid artery stenosis (AsxCS). The rationale behind this recommendation is that detection of AsxCS may lead to an unnecessary carotid intervention. In contrast, screening for abdominal aortic aneurysms is strongly recommended. METHODS: A critical analysis of the literature was performed to evaluate the implications of detecting AsxCS. RESULTS: Patients with AsxCS are at high risk for future stroke, myocardial infarction and vascular death. Population-wide screening for AsxCS should not be recommended. Additionally, screening of high-risk individuals for AsxCS with the purpose of identifying candidates for a carotid intervention is inappropriate. Instead, selective screening for AsxCS should be considered and should be viewed as an opportunity to identify individuals at high risk for atherosclerotic cardiovascular disease and future cardiovascular events for the timely initiation of intensive medical therapy and risk factor modification. CONCLUSIONS: Although mass screening should not be recommended, there are several arguments suggesting that selective screening for AsxCS should be considered. The rationale supporting such selective screening is to optimize risk factor control and to initiate intensive medical therapy for prevention of future cardiovascular events, rather than to identify candidates for an intervention.

Inflammatory and Prothrombotic Biomarkers, DNA Polymorphisms, MicroRNAs and Personalized Medicine for Patients with Peripheral Arterial Disease.

Classical risk factors play a major role in the initiation and development of atherosclerosis. However, the estimation of risk for cardiovascular events based only on risk factors is often insufficient. Efforts have been made to identify biomarkers that indicate ongoing atherosclerosis. Among important circulating biomarkers associated with peripheral arterial disease (PAD) are inflammatory markers which are determined by the expression of different genes and epigenetic processes. Among these proinflammatory molecules, interleukin-6, C-reactive protein, several adhesion molecules, CD40 ligand, osteoprotegerin and others are associated with the presence and progression of PAD. Additionally, several circulating prothrombotic markers have a predictive value in PAD. Genetic polymorphisms significantly, albeit moderately, affect risk factors for PAD via altered lipoprotein metabolism, diabetes, arterial hypertension, smoking, inflammation and thrombosis. However, most of the risk variants for PAD are located in noncoding regions of the genome and their influence on gene expression remains to be explored. MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that modulate gene expression at the post-transcriptional level. Patterns of miRNA expression, to some extent, vary in different atherosclerotic cardiovascular diseases. miRNAs appear to be useful in the detection of PAD and the prediction of progression and revascularization outcomes. In conclusion, taking into account one's predisposition to PAD, i.e., DNA polymorphisms and miRNAs, together with circulating inflammatory and coagulation markers, holds promise for more accurate prediction models and personalized therapeutic options.

Comparison of Recent Practice Guidelines for the Management of Patients With Asymptomatic Carotid Stenosis.

Despite the publication of several national/international guidelines, the optimal management of patients with asymptomatic carotid stenosis (AsxCS) remains controversial. This article compares 3 recently released guidelines (the 2020 German-Austrian, the 2021 European Stroke Organization [ESO], and the 2021 Society for Vascular Surgery [SVS] guidelines) vs the 2017 European Society for Vascular Surgery (ESVS) guidelines regarding the optimal management of AsxCS patients.The 2017 ESVS guidelines defined specific imaging/clinical parameters that may identify patient subgroups at high future stroke risk and recommended that carotid endarterectomy (CEA) should or carotid artery stenting (CAS) may be considered for these individuals. The 2020 German-Austrian guidelines provided similar recommendations with the 2017 ESVS Guidelines. The 2021 ESO Guidelines also recommended CEA for AsxCS patients at high risk for stroke on best medical treatment (BMT), but recommended against routine use of CAS in these patients. Finally, the SVS guidelines provided a strong recommendation for CEA+BMT vs BMT alone for low-surgical risk patients with >70% AsxCS. Thus, the ESVS, German-Austrian, and ESO guidelines concurred that all AsxCS patients should receive risk factor modification and BMT, but CEA should or CAS may also be considered for certain AsxCS patient subgroups at high risk for future ipsilateral ischemic stroke.

The COVID-19 Pandemic and the Need for an Integrated and Equitable Approach: An International Expert Consensus Paper.

BACKGROUND: One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. MANAGEMENT: Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. CURRENT ISSUES: The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. PERSPECTIVES: There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). CONCLUSION: The "PDA strategy" integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.

Coagulopathy, thromboembolic complications, and the use of heparin in COVID-19 pneumonia.

The SARS-CoV-2 (COVID-19) is causing a pandemic and potentially fatal disease of global public health concern. Viral infections are known to be associated with coagulation impairment; thus, thrombosis, hemorrhage, or both may occur. Understanding the pathophysiologic mechanisms underlying the development of coagulation disorders during viral infection is essential for the development of therapeutic strategies. Coagulopathy in COVID-19 infection is emerging as a precipitant factor for severe respiratory complications and death. An increase in coagulation markers, such as fibrinogen and D-dimer, has been found in severe COVID-19 cases. Heparin, clinically used as an anticoagulant, also has anti-inflammatory properties, including binding of inflammatory cytokines, inhibition of neutrophil chemotaxis, and protection of endothelial cells, and a potential antiviral effect. We hypothesized that low-molecular-weight heparin may attenuate cytokine storm in COVID-19 patients; therefore, low-molecular-weight heparin could be a valid adjunctive therapeutic drug for the treatment of COVID-19 pneumopathy. In this paper, we review potential mechanisms involved in coagulation impairment after viral infection and the possible role of heparin in the treatment of COVID-19 patients.

The Strategic Alliance between Clinical and Molecular Science in the War against SARS-CoV-2, with the Rapid-Diagnostics Test as an Indispensable Weapon for Front Line Doctors.

Our work concerns the actual problem of spread of SARS- CoV-2 outbreak which requires fast and correct as possible answer. In current scenario, the need of rapid answer put away the imperative of proper methodology. We focus on the serogical immunoassay for diagnosis of Covid-19 as an important weapon not only for diagnostic purpose, but also for epidemiologic one. The right equilibrium between high speed, low cost and accuracy is obtained with easy-to-use decentralized point-of-care test as the colloidal gold-based immunochromatographic strip assay which detects IgM and IgG antibodies directed against SARS-CoV-2. As our aim is to evaluate the efficacy of Covid-19 rapid tests and of serological assays in real-life settings, we designed a research protocol aimed to establish how to use correctly these diagnostics, taking into account the different possible clinical and epidemiological scenarios.

Compression therapy after invasive treatment of superficial veins of the lower extremities: Clinical practice guidelines of the American Venous Forum, Society for Vascular Surgery, American College of Phlebology, Society for Vascular Medicine, and International Union of Phlebology.

Guideline 1.1: Compression after thermal ablation or stripping of the saphenous veins. When possible, we suggest compression (elastic stockings or wraps) should be used after surgical or thermal procedures to eliminate varicose veins. [GRADE - 2; LEVEL OF EVIDENCE - C] Guideline 1.2: Dose of compression after thermal ablation or stripping of the varicose veins. If compression dressings are to be used postprocedurally in patients undergoing ablation or surgical procedures on the saphenous veins, those providing pressures >20 mm Hg together with eccentric pads placed directly over the vein ablated or operated on provide the greatest reduction in postoperative pain.[GRADE - 2; LEVEL OF EVIDENCE - B] Guideline 2.1: Duration of compression therapy after thermal ablation or stripping of the saphenous veins. In the absence of convincing evidence, we recommend best clinical judgment to determine the duration of compression therapy after treatment. [BEST PRACTICE] Guideline 3.1: Compression therapy after sclerotherapy. We suggest compression therapy immediately after treatment of superficial veins with sclerotherapy to improve outcomes of sclerotherapy. [GRADE - 2; LEVEL OF EVIDENCE - C] Guideline 3.2: Duration of compression therapy after sclerotherapy. In the absence of convincing evidence, we recommend best clinical judgment to determine the duration of compression therapy after sclerotherapy. [BEST PRACTICE] Guideline 4.1: Compression after superficial vein treatment in patients with a venous leg ulcer. In a patient with a venous leg ulcer, we recommend compression therapy over no compression therapy to increase venous leg ulcer healing rate and to decrease the risk of ulcer recurrence. [GRADE - 1; LEVEL OF EVIDENCE - B] Guideline 4.2: Compression after superficial vein treatment in patients with a mixed arterial and venous leg ulcer. In a patient with a venous leg ulcer and underlying arterial disease, we suggest limiting the use of compression to patients with ankle-brachial index exceeding 0.5 or if absolute ankle pressure is >60 mm Hg. [GRADE - 2; LEVEL OF EVIDENCE - C].

An isolated aneurysm of the thigh anterolateral branch of the greater saphenous vein in a young patient presenting as an inguinal hernia.

We report the first case of isolated aneurysm of the anterolateral branch of the greater saphenous vein in a 24-year-old man. The aneurysm was initially confused with an inguinal hernia. The patient referred with a respiratory distress due to a pulmonary embolism. The Doppler ultrasounds permitted to clarify the diagnosis. The aneurysm was removed en block under local anaesthesia. Surgeons should be aware to consider a venous aneurysm in the differential diagnosis of an inguinal mass. Indeed, due to its potential risk or embolism, the surgical treatment is mandatory.

Propionyl-L-carnitine in Leriche-Fontaine stage II peripheral arterial obstructive disease.

Peripheral arterial obstructive disease (PAOD) of the lower limbs affects 5% of the adult population. Uncontrolled arteriopathy is established due to a microcirculatory deficit, which may be present despite a good Winsor index and which leads to exhaustion of the functional microcirculatory reserve. The target of this study was to examine possible improvements in microvascular and tissue homeostasis by the administration of propionyl-L-carnitine (PLC). A total of 26 patients were enrolled in this study, aged 65 +/- 15 years; two males were diagnosed at stage IIA and 17 males and seven females at stage IIB PAOD. The main criterion of inclusion was the worsening of walking distance during the last month. In this study the duration of therapy was 33 days. PLC was administered in three flasks, each containing 300 mg in 250 cc saline by continuous infusion. The following parameters were measured before and after treatment: pain-free and maximum walking distance (measured on a treadmill at 3.2 km/hr with a gradient of 12%), recovery time from pain after maximum walking distance, ankle-brachial index by means of the Doppler apparatus, and evaluation of the microcirculation using capillaroscopy. The results showed that therapy with PLC was effective at restoring activity of skeletal muscle in ischemic conditions. In particular, capillaroscopy showed improvement in the angioarchitecture in the microcirculation fields, expressed as increased numbers of visible capillaries and diminution in the time of loss of sodium fluorescein marker. The clinical data showed increased walking distance and diminished time to recover from pain, and the clinical improvement correlated with improved microcirculatory function. From these preliminary data has emerged an indication of therapy with PLC for chronic obstructive arteriopathy of the lower limbs at stage II. Further studies with higher numbers of patients and more controlled variables are planned.

Clinical and hemodynamic significance of corona phlebectatica in chronic venous disorders.

BACKGROUND: Corona phlebectatica (corona) is a clinical sign associated with chronic venous disorders but is not yet included in the CEAP classification. Our aim was to analyze the clinical and hemodynamic correlations of corona to determine its significance and potential usefulness in classification grading and systems such as the CEAP classification. METHODS: A full clinical and duplex ultrasound record of 287 patients was collected by 60 vascular physicians from 10 European countries. They used the same computer software. This was designed to improve the interobserver consistency of computer-assisted procedures for clinical data gathering. Corona was defined as fan-shaped intradermal telangiectases in the medial and sometimes lateral portions of the ankle and foot. This definition was further refined into three severity grades of light, moderate, and severe, according to reference pictures provided by the software. To avoid overpowering the statistical tests, only data from right lower limbs were analyzed. RESULTS: In this series of 287 unselected patients, a corona was detected in 96 right lower limbs (27.7%) and graded as light in 61 (21.1%), moderate in 24 (8.3%), and severe in 11 (3.8%). The presence of a corona and its severity grade were found significantly related to two risk factors of chronic venous disorders (age and personal history of deep vein thrombosis), the presence of so-called venous symptoms, including pain, pruritus, burning sensation, feeling of swelling, cramps, heavy legs; and most individual items of CEAP clinical classes (varicose veins, edema, all skin changes, C5; and open ulcers, C6). Furthermore, among the patients without skin changes (classes C1 to C3), the presence and grade of corona appeared to be significantly associated with the severity of the disease, with increasing CEAP (P < .05), disability (P < .03), and anatomic (P < .01) scores. The presence of a corona and its severity grade were also found significantly related to the CEAP clinical classes themselves (P < .001), the CEAP disability (P < .001) and clinical severity scores (P < .001), and the presence of superficial reflux in the saphenous and nonsaphenous territories (P = .05) and in the perforators (P < .001). The presence of a deep venous reflux was not found to be significant in this series. The relative risk of finding incompetent leg or calf perforators by duplex ultrasound is 4.4 times greater in patients with corona (P < .001). A comparison between the CEAP classification without corona and a modified classification including corona in C3 shows a better reliability coefficient of Cronbach. CONCLUSION: Corona strongly correlates with the clinical severity and hemodynamic disturbances of the disease. The inclusion of corona in the C3 class should probably improve the reliability of the CEAP clinical classes.

Appraisal of the information content of the C classes of CEAP clinical classification of chronic venous disorders: a multicenter evaluation of 872 patients.

OBJECTIVE: Clinical classifications attempt to summarize a large amount of information in a few indices. CEAP is the most comprehensive and widely used classification of chronic venous disorders. The objective was to evaluate, in a routine clinical setting, the information associated with each CEAP clinical class and their ascending severity and additivity. METHODS: This work was a multicenter evaluation of newly designed software dedicated to the management of venous diseases. Forty-nine angiologists from nine European countries entered a total of 872 full records of unselected patients. The data were analyzed to evaluate the informational value of each of the clinical classes and to test their ascending severity and additivity, with monovariate and multivariate statistical techniques with SPSS/PC software on the database of the 872 right lower limbs. RESULTS: The series consisted of 700 women (80.3%) and 172 men, aged 18 to 100 years (median, 53 years). The ascending severity of the classes was shown with the statistical association of higher severity C classes with the age of the patient, a history of previous deep vein thrombosis, the diameter class of the most dilated varicose vein, venous symptoms, and the presence of a corona phlebectatica. The additivity, as measured with the Cronbach alpha coefficient analysis, was satisfactory in highest classes but poorer within the first three classes, and factor analysis of correspondences showed the heterogeneity of the variables that make the classification. CONCLUSION: The information summarized with the CEAP clinical classes shows a good ascending severity but a poorer additivity. These limitations seem to be related to the heterogeneity of the information content, which suggests some refinements of this basic tool for clinical research in the field of chronic venous disorders.