Why selective screening for asymptomatic carotid stenosis is currently appropriate: a special report.

INTRODUCTION: Two of the main reasons recent guidelines do not recommend routine population-wide screening programs for asymptomatic carotid artery stenosis (AsxCS) is that screening could lead to an increase of carotid revascularization procedures and that such mass screening programs may not be cost-effective. Nevertheless, selective screening for AsxCS could have several benefits. This article presents the rationale for such a program. AREAS COVERED: The benefits of selective screening for AsxCS include early recognition of AsxCS allowing timely initiation of preventive measures to reduce future myocardial infarction (MI), stroke, cardiac death and cardiovascular (CV) event rates. EXPERT OPINION: Mass screening programs for AsxCS are neither clinically effective nor cost-effective. Nevertheless, targeted screening of populations at high risk for AsxCS provides an opportunity to identify these individuals earlier rather than later and to initiate a number of lifestyle measures, risk factor modifications, and intensive medical therapy in order to prevent future strokes and CV events. For patients at 'higher risk of stroke' on best medical treatment, a prophylactic carotid intervention may be considered.

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.

Perioperative Prevention of Venous Thromboembolism in Abdominal Surgery Patients Based on the Caprini or the Padua Risk Score-A Single Centre Prospective Observational Study.

Surgical patients should receive perioperative thromboprophylaxis based on risk assessment, and the Caprini score is validated for this purpose. Whether the Padua score, originally devised for medical patients, can be useful in surgical patients remains to be fully clarified. This study aimed to evaluate perioperative thromboprophylaxis based on the Caprini or the Padua score in elective abdominal surgery. A total of 223 patients undergoing elective abdominal surgery for malignant or benign disease were prospectively evaluated. The patients were divided into two groups in which thromboprophylaxis was prescribed according to either the Caprini score (n = 122) or the Padua score (n = 101). Patients with high-risk scores in both groups received nadroparin. The alternate risk score in each group was calculated for evaluation purposes only. During a 3-month follow-up, we assessed patients for symptomatic venous thromboembolism (VTE), bleeding, or mortality. In the Caprini score group, 87 patients (71%) had a high risk for VTE (≥5 points), while 38 patients (38%) had a high risk for VTE (≥4 points) in the Padua score group; p < 0.00001. The overall correlation between the Caprini and Padua scores was moderate (r= 0.619), with 85 patients having high Caprini and discordant Padua scores. Ten patients died during follow-up (4.5%), and five developed non-fatal symptomatic VTE (2.2%). Among the five major bleeding incidents recorded (1.8%), two cases were possibly associated with pharmacological thromboprophylaxis. The incidence of adverse outcomes did not differ between the two groups. The odds ratio for adverse outcomes was significantly higher with a high Caprini or Padua risk score, malignant disease, age ≥65 years, and active smoking. We found no significant differences in adverse outcomes between abdominal surgical patients who received perioperative thromboprophylaxis based on either the Caprini or the Padua risk score. However, a discordant Padua score was noted in almost 40% of patients who had a high Caprini score, suggesting that the latter may be more sensitive than the Padua score in surgical patients.

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.

Progression of coronary calcium burden and carotid stiffness in patients with essential thrombocythemia associated with JAK2 V617F mutation.

BACKGROUND AND AIMS: Patients with myeloproliferative neoplasms often succumb to cardiovascular events, but little is known on the early stages of their vascular disease. We studied how patients with JAK2 V617F positive essential thrombocythemia (ET) without overt atherosclerotic disease differed from control subjects in the progression of carotid artery stiffness and preclinical atherosclerosis. METHODS: Thirty-six patients with JAK2 V617F positive ET and 38 age-, gender- and Framingham coronary heart disease (CHD) -matched control subjects were examined twice within 4 years. Clinical and laboratory testing, echo-tracking ultrasound of carotid arteries, coronary calcium measurement and digital plethysmography were performed (ClinTrials.gov NCT03828422). RESULTS: Coronary calcium correlated with the Framingham CHD risk score at the first examination in the control group (rs = 0.410), but not among the ET patients (rs = 0.116). Both groups progressed in coronary calcium, but the outliers were more prominent among ET patients. Carotid artery stiffness increased with time in the ET patients much more than in the control group: the increase in ß-index 1.95 (SD 2.18) vs. 0.22 (SD 1.99), p < 0.001, and the increase in carotid pulse wave velocity 0.72 (SD 0.92) vs. 0.08 (SD 0.72) m/s, p = 0.001. There was no correlation between carotid stiffness and Framingham CHD risk in either group. Digital endothelial function did not change. CONCLUSION: Carotid artery stiffness progressed faster in patients with JAK2 V617F positive ET than in control subjects. Coronary calcium correlated with the Framingham CHD risk only in control subjects. This indicates that JAK2 V617F positive ET acted as a non-classical risk factor for vascular disease.

Patients' radiation doses during percutaneous endovascular procedures in arteries of the lower limbs.

BACKGROUND: Percutaneous endovascular revascularisation interventions are increasingly used in treatment of lower extremity artery disease and may expose patients to substantial radiation. PATIENTS AND METHODS: Dose-area product (DAP) was retrospectively analysed in 1063 consecutive interventions performed in adult patients with lower extremity artery disease in a single tertiary medical centre. Differences between procedure types, stratified according to anatomical region and arterial lesion complexity were evaluated. RESULTS: Median DAP for diagnostic interventions was 35.6 (15.0-52.4) Gy cm2 in aorto-below-knee arteriography and 3.2 (2.0-4.5) Gy cm2 in ipsilateral femoral arteriography (p < 0.001). For angioplasty without stenting, median DAP was 53.4 (28.6-87.4) Gy cm2 for pelvic interventions vs. 5.9 (4.3-8.6) Gy cm2 for antegrade ipsilateral femoropopliteal interventions (p < 0.001). For stenting, median DAP was 54.9 (32.5-91.2) Gy cm2 for pelvic interventions vs. 8.3 (6.0-12.3) Gy cm2 for antegrade ipsilateral femoropopliteal interventions (p < 0.001). Inside the same anatomical region, diagnostic interventions were associated with significantly lower DAP than therapeutic interventions. Stenting vs no stenting increased DAP values only in antegrade ipsilateral femoropopliteal interventions (8.3 (6.0-12.3) vs 5.9 (4.3-8.6) Gy cm2 (p < 0.001). Arterial lesion complexity affected DAP values only in antegrade ipsilateral femoropopliteal therapeutic interventions. CONCLUSIONS: The most important factor influencing patients' radiation doses was the anatomical region. Pelvic interventions were associated with 6-11-times higher DAP values than femoropopliteal interventions with antegrade ipsilateral approach. Stenting and complexity of lesions increased DAP only in antegrade ipsilateral femoropopliteal interventions.

Diabetes and smoking are more important for prognosis of patients with peripheral arterial disease than some genetic polymorphisms.

Background: The role of genetic polymorphisms in peripheral arterial disease (PAD) is incompletely understood. We tested whether selected single nucleotide polymorphisms (SNPs) were associated with PAD and with adverse events in an observational study cohort. Also, the role of diabetes and smoking was studied. Patients and methods: 742 patients with PAD and 713 age- and gender-matched control subjects were subjected to yearly physical and laboratory investigations and were managed for 5 years according to the European guidelines on cardiovascular disease prevention. The occurrence of all-cause death, cardiovascular death, non-fatal myocardial infarction, ischemic stroke or critical limb ischemia (major events) and revascularization procedures (minor events) was recorded. In 655 patients with PAD and 612 control subjects the following SNPs were determined: rs1466408, rs13428968 and rs12803 of NR4A2 gene, rs10499563 of IL6 gene, rs668 and rs12953 of PECAM1 gene, and rs10861032 of Chr12 locus. Results: The distribution of selected SNPs did not differ between patients with PAD and control subjects, and neither between subjects with or without major adverse events. In contrast, diabetes and smoking affected survival and event-free survival. Among patients with PAD, diabetes doubled the hazard ratio (HR) for cardiovascular death and smoking doubled the HR for death or major event. The 5-year survival of diabetics with PAD was 0.80 (CI 0.75-0.85) and of non-diabetics with PAD 0.87 (CI 0.84-0.90), p = 0.045. The 5-year survival of active smokers with PA D was 0.80 (CI 0.75-0.62), of former smokers 0.83 (CI 0.79-0.88), and of never-smokers 0.89 (CI 0.86-0.93), p = 0.024. Conclusions: SNPs of NR4A2, IL6, PECAM1 and Chr12 were not associated with PAD or with major adverse events. However, diabetes and smoking were associated with worse survival and event-free survival in patients with PAD.

Increased Plasma Cathepsin s at the Time of Percutaneous Transluminal Angioplasty is Associated with 6-months' Restenosis of the Femoropopliteal Artery.

BACKGROUND: We tested the hypothesis that increased levels of cathepsin S and decreased levels of cystatin C in plasma at the time of percutaneous transluminal angioplasty (PTA) are associated with the occurrence of 6-months' restenosis of the femoropopliteal artery (FPA). METHODS: 20 patients with restenosis and 24 matched patients with patent FPA after a 6-months follow-up were in - cluded in this study. They all exhibited disabling claudication or critical limb ischemia and had undergone technically successful PTA. They were all receiving statins and ACE in hi - bitors (or angiotensin II receptor antagonist) before the PTA and the therapy did not change throughout the observational period. Plasma concentrations of C-reactive protein were < 10 mg/L and of creatinine within the reference range at the time of the PTA. Plasma concentration and activity of cathepsin S, together with its potent inhibitor cystatin C, were measured the day before and the day after the PTA. RESULTS: The increased plasma concentration and activity of cathepsin S at the time of PTA was associated with the occurrence of 6-months' restenosis of FPA, independently of established risk factors (lesion complexity, infrapopliteal run-off vessels, type of PTA, age, gender, smoking, diabetes, lipids) and of cystatin C. Plasma cystatin C concentration was not associated with restenosis and did not correlate with cathepsin S activity and concentration in the plasma. CONCLUSION: Increased level of plasma cathepsin S at the time of PTA is associated with 6-months' restenosis of PTA, independently of established risk factors.

Carotid Artery Stiffness, Digital Endothelial Function, and Coronary Calcium in Patients with Essential Thrombocytosis, Free of Overt Atherosclerotic Disease.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) are at increased risk for atherothrombotic events. Our aim was to determine if patients with essential thrombocytosis (ET), a subtype of MPNs, free of symptomatic atherosclerosis, have greater carotid artery stiffness, worse endothelial function, greater coronary calcium and carotid plaque burden than control subjects. PATIENTS AND METHODS: 40 ET patients without overt vascular disease, and 42 apparently healthy, age and sex-matched control subjects with comparable classical risk factors for atherosclerosis and Framingham risk of coronary disease were enrolled. All subjects were examined by physical and laboratory testing, carotid echo-tracking ultrasound, digital EndoPat pletysmography and CT coronary calcium scoring. RESULTS: No significant differences were found between ET patients and controls in carotid plaque score [1 (0-1.25) vs. 0 (0-2), p=0.30], ß- index of carotid stiffness [7.75 (2.33) vs. 8.44 (2,81), p=0.23], pulse wave velocity [6,21 (1,00) vs. 6.45 (1.04) m/s; p=0.46], digital reactive hyperemia index [2.10 (0.57) vs. 2.35 (0.62), p=0.07], or augmentation index [19 (3-30) vs. 13 (5-22) %, p=0.38]. Overall coronary calcium burden did not differ between groups [Agatston score 0.1 (0-16.85) vs. 0 (0-8.55), p=0.26]. However, significantly more ET patients had an elevated coronary calcium score of >160 [6/40 vs. 0/42, p < 0.01]. CONCLUSIONS: No significant differences between groups were found in carotid artery morphology and function, digital endothelial function or overall coronary calcium score. Significantly more ET patients had an elevated coronary calcium score of >160, indicating high cardiovascular risk, not predicted by the Framingham equation.

Platelet reactivity in comatose survivors of cardiac arrest undergoing percutaneous coronary intervention and hypothermia.

AIMS: To investigate the effects of clopidogrel and eptifibatide on platelet reactivity in patients resuscitated from cardiac arrest undergoing percutaneous coronary intervention (PCI) and hypothermia. METHODS AND RESULTS: VerifyNow® and Multiplate® aggregometry were used before, and 4, 12, 22 and 48 hours after 600 mg clopidogrel treatment in 28 post-cardiac arrest hypothermic patients and in 14 normothermic patients with acute coronary syndrome. Basal platelet reactivity after stimulation with iso-thrombin receptor-activating peptide (TRAP) and PAR4-activating peptide (BASE) was significantly lower in the post-cardiac arrest group and persisted up to 48 hours. The antiplatelet effect of clopidogrel measured by VerifyNow and expressed as % inhibition was significantly lower in the post-cardiac arrest group. It was close to zero with an increase to only around 10% after 48 hours. Post-cardiac arrest patients receiving eptifibatide showed profound platelet inhibition measured by both VerifyNow IIb/IIIa and Multiplate TRAP tests for at least 22 hours after administration. CONCLUSIONS: Post-resuscitation syndrome with ongoing hypothermia is associated with decreased platelet reactivity. Clopidogrel loading does not significantly affect platelet function during the first 48 hours. This is in contrast with eptifibatide which produces profound platelet inhibition, and may be used to bridge insufficient inhibition by clopidogrel.

Characterization of pulmonary emboli ex vivo by magnetic resonance imaging and ultrasound.

INTRODUCTION: Magnetic resonance imaging (MRI) and transesophageal ultrasound (US) are promising methods for detection and characterization of central pulmonary emboli. Both methods employ different physical principles. We tested how US and MRI characterized pulmonary emboli ex vivo. METHODS: Thirty six ex vivo pulmonary emboli, obtained during routine autopsies of patients who died of massive pulmonary embolism, were subjected to US imaging (linear vascular probe, 5.7-10 MHz) and to high resolution three-dimensional T1-weighted spin-echo MRI. In another 3 pulmonary thromboemboli and 2 tumor emboli, we compared MRI with immunohistochemistry to platelets, red blood cells and renal carcinoma cells. We also studied model clots in vitro (retracted and non-retracted red whole-blood clots, platelet aggregates and compacted and non compacted fibrin-rich plasma clots) with MRI and US. RESULTS: T1-weighted MR images of pulmonary thromboemboli consistently showed dark regions that corresponded to red cell-rich regions and bright layers that corresponded to platelet aggregates, but bright signal was obtained also from viable carcinoma cells and necrotic regions in tumor emboli. US images provided less structural detail than MRI, but clot retraction or compaction increased image brightness. The correlation between US and MRI characteristics of pulmonary emboli was poor. CONCLUSIONS: T1-weighted MRI of pulmonary emboli is capable of non-invasive assessment of the red cell-rich and platelet-rich components of pulmonary thromboemboli. US imaging shows increased brightness with clot retraction or compaction. Thus, both methods detect clot characteristics that influence susceptibility to thrombolytic treatment.