Christos D. Liapis

ESVS Guidelines. Invasive Treatment for Carotid Stenosis: Indications, Techniques

The European Society for Vascular Surgery brought together a group of experts in the field of carotid artery disease to produce updated guidelines for the invasive treatment of carotid disease. The recommendations were rated according to the level of evidence. Carotid endarterectomy (CEA) is recommended in symptomatic patients with >50% stenosis if the perioperative stroke/death rate is <6% [A], preferably within 2 weeks of the patients last symptoms [A]. CEA is also recommended in asymptomatic men <75 years old with 70-99% stenosis if the perioperative stroke/death risk is <3% [A]. The benefit from CEA in asymptomatic women is significantly less than in men [A]. CEA should therefore be considered only in younger, fit women [A]. Carotid patch angioplasty is preferable to primary closure [A]. Aspirin at a dose of 75-325 mg daily and statins should be given before, during and following CEA. [A] Carotid artery stenting (CAS) should be performed only in high-risk for CEA patients, in high-volume centres with documented low peri-operative stroke and death rates or inside a randomized controlled trial [C]. CAS should be performed under dual antiplatelet treatment with aspirin and clopidogrel [A]. Carotid protection devices are probably of benefit [C].

General anaesthesia versus local anaesthesia for carotid surgery (GALA): a multicentre, randomised controlled trial

BACKGROUND The effect of carotid endarterectomy in lowering the risk of stroke ipsilateral to severe atherosclerotic carotid-artery stenosis is offset by complications during or soon after surgery. We compared surgery under general anaesthesia with that under local anaesthesia because prediction and avoidance of perioperative strokes might be easier under local anaesthesia than under general anaesthesia. METHODS We undertook a parallel group, multicentre, randomised controlled trial of 3526 patients with symptomatic or asymptomatic carotid stenosis from 95 centres in 24 countries. Participants were randomly assigned to surgery under general (n=1753) or local (n=1773) anaesthesia between June, 1999 and October, 2007. The primary outcome was the proportion of patients with stroke (including retinal infarction), myocardial infarction, or death between randomisation and 30 days after surgery. Analysis was by intention to treat. The trial is registered with Current Control Trials number ISRCTN00525237. FINDINGS A primary outcome occurred in 84 (4.8%) patients assigned to surgery under general anaesthesia and 80 (4.5%) of those assigned to surgery under local anaesthesia; three events per 1000 treated were prevented with local anaesthesia (95% CI -11 to 17; risk ratio [RR] 0.94 [95% CI 0.70 to 1.27]). The two groups did not significantly differ for quality of life, length of hospital stay, or the primary outcome in the prespecified subgroups of age, contralateral carotid occlusion, and baseline surgical risk. INTERPRETATION We have not shown a definite difference in outcomes between general and local anaesthesia for carotid surgery. The anaesthetist and surgeon, in consultation with the patient, should decide which anaesthetic technique to use on an individual basis. FUNDING The Health Foundation (UK) and European Society of Vascular Surgery.

The anti-inflammatory effects of exercise training in patients with type 2 diabetes mellitus:

Background Diabetes mellitus (DM) and chronic inflammation are strongly related to increased cardiovascular risk. The purpose of this study was to evaluate whether an aerobic training programme would ameliorate inflammatory and anti-inflammatory markers in patients with type 2 DM. Design Interventional study. Methods A total of 60 overweight individuals with type 2 DM, but without vascular complications, were randomly assigned to either a 6-month aerobic exercise training programme (four times/week, 45-60 min/session), designated as exercise group, or to the control group. All participants were on an oral antidiabetic regimen and none was receiving lipid-lowering medications. Anthropometric parameters, cardiorespiratory fitness, glycaemic and lipid profiles, high sensitivity C-reactive protein (hs CRP), adiponectin, interleukin (IL)-10, IL-18, tumour necrosis factor (TNF)-a, insulin, reciprocal index of homoeostasis model assessment (HOMA-IR), body fat and blood pressure (BP) were measured at baseline and at the end of the study. Results In comparison with baseline and control group, exercise-treated patients improved glucose control, lipid profile, exercise capacity (Vo2 peak) and exhibited decreased insulin resistance and systolic BP considerably (P < 0.05). Plasma adiponectin, TNF-α and body weight changed slightly across treatment (P > 0.05), whereas diastolic BP and fat mass tended to decrease (P = 0.071 and 0.061, respectively). Exercise training reduced hs CRP (from 0.48 ± 0.16 to 0.29 ± 0.2 mg/dl; P = 0.04) and IL-18 (from 315.19 ± 122.76 to 203.77 ± 96.02 pg/ml; P = 0.02). Moreover, exercise provided anti-inflammatory protection through IL-10 increment (P = 0.039) and IL-18/IL-10 ratio downregulation (P = 0.014). In multiple regression analysis, alteration in IL-18 was independently correlated with hs CRP and Vo2 peak changes (P < 0.05). Conclusion Aerobic exercise training without significant weight loss improves metabolic profile and exerts anti-inflammatory effects in patients with type 2 DM. Eur J Cardiovasc Prev Rehabil 14: 837-843

Matrix metalloproteinases: contribution to pathogenesis, diagnosis, surveillance and treatment of abdominal aortic aneurysms

SUMMARY Background: Aortic abdominal aneurysm (AAA) represents a common chronic degenerative disease of the aortic wall. Chronic inflammation and enzymatic degradation of elastic lamellae and extracellular matrix (ECM) proteins constitute the most prominent characteristics of AAAs. There is mounting evidence that matrix metalloproteinases (MMPs) are the predominant proteinases in the AAA wall. These enzymes represent a potential target for therapeutic intervention to modify vascular pathology. This paper is an overview of matrix metalloproteinases and their role in the pathophysiology, diagnosis and treatment of AAA. Literature search: Comprehensive search of the MEDLINE, EMBASE and HEAL-Link databases from 1980 to 2003. Findings: Increased levels of MMPs expression and activity have been demonstrated within the aortic wall of AAA, associating with histological alterations. An imbalance between MMPs and their inhibitors (Tissue Inhibitors of Matrix Metalloproteinases – TIMPs), may tip the equilibrium towards matrix degradation. MMPs as systemic biochemical markers of AAAs may contribute to diagnosis of unsuspected AAAs or to the surveillance of patients with small AAAs. Evidence of variations in MMPs, TIMPs and their mediator genes promoting the increased inheritance susceptibility of AAAs is less well documented. However, a broad spectrum of pharmaceutical agents (e.g. doxycycline, statins etc.) is known to inhibit MMP activity and attenuate medial destruction. Conclusion: Randomized clinical studies in patients in the early stages of AAA or in healthy individuals with great propensity to AAA development are required to demonstrate the causative relationship between MMPs and AAA. It still remains obscure whether long-term administration of MMP inhibitors can decelerate or even prevent the need for surgical repair.

Effects of Cyclic Strain on Vascular Cells

Hemodynamic forces, including shear stress and cyclic strain, have been recognized as important modulators of vascular cell morphology and function. The mechanism by which vascular cells sense and transduce the extracellular mechanical signals into the cell nucleus has only recently begun to come to light. Integrins, ion channels, platelet-derived growth factor receptors, and G proteins have been recognized as mechanosensors, converting the mechanical stimuli into chemical signals. Activation of second messengers, including mitogen-activated protein kinases, protein kinase C, and Akt, follows, leading to an increase in the activity of transcription factors such as activator protein (AP)-1, AP-2, cAMP-responsive element (CRE), early growth response (Egr)-1, and nuclear factor (NF)-kappa B. Binding of these factors to the DNA leads to activation of numerous genes that regulate cell proliferation, apoptosis, differentiation, morphology, migration, and secretory function. Understanding of these responses has provided new insights in the pathogenesis and treatment of vascular diseases, such as atherosclerosis and intimal hyperplasia.

Matrix Metalloproteinases and Diabetic Vascular Complications

Diabetes mellitus (DM) is associated with an increased incidence of cardiovascular events and microvascular complications. These complications contribute to the morbidity and mortality associated with DM. There is increasing evidence supporting a role for matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of matrix metalloproteinases—TIMPs) in the atherosclerotic process. However, the relationship between MMPs/TIMPs and diabetic angiopathy is less well defined. Hyperglycemia directly or indirectly (eg, via oxidative stress or advanced glycation products) increases MMP expression and activity. These changes are associated with histologic alterations in large vessels. On the other hand, low proteolytic activity of MMPs contributes to diabetic nephropathy. Within atherosclerotic plaques an imbalance between MMPs and TIMPs may induce matrix degradation, resulting in an increased risk of plaque rupture. Furthermore, because MMPs enhance blood coagulability, MMPs and TIMPs may play a role in acute thrombotic occlusion of vessels and consequent cardiovascular events. Some drugs can inhibit MMP activity. However, the precise mechanisms involved are still not defined. Further research is required to demonstrate the causative relationship between MMPs/TIMPs and diabetic atherosclerosis. It also remains to be established if the long-term administration of MMP inhibitors can prevent acute cardiovascular events.

Flow-diverting stents for the treatment of arterial aneurysms

BACKGROUND Anatomic factors may limit the application of stent grafts for the treatment of arterial aneurysms. Flow- diverting stents (FDSs) are specially designed to reduce flow velocity in the aneurysm sac and promote thrombosis while maintaining flow in the main artery and branch vessels. FDSs include the Pipeline Embolization Device (ev3, Plymouth, Minn), the SILK Arterial Reconstruction Device (Balt Extrusion, Montmorency, France), and the Cardiatis Multilayer Stent (Cardiatis, Isnes, Belgium). The first two have been mainly used for the treatment of intracranial aneurysms. The aim of this study was to review the current role of FDSs in the treatment of extracranial arterial aneurysms. METHODS A systematic electronic health database search was conducted using PubMed, Ovid, Medline, and the Cochrane Database on all accessible published articles through March 2012. An additional search for abstracts presented in international congresses for vascular surgery was also performed. Full-text articles and abstracts were analyzed separately due to the heterogeneity of the data. RESULTS Results of the use of FDSs in arterial aneurysms were reported in 12 full-text articles including 35 patients (26 men, age 65.4) with 38 aneurysms. The aneurysms were located in the hepatic (n = 12), splenic (n = 6), renal (n = 5), celiac (n = 4), superior mesenteric (n = 3), subclavian (n = 2), gastroduodenal (n = 1), and popliteal arteries (n = 1) and in the descending thoracic (n = 1), suprarenal (n = 1) and infrarenal aorta (n = 2). The 30-day mortality was 5.7% (2 of 35 patients). Three stent thromboses occurred (8.3%), none of them with clinical consequences. Thirty patients with 33 aneurysms and patent FDSs were monitored for an average of 9.2 months. Thrombosis occurred in 90.6%, and volume reduction was observed in 81% of the aneurysms. No branch vessel occlusion occurred. Twelve abstracts were identified, including 133 patients (mean age, 64.7 years). They included 62 peripheral, 28 visceral, and 43 abdominal and thoracoabdominal aneurysms. The Cardiatis Multilayer Stent was used in all cases. Thrombosis was achieved in all but two peripheral and visceral aneurysms. Volume reduction was observed in 82.7%, and no branch vessel occlusion occurred. In aortic aneurysms, better results regarding aneurysm thrombosis, reduction of the volume, and patency of collateral branches were reported at 12 months rather than at 6 months postoperatively. No aneurysm rupture has yet been described. CONCLUSIONS Initial clinical experience with the use of FDSs in the treatment of visceral and peripheral aneurysms yielded satisfactory results in technical success, aneurysm thrombosis and shrinkage, and in patency of branch vessels. The results in aortic aneurysms are still under investigation. No aneurysm rupture has yet been described. There is a significant incidence of FDS thrombosis. Volume reduction of the aneurysm is a clearer evidence of the clinical success after treatment with FDSs than aneurysm thrombosis.

Visfatin (Nampt) and Ghrelin as Novel Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes

OBJECTIVE Visfatin (nampt) and ghrelin are the most recently identified adipocytokines, but their role in atherosclerosis is poorly clarified. In our study we investigated their association with advanced carotid atherosclerosis and carotid intima-media thickness (CIMT) in patients with type 2 diabetes mellitus (T2DM). METHODS 122 patients (50 males) with T2DM, aged 55-70 were enrolled. Sixty-four age- and sex-matched healthy individuals served as controls (group A). CIMT was assayed in all participants by ultrasound. Among diabetic patients, 47 appeared with carotid plaques (group B), while 75 without plaques (group C). Anthropometric parameters, blood pressure, glycemic and lipid profile, high-sensitivity CRP (hsCRP), insulin resistance (HOMA-IR), fibrinogen, nampt and ghrelin were measured. RESULTS Diabetic patients had a higher mean-CIMT, increased body-mass index, worse lipid profile, elevated blood pressure and higher levels of white blood cells count, nampt and hsCRP with respect to controls (p<0.01). Among diabetic patients, groups B and C were comparable in anthropometric, glycemic and lipid parameters. Serum nampt was significantly higher in group B rather than in groups A and C (p<0.05). On the other hand, ghrelin levels were considerably lower only in diabetic patients with carotid atherosclerosis compared with healthy individuals. In univariate analysis, mean-CIMT correlated with age (r=0.312; p=0.003), nampt (r=0.341; p<0.001) and ghrelin (r=-0.421; p=0.002) and the latter associations remained significant in multiple regression analysis. CONCLUSIONS High nampt and low ghrelin serum levels are significantly associated with advanced carotid atherosclerosis in patients with T2DM. Moreover these adipocytokines are independently associated with CIMT, implicating their role as novel atherosclerotic biomarkers and providing another important link between adiposity and atherosclerosis.

The relationship between serum levels of vascular calcification inhibitors and carotid plaque vulnerability.

OBJECTIVE Osteopontin (OPN) and osteoprotegerin (OPG) are well-known vascular calcification inhibitors, which have been recently demonstrated to correlate with inflammation and cardiovascular events incidence. The aim of this cross-sectional study is to survey whether OPN and OPG are involved in carotid plaque vulnerability. For this reason, we assessed serum OPN and OPG levels in patients with carotid stenosis, and we explored their relationship with carotid plaque echogenicity and subsequent cerebrovascular ischemic events. METHODS A total of 164 Whites were selected from a large cohort of 297 subjects to participate. In particular, 114 patients (61 men, 53 women), aged 55 to 80, had recently-diagnosed ICA stenosis higher than 50%. A group of 50 age-, sex-, and body mass index (BMI)-matched healthy individuals served as healthy controls. Patients with renal failure, hypothyroidism, osteoporosis, and lipid-lowering therapy were excluded. Images of both carotids were obtained from all participants using a high-resolution color duplex ultrasound and the gray-scale median (GSM) score was calculated. Brain computed tomography (CT), and magnetic resonance imaging (MRI) scans when CT was questionable, were performed on all patients with carotid stenosis. Clinical parameters, lipid and glycemic indexes, hsCRP, fibrinogen, white blood cells (WBC) count, OPN, and OPG were measured. Independent t test, one-way ANOVA, Pearson correlation, and multiple regression analysis were used for statistical analysis. RESULTS Among patients with carotid stenosis, 60 had history of ipsilateral stroke or TIA and positive CT or MRI findings (group A), while 54 had no neurological symptoms and negative CT and MRI scan (group B). Overall, patients with carotid stenosis showed worse lipid profile and increased waist circumference, blood pressure, hsCRP, fibrinogen, WBC count, OPN, and OPG levels compared with healthy subjects (group C) (P <.05). Statistical analysis revealed that group A had significantly lower levels of GSM than group B (57.41 +/- 38.19 vs 76.32 +/- 36.72; P = .008) and higher levels of hsCRP, OPN, and OPG than groups B and C (P < .05). Concerning the latter, biochemical markers group B showed only elevated OPG levels compared with group C (P = .038). Notably, GSM was considerably associated with serum OPN and OPG and waist circumference in patients with carotid atherosclerosis in univariate (r = -0.333; P = .032, r = -0.575; P < .001, r = -0.590; P =.006, respectively) and multiple regression analysis (R(2) = 0.445; P =.006). CONCLUSIONS The present study demonstrated elevated serum OPN and OPG levels in patients with carotid stenosis and documented an independent association between these biochemical markers, GSM and carotid-induced symptomatology. Therefore bone-matrix proteins combined with GSM could be potential markers for vulnerable carotid plaques.

Intensive Lipid-lowering Therapy Ameliorates Novel Calcification Markers and GSM Score in Patients with Carotid Stenosis

OBJECTIVES/DESIGN Carotid plaque echogenicity quantified by the Gray-Scale Median (GSM) score has been associated with plaque vulnerability. The aim of this study was to assess whether intensive lipid-lowering treatment with atorvastatin in patients with carotid artery stenosis ameliorates novel vascular calcification inhibitors, such as osteopontin (OPN) and osteoprotegerin (OPG), and improves GSM score. METHODS Ninety-seven patients with carotid stenosis (>40%), but without indication for intervention, were treated for 6 months with atorvastatin (10mg-80mg) to target LDL<100mg/dl. Fifty-two age-and sex-matched healthy individuals served as the control group. Blood samples and GSM were obtained at the beginning and after 6 months. RESULTS Systolic blood pressure, hsCRP, fibrinogen, OPN and OPG levels differed significantly between patients with carotid stenosis and healthy controls at baseline (p<0.05). Atorvastatin treatment improved lipid profile and significantly reduced hsCRP (p=0.002), WBC count (p=0.041), OPN (p<0.001) and OPG levels (p<0.001). GSM score increased considerably after atorvastatin therapy (from 58.33+/-24.38 to 79.33+/-22.3; p<0.001) and that effect appeared related to OPN (p=0.001), OPG (p=0.013) and LDL (p=0.01) reduction. CONCLUSIONS In patients with carotid stenosis, intensive lipid-lowering therapy with statins attenuates serum OPN and OPG levels and enhances carotid plaque echogenicity, outlining their beneficial effects on plaque stability.