Long-term Mortality in Patients with Asymptomatic Carotid Stenosis: Implications for Statin Therapy.

OBJECTIVE: Recent studies with asymptomatic carotid patients on best medical management have shown that the annual risk of stroke has decreased to approximately 1%. There is no evidence that a similar decrease in mortality has occurred. In addition, the intensity of statin therapy for these patients has not yet been determined. The aims of this review were to determine (a) the reported long-term all-cause and cardiac-related mortality in patients with asymptomatic carotid stenosis (ACS) > 50%, (b) whether there has been a decrease in mortality in recent years, (c) the available methods of mortality risk stratification, and (d) whether the latest ACC/AHA guidelines on the treatment of serum lipids can be applied to this group of patients. METHODS: Systematic review of PubMed, EuroPubMed, and Cochrane Library and meta-analysis using random effects for pooled proportions were performed regarding long-term all-cause and cardiac-related mortality and the associated risk factors in ACS patients. The last day for literature search was October 30, 2014. RESULTS: Seventeen studies were retrieved reporting 5-year all-cause mortality in 11,391 patients with ACS >50%. The 5-year cumulative all-cause mortality across all 17 studies was 23.6% (95% CI 20.50-26.80). Twelve additional studies, reporting both all-cause and cardiac mortality with a minimum of 2 year follow-up and involving 4,072 patients were identified. Of the 930 deaths reported, 589 (62.9%; 95% CI 58.81-66.89) were cardiac-related. This translates into an average cardiac-related mortality of 2.9% per year. CONCLUSIONS: All-cause and cardiac mortality in ACS patients are very high. Although risk stratification is possible, most patients are classified as high risk. In view of this high risk, aggressive statin therapy is indicated if the new ACC/AHA guidelines on serum lipids are to be adhered to.

Descending phlebography in patients with venous ulceration: hemodynamic implications.

AIM: The aim of this paper is to report on the hemodynamic significance of the various degrees reflux as demonstrated on descending phlebography, by comparing the phlebographic findings with ambulatory venous pressure (AVP) measurements. METHOD: Thirty-two patients (45 affected limbs) with active or healed venous ulceration were admitted to the study. Descending phlebography with grading of reflux (0-4 using Herman's grading), AVP and refilling time 90 (RT90) were performed in all patients. In addition, the presence of deep to superficial reflux into the great saphenous vein at the sapheno-femoral junction, thigh incompetent perforating veins, small saphenous vein at the saphenopopliteal junction and incompetent calf perforating veins was recorded using ascending functional phlebography. The examined limbs were separated into two groups according to the Grade of reflux. Group I consisted of limbs in which popliteal valve incompetence was not demonstrated on descending phlebography, i.e., Grades 0-2 (18 limbs). Group II consisted of limbs with popliteal reflux as demonstrated by descending venography, i.e., grades 3 and 4 (27 limbs). RESULTS: In Group I the mean AVP ± SD was 47.2 ± 9.3 mmHg (range 31-67 mmHg). After the application of the ankle tourniquet to exclude the effects of the superficial venous incompetence on the pressure recordings, the mean AVP ± SD became 28.1 ± 9.9 mmHg (range 11-44) (paired t test: P < 0.001). In Group II (limbs with incompetent popliteal valves) the mean AVP ± SD was 71.6 ± 12.7 mmHg (range 49-95 mmHg) before the tourniquet. This was significantly higher than in Group I (t test: P < 0.001). The application of the ankle tourniquet in this group produced a small but significant decrease in the AVP (mean AVP ± SD: 66 ± 14.5 mmHg) (paired t test: P < 0.001). CONCLUSION: Incompetence of the femoral valves in the presence of competent popliteal valves adds very little to the hemodynamic abnormality produced by superficial venous reflux. In the majority of these patients, there is co-existing reflux from deep to superficial veins with associated superficial valve incompetence which is responsible for the venous hypertension, skin changes and ulceration. The hemodynamic changes which in the past had been associated with deep venous insufficiency (AVP >45 mmHg and RT90 < 14 seconds despite the application of an ankle tourniquet) occur only when there is popliteal incompetence.

Comparison between insulin resistance indices and carotid and femoral atherosclerosis: a cross-sectional population study.

AIM: The aim of this study was to investigate the association between commonly used insulin resistance (IR) indices and the presence and extent of carotid and femoral atherosclerosis in a general population setting. METHODS: Cross-sectional analysis of 762 volunteers from the ongoing epidemiological Cyprus Study (46.6% male; mean age=60.5±10.2). 1) Carotid intima-media thickness (IMTcc), 2) carotid and femoral atherosclerotic plaque presence, 3) total plaque area in the carotid/femoral bifurcations (sum of the largest plaques in each carotid/femoral bifurcation-SPAcar/fem), and 4) total plaque area in both carotid and femoral bifurcations (sum of the areas of the largest plaques present in each of the four bifurcations-SPA) were measured using ultrasound at baseline. The HOMA-IR, QUICKI and McAuley indices as well as fasting insulin levels were estimated and their quartiles were used in linear and logistic regression analysis. RESULTS: All IR indices studied were strongly associated with IMTcc (P<0.01for all) even after adjustment for age and sex and exclusion of diabetic subjects. However, when looking at plaque presence and size (i.e.area) only the HOMA-IR and especially the McAuley Index were associated with both carotid plaque presence (ORadj=1.17; 95%CI=1.01 to 1.36; P=0.03 and ORadj=0.86; 95%CI=0.74 to 0.99; P=0.04 respectively) and area (ORadj=0.10; 95%CI=0.008 to 0.20; P=0.03 and ORadj=-0.11; 95%CI=-0.20 to -0.009; P=0.03 respectively), after adjustment. The McAuley Index remained a significant predictor of both carotid plaque presence and area even after exclusion of diabetic subjects (P=0.04). CONCLUSION: Our results show that while all indices were associated with carotid IMT, supporting a strong role for IR in intimal-medial thickening, only the HOMA-IR and especially the McAuley Index were associated with both carotid plaque presence and area, after adjustment. This highlights the importance of including triglyceride levels in estimating the risk for atherosclerotic plaque in the carotids as well as the possible differences in determinants for atherosclerosis between arterial sites.

Consensus Document on Intermittent Claudication from the Central European Vascular Forum (C.E.V.F.)-3rd revision (2013) with the sharing of the Mediterranean League of Angiology and Vascular Surgery, and the North Africa and Middle East Chapter of International Union of Angiology.

This paper is the review of the Consensus Document on Intermittent Claudication of the Central European Vascular Forum (CEVF), published in 2008, and and shared with the North Africa and Middle East Chapter of International Union of Angiology and the Mediterranean League of Angiology and Vascular Surgery. The Document presents suggestions for general practitioners and vascular specialists for more precise and appropriate management of PAD, particularly of intermittent claudication, and underlines the investigations that should be required by GPs and what the GP should expect from the vascular specialist (angiologist, vascular surgeon). The idea of the Faculty is to produce a short document, which is an easy reference in daily clinical practice, both for the GPs and vascular specialists.

Despeckle Filtering for Multiscale Amplitude-Modulation Frequency-Modulation (AM-FM) Texture Analysis of Ultrasound Images of the Intima-Media Complex.

The intima-media thickness (IMT) of the common carotid artery (CCA) is widely used as an early indicator of cardiovascular disease (CVD). Typically, the IMT grows with age and this is used as a sign of increased risk of CVD. Beyond thickness, there is also clinical interest in identifying how the composition and texture of the intima-media complex (IMC) changed and how these textural changes grow into atherosclerotic plaques that can cause stroke. Clearly though texture analysis of ultrasound images can be greatly affected by speckle noise, our goal here is to develop effective despeckle noise methods that can recover image texture associated with increased rates of atherosclerosis disease. In this study, we perform a comparative evaluation of several despeckle filtering methods, on 100 ultrasound images of the CCA, based on the extracted multiscale Amplitude-Modulation Frequency-Modulation (AM-FM) texture features and visual image quality assessment by two clinical experts. Texture features were extracted from the automatically segmented IMC for three different age groups. The despeckle filters hybrid median and the homogeneous mask area filter showed the best performance by improving the class separation between the three age groups and also yielded significantly improved image quality.

Association of ultrasonic texture and echodensity features between sides in patients with bilateral carotid atherosclerosis.

OBJECTIVES: Our objective was to estimate the correlation of echodensity and textural features, using ultrasound and digital image analysis, between plaques in patients with bilateral carotid stenosis. DESIGN: Cross-sectional observational study. METHODS: Patients undergoing carotid endarterectomy were recruited from Vascular Surgery at the Royal Victoria and Jewish General hospitals in Montreal, Canada. Bilateral pre-operative carotid ultrasound and digital image analysis was performed to extract echodensity and textural features using a commercially available Plaque Texture Analysis software (LifeQMedical Ltd). Principal component analysis (PCA) was performed. Partial correlation coefficients for PCA and individual imaging variables between surgical and contralateral plaques were calculated with adjustment for age, sex, contralateral stenosis, and statin use. RESULTS: In the whole group (n = 104), the six identified PCA variables and 42/50 individual imaging variables were moderately correlated (r = .211-.641). Correlations between sides were increased in patients with ≥50% contralateral stenosis and symptomatic patients. CONCLUSION: Textural and echodensity features of carotid plaques were similar between two sides in patients with bilateral stenosis, supporting the notion that plaque instability is determined by systemic factors. Patients with unstable features of one plaque should perhaps be monitored more closely or treated more aggressively for their contralateral stenosis, particularly if this is hemodynamically significant.

Prevention and treatment of venous thromboembolism--International Consensus Statement.

The aim of this document is to provide a clear and concise account of the evidence regarding efficacy or harm for various methods available to prevent and manage venous thromboembolism (VTE).

Asian venous thromboembolism guidelines: prevention of venous thromboembolism.

Venous thromboembolism (VTE) prophylaxis is under-utilized in Asia because of the misconception that its incidence is lower in Asians as compared to the Caucasians. The available data on VTE in Asia is limited due to the lack of well-designed multicenter randomized controlled trials as well as non-standardized research designs, making data comparison difficult. Emerging data indicates that the VTE incidence is not low in Asia, and is comparable to that reported in the Western literature in some instances. There is also a trend towards increasing incidence of VTE, as demonstrated by a number of hospital-based studies in Asia. This could be attributed to lifestyle changes, ageing population, increasing awareness of VTE and wider availability of Duplex ultrasound. The risk of VTE in hospitalized patients remain the same in Asians and Caucasians, even though there may be factors that are inherent to patients in Asia that influence the slight variation in incidence. The utilization rate of VTE prophylaxis remains suboptimal in Asia. The Asian Venous Thrombosis Forum (AVTF) comprises participants from various countries such as China, Hong Kong, India, Indonesia, Korea, Malaysia, Philippines, Singapore, Taiwan, Thailand and experts from Australia and Europe. The forum evaluated the available data on VTE from the Asian region and formulated guidelines tailored to meet the needs of the region. We recommend that serious considerations are given to VTE prophylaxis especially in the at-risk group and a formal hospital policy be established to facilitate the implementation. On admission to the hospital, we recommend assessing the patients for both VTE and bleeding risk. We recommend mechanical prophylaxis for patients at increased risk of bleeding and utilizing it as an adjunctive measure in combination with pharmacological prophylaxis in patients with high risk of VTE. For patients undergoing general or gynecological surgery and with moderate risk for VTE, we recommend prophylaxis with one of the following: low dose unfractionated heparin (LDUH), low molecular weight heparin (LMWH), fondaparinux or intermittent pneumatic compression (IPC). For the same group of patients at high risk of VTE, we recommend pharmacological or combination of pharmacological and mechanical prophylaxis. For patients undergoing major orthopedic surgeries like total hip replacement, total knee replacement and proximal hip fracture surgery, we recommend using one of the following: LMWH, fondaparinux, rivaroxaban, apixaban, edoxaban, dabigatran, warfarin or aspirin with IPC. For patients admitted to the hospital with acute medical illness and has moderate risk of VTE, we recommend prophylaxis with LDUH, LMWH or Fondaparinux. For the same group at high risk of VTE, we recommend combination of pharmacological and mechanical prophylaxis.

Combined (mechanical and pharmacological) modalities for the prevention of venous thromboembolism in joint replacement surgery.

We performed a systematic review and meta-analysis to compare the efficacy of intermittent mechanical compression combined with pharmacological thromboprophylaxis, against either mechanical compression or pharmacological prophylaxis in preventing deep-vein thrombosis (DVT) and pulmonary embolism in patients undergoing hip or knee replacement. A total of six randomised controlled trials, evaluating a total of 1399 patients, were identified. In knee arthroplasty, the rate of DVT was reduced from 18.7% with anticoagulation alone to 3.7% with combined modalities (risk ratio (RR) 0.27, p = 0.03; number needed to treat: seven). There was moderate, albeit non-significant, heterogeneity (I(2) = 42%). In hip replacement, there was a non-significant reduction in DVT from 8.7% with mechanical compression alone to 7.2% with additional pharmacological prophylaxis (RR 0.84) and a significant reduction in DVT from 9.7% with anticoagulation alone to 0.9% with additional mechanical compression (RR 0.17, p < 0.001; number needed to treat: 12), with no heterogeneity (I(2) = 0%). The included studies had insufficient power to demonstrate an effect on pulmonary embolism. We conclude that the addition of intermittent mechanical leg compression augments the efficacy of anticoagulation in preventing DVT in patients undergoing both knee and hip replacement. Further research on the role of combined modalities in thromboprophylaxis in joint replacement and in other high-risk situations, such as fracture of the hip, is warranted.

Can combined (mechanical and pharmacological) modalities prevent fatal VTE?

AIM: The aim of this paper was to perform a systemic review and meta-analysis of the efficacy of combined modalities (intermittent pneumatic leg compression and pharmacological prophylaxis, treatment group) against single modalities alone (control group) in preventing pulmonary embolism (PE), including fatal PE and deep-vein thrombosis (DVT) in high-risk patients. METHODS: Databases searched included the Cochrane Central Register of Controlled Trials, the Specialized Register of the Peripheral Vascular Diseases Group, MEDLINE and EMBASE. RESULTS: Seventeen studies, six of them randomized controlled trials (RCTs), which enrolled a total of 9998 patients in a variety of specialties were identified. Sixteen of the included studies evaluated the role of combined modalities on the incidence of symptomatic PE. These showed a reduction in symptomatic PE from 2.83% (122/4313) in the control group to 0.86% (33/3838) in the treatment group. Odds ratio was 0.34, 95% Confidence interval (CI) 0.23 to 0.50. Fatal PE was reduced from 0.56% (11/1972) in the control group to 0.07% (1/1377) in the treatment group (results were available in 10 studies). Odds ratio was 0.37 (95% CI; 0.09 to 1.48). Fourteen studies investigated the role of combined modalities on the incidence of DVT. These showed a reduction in DVT from 6.18% (200/3238) in the control group to 2.05% (63/3074) in the treatment group. Odds ratio was 0.31, 95% CI 0.23 to 0.43. CONCLUSION: Combined prophylactic modalities decrease significantly the incidence of PE and DVT, compared to single modalities, but the reduction seen in fatal PE did not reach statistical significance. Further research on the role of combined modalities in reducing DVT and PE is necessary.

Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound--recommendations for a protocol.

Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome characterized by stenoses or obstructions of the internal jugular and/or azygos veins with disturbed flow and formation of collateral venous channels. Studies using ultrasound in patients with multiple sclerosis (MS) have demonstrated a high prevalence of CCSVI (mean 70%; range 0-100%; N.=1496), whereas, in normal controls and patients without MS the prevalence was much lower (mean 10%; range 0-36%; N.=635). Ultrasound uses a combination of physiological measurements as well as anatomical imaging and has been used for the detection of CCSVI by different centers with variable results. A high prevalence ranging from 62% to 100% of obstructive lesions has been found by some teams in patients with MS compared with a lower prevalence of 0-25% in controls. However, absence of such lesions or a lower prevalence (16-52%) has been reported by others. This variability could be the result of differences in technique, training, experience or criteria used. The current lack of a methodology shared among experts is a confounding element in epidemiologic studies, and does not permit further Bayesan or other kind of analysis. In order to ensure a high reproducibility of Duplex scanning with comparable accuracy between centers, a detailed protocol with standard methodology and criteria is proposed. This is also necessary for training. It has been shown that inter-rater variability increases post-training (from k=0.47 to k=0.80), while within-rater reproducibility in trained operators was k=0.75. Finally, the consensus document proposes a reporting standard of Duplex measurements, and future research to answer areas of uncertainty.

Screening for chronic cerebrospinal venous insufficiency (CCSVI) using ultrasound: recommendations for a protocol.

Chronic cerebrospinal venous insufficiency (CCSVI) is a syndrome characterized by stenoses or obstructions of the internal jugular and/or azygos veins with disturbed flow and formation of collateral venous channels. Ultrasound and venographic studies of the internal jugular and azygos venous systems in patients with multiple sclerosis (MS) have demonstrated a high prevalence of CCSVI (mean 71%, range 0-100%; n=1336) associated with activation of collaterals. By contrast, ultrasound and venographic examinations of normal controls and patients without MS have demonstrated a much lower prevalence (mean 7.1%, range 0-22%; n=505). Ultrasound in the form of duplex scanning uses a combination of physiological measurements as well as anatomical imaging and has been used for the detection of CCSVI by different centers with variable results. A high prevalence of obstructive lesions, ranging from 62% to 100%, has been found by some teams in patients with MS compared with a low prevalence (0-25%) in controls. However, others have reported absence of these lesions or a lower prevalence (16-52%). This variability could be the result of differences in technique, training, experience or criteria used. In order to ensure a high reproducibility of duplex scanning with comparable accuracy between centers a detailed protocol with standard methodology and criteria is needed. Also, standardization of the method of reporting of duplex measurements and other findings will facilitate validation of the proposed criteria by different centers. The aim of this document is to produce recommendations for such a protocol and indicate what future research is needed in order to address areas of uncertainty.

Introduction to the biomechanics of carotid plaque pathogenesis and rupture: review of the clinical evidence.

The management of patients with asymptomatic carotid disease is currently under debate and new methods are warranted for better risk stratification. The role of the biomechanical properties of the atherosclerotic arterial wall together with the effect of different stress types in plaque destabilisation has only been recently investigated. PubMed and Scopus databases were reviewed. There is preliminary clinical evidence demonstrating that the analysis of the combined effect of the various types of biomechanical stress acting on the carotid plaque may help us to identify the vulnerable plaque. At present, MRI and two-dimensional ultrasound are combined with fluid-structure interaction techniques to produce maps of the stress variation within the carotid wall, with increased cost and complexity. Stress wall analysis can be a useful tool for carotid plaque evaluation; however, further research and a multidisciplinary approach are deemed as necessary for further development in this direction.

The efficacy of a new stimulation technology to increase venous flow and prevent venous stasis.

OBJECTIVES: Electrical stimulation of calf muscles has been shown to be effective in prevention of DVT. The aim was to determine: (a) dependence of venous blood velocity and ejected volume on the rates of stimulated calf contractions: (b) clinical factors affecting efficacy in healthy individuals. METHODS: The maximum intensity stimulus tolerated was applied to calves of 24 volunteers. In popliteal veins, peak systolic velocities (PSV), ejected volume per individual stimulus (stroke volume SV) and ejected total volume flow per minute (TVF) of expelled blood were determined using ultrasound. Stimulation rates from 2 to 120 beats per minute (bpm) were applied. RESULTS: Mean baseline popliteal PSV was 10 cm/s. For stimulation rates between 2 and 8 bpm, the PSV was 10 times higher and reached 96-105 cm/s. Stroke volume (SV) per individual stimulus decreased in a similar fashion. With increasing rates of stimulation the TVF increased by a factor of 12 times (from 20 ml/min to 240 ml/min). CONCLUSION: Electrical stimulation is an effective method of activating the calf muscle pump. Enhancements of popliteal blood velocity and volume flow are key factors in the prevention of venous stasis and DVT. Further studies are justified to determine the stimulation rates in those with a compromised venous system.

Association of plaque echostructure and cardiovascular risk factors with symptomatic carotid artery disease.

AIM: Severity of stenosis remains the main factor for assessing risk of stroke in patients with internal carotid artery (ICA) disease. This study was conducted to investigate the association of plaque echostructure and other established and emerging cardiovascular risk factors with symptomatic ICA disease. METHODS: Cross-sectional study of consecutive patients with significant (>50%) ICA stenosis. Carotid plaque echostructure, smoking, hypertension, diabetes mellitus, serum lipoprotein (a), homocysteine, vitamin B12, folate, cholesterol to high-density lipoprotein ratio, triglycerides, C-reactive protein, and the Framingham risk score were assessed in 124 consecutive patients (70 asymptomatic; 54 symptomatic) with significant (>50%) ICA stenosis. RESULTS: The asymptomatic and symptomatic groups did not differ in terms of gender distribution (P=0.76) and severity of stenosis (P=0.62). Echolucent plaques (type 1 and 2) were more predominant in patients with symptomatic disease (P=0.004, OR=2.13, 95% CI=1.26-3.6). Patients with plaques type 1 were relatively younger than those with type 4 (P=0.02). None of the other factors assessed had any significant association with symptomatic disease and any type of carotid plaque. CONCLUSION: Besides the severity of carotid stenosis, the presence of an echolucent plaque appears as an important factor associated with symptomatic ICA disease. Also young patients are more likely to have an echolucent plaque suggesting an age-related association with plaque maturation.

Leukocyte telomere length is associated with measures of subclinical atherosclerosis.

AIMS: Our aim was to test the association of mean leukocyte telomere length (LTL) with ultrasonic measures of subclinical atherosclerosis such as intima-media thickness in the common carotid (IMTcc) and sum of plaque areas (SPA) and with serological markers. METHODS AND RESULTS: Carotid and femoral bifurcations were scanned in 762 general population volunteers (46% men) over 40. Four features were considered: (a) IMTcc, (b) sum plaque areas of carotid plaques (SPAcar), (c) sum plaque area of common femoral plaques (SPAfem) and (d) sum plaque area (SPA--sum of the plaque areas of the largest plaques present in each of both carotid and femoral bifurcations). Mean LTL was determined with a quantitative real-time PCR-based method. IMTcc was strongly associated with mean LTL both before and after correction for traditional risk factors (B=-0.002; 95% CI=-0.004 to -0.00; p=0.014). In sex-specific analysis, the association was stronger in men (p for sex interaction<0.001). SPAfem was associated with LTL in women before and after correction (B=-0.195; 95% CI=-0.38 to -0.01; p=0.037) (p for sex interaction<0.001). LTL was also associated with age and sex-adjusted levels of hsCRP (p=0.012), sCD40L (p=0.042), homocysteine (p=0.006), creatinine (p=0.02), ApoA1 (p=0.01), Lp(a) (p=0.04) and HOMA-IR (p=0.008). CONCLUSIONS: Our results support the telomere hypothesis and highlight potential differences in the biological mechanisms leading to intima-media thickening and/or plaque formation between vascular beds. They may provide insights into a novel treatment of antisenescence to prevent atherosclerosis.