Samuela Castelnuovo

Carotid intima‐media thickness and markers of inflammation, endothelial damage and hemostasis

Background. Different soluble molecules involved in inflammation, endothelial damage, or hemostasis are recognized as potential cardiovascular risk markers. Studies to assess the role of these markers in the atherosclerotic process by evaluating their relationship to carotid intima‐media thickness (C‐IMT) tend to provide contrasting results. Purpose. To perform a review of studies addressing the association between C‐IMT and soluble markers and to investigate whether the observed inconsistencies could be explained by the characteristics of the patients included in different studies, for example prevalence of atherosclerotic disease (atherosclerotic burden), gender, age, or occurrence of specific vascular risk factors (VRFs). Data sources. PubMed and Embase (January 1990 to March 2006). Study selection. Articles in English reporting original cross‐sectional studies. Data extraction. Two authors independently extracted data on study design, population, sample size, ultrasonic methodology, and statistical approach. Data synthesis. Despite the marked heterogeneity of results presented in the literature, meta‐analysis established that studies showing positive associations between C‐IMT and plasma levels of C‐reactive protein (CRP) or fibrinogen are in the majority. Funnel plot analyses suggested the absence of an important publication bias. Data on the relationships between C‐IMT and other soluble markers are by contrast scanty, contradictory, or unconfirmed by multivariate (as opposed to univariate) analyses, and the freedom from publication bias here cannot be vouched for. The degree of atherosclerotic burden in the population studied does not account for the heterogeneity of findings reported. Gender, noninsulin‐dependent diabetes mellitus (NIDDM) and hypercholesterolemia influence the association between C‐IMT and CRP. Blood pressure and hypercholesterolemia influence the association between C‐IMT and fibrinogen. For all the other soluble markers considered, the number of groups was too small for this kind of statistical considerations. Limitations. Heterogeneity in ultrasound methodologies and in statistical approach limited comparability between studies. For most soluble markers, publication bias of positive results cannot be excluded. Conclusions. Only CRP and fibrinogen seem to be unequivocally related to C‐IMT. For all the other soluble markers considered, no clear‐cut conclusions can be drawn.

Effects of Timing and Extent of Smoking, Type of Cigarettes, and Concomitant Risk Factors on the Association Between Smoking and Subclinical Atherosclerosis

Background and Purpose— The purpose of this study was to evaluate the effects of timing and extent of smoking, type of cigarettes, and concomitant vascular risk factors (VRFs) on the association between smoking and carotid intima-media thickness (C-IMT) in a lipid clinic population. Methods— 1804 patients (869 men, age 21 to 85 year) participated in the study. Smoking habits were recorded and C-IMTs were measured by B-mode ultrasound. The associations of C-IMT with smoking status (never, former, and current) and with the cigarettes’ content of tar, nicotine, and carbon monoxide (alone or combined to define “light” or “regular” cigarettes) as well as the interactions between smoking status, gender, and VRFs were evaluated before and after adjustment for confounders. Results— C-IMT was highest in current smokers, lower in former, and lowest in never smokers. C-IMT of former and current smokers differed only after data adjustment for variables describing the extent and timing of smoking exposure. C-IMT was positively related to the number of pack-years (number of cigarettes smoked per day [cigarettes/d] multiplied by number of years smoked/20) in both former and current smokers. There were no differences in C-IMT between smokers of cigarettes with high or low nicotine, tar, or carbon monoxide content. Both diabetes and hypertension interacted positively with smoking in determining C-IMTs. Conclusions— In the present cross-sectional observational investigation, carried out in a cohort of patients attending a lipid clinic, consumption of light cigarettes does not reduce the atherogenic effect of smoking on C-IMT. The number of pack-years, cigarettes/d, and years of smoking are relevant covariates in evaluating the effects of smoking on vascular health. The presence of diabetes or hypertension strengthens the association between smoking and cardiovascular risk.

Plasma lecithin: cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis.

Effects of smoking regular or light cigarettes on brachial artery flow-mediated dilation

BACKGROUND AND PURPOSE To compare the effects of regular cigarettes (RCs) and light cigarettes (LCs) on brachial artery flow-mediated dilation (FMD) and sublingual glyceryl trinitrate-induced dilation (GTN), markers of endothelial dependant and independent function, respectively. METHODS 206 subjects (age 51.5 ± 12.8 yr, 122 men) had their smoking habits recorded and FMD and GTN measured by B-mode ultrasound. Cigarettes were categorized as RCs or LCs according to their content of tar, nicotine and CO. The chronic effect was assessed in current smokers of RCs (n = 85) or LCs (n = 53) and in never smokers (NS; n = 68). The acute effect was assessed in current smokers by measuring FMD before and 10-min after smoking a single regular (n = 29) or light (n = 51) cigarette. RESULTS FMD was significantly lower in consumers of RCs (6.26%, 95% C.I. 5.58, 6.94) or LCs (5.59%, 95% C.I. 4.74, 6.45) compared to NS (8.68%, 95% C.I. 7.92, 9.44) (both P < 0.0001), but did not differ (P > 0.05) when compared to each other. GTN was similar in the three groups. Analyses adjusted for clinical confounders and for markers involved in oxidative stress, arginine/nitric oxide pathway, and inflammation provided identical results. Smoking a single cigarette, either regular or light, reduced FMD (-0.88% and -1.17%, respectively, both P < 0.05), without significant difference between cigarette type. RCs and LCs produced analogous chronic and acute effects when FMD was calculated with respect to the last 60 s of the low-flow phase (FMD60s). CONCLUSIONS LCs impair endothelial-dependant vasodilation as much as RCs. Thus, smoking LCs cannot be considered an alternative to the only safe choice of a complete and permanent smoking cessation.

Recognition of patients with cardiovascular disease by artificial neural networks.

BACKGROUND. Artificial neural networks (ANNs) are computer algorithms inspired by the highly interactive processing of the human brain. When exposed to complex data sets, ANNs can learn the mechanisms that correlate different variables and perform complex classification tasks. AIMS. A database, of 949 patients and 54 variables, was analysed to evaluate the capacity of ANNs to recognise patients with ( VE +  = 196) or without (VE −  = 753) a history of vascular events on the basis of vascular risk factors (VRFs), carotid ultrasound variables (UVs) or both. METHOD. The performance of ANN was assessed by calculating the percentage of correct identifications of VE + and VE − patients (sensitivity and specificity, respectively) and the prediction accuracy (weighted mean between sensitivity and specificity).  RESULTS. The results showed that ANNs can be trained to identify VE + and VE − subjects more accurately than discriminant analyses. When VRFs and UVs were used as input variables, the prediction accuracies of the ANN providing the best results were 80.8% and 79.2%, respectively. The addition of gender, age, weight, height and body mass index to UVs increased accuracy of prediction to 83.0%. When the ANNs were allowed to choose the relevant input data automatically (I.S. system‐Semeion), 37 variables were selected among 54, five of which were UVs. Using this set of variables as input data, the performance of the ANNs in the classification task reached a prediction accuracy of 85.0%, with the 92.0% correct classification of VE + patients.  CONCLUSIONS. Artificial neural network technology is highly promising in the development of accurate diagnostic tools designed to recognize patients at high risk of cardiovascular diseases.

Carotid plaque-thickness and common carotid IMT show additive value in cardiovascular risk prediction and reclassification

Background and aims Carotid plaque size and the mean common carotid intima-media thickness measured in plaque-free areas (PF CC-IMTmean) have been identified as predictors of vascular events (VEs), but their complementarity in risk prediction and stratification is still unresolved. The aim of this study was to evaluate the independence of carotid plaque thickness and PF CC-IMTmean in cardiovascular risk prediction and risk stratification. Methods The IMPROVE-study is a European cohort (n = 3703), where the thickness of the largest plaque detected in the whole carotid tree was indexed as cIMTmax. PF CC-IMTmean was also assessed. Hazard Ratios (HR) comparing the top quartiles of cIMTmax and PF CC-IMTmeanversus their respective 1–3 quartiles were calculated using Cox regression. Results After a 36.2-month follow-up, there were 215 VEs (125 coronary, 73 cerebral and 17 peripheral). Both cIMTmax and PF CC-IMTmean were mutually independent predictors of combined-VEs, after adjustment for center, age, sex, risk factors and pharmacological treatment [HR (95% CI) = 1.98 (1.47, 2.67) and 1.68 (1.23, 2.29), respectively]. Both variables were independent predictors of cerebrovascular events (ischemic stroke, transient ischemic attack), while only cIMTmax was an independent predictor of coronary events (myocardial infarction, sudden cardiac death, angina pectoris, angioplasty, coronary bypass grafting). In reclassification analyses, PF CC-IMTmean significantly adds to a model including both Framingham Risk Factors and cIMTmax (Integrated Discrimination Improvement; IDI = 0.009; p = 0.0001) and vice-versa (IDI = 0.02; p < 0.0001). Conclusions cIMTmax and PF CC-IMTmean are independent predictors of VEs, and as such, they should be used as additive rather than alternative variables in models for cardiovascular risk prediction and reclassification.

A New Noninvasive Method for the Accurate and Precise Assessment of Varicose Vein Diameters

The feasibility and reproducibility of a new ultrasonic method for the direct assessment of maximal varicose vein diameter (VVD) were evaluated. A study was also performed to demon strate the capacity of the method to detect changes in venous diameter induced by a phar macologic treatment. Patients with varicose vein disease were recruited. A method that allows the precise positioning of patient and transducer and performance of scans in a gel-bath was developed. Maximal WD was recorded both in the standing and supine positions. The intraassay reproducibility was determined by replicate scans made within 15 minutes in both positions. The interobserver variability was assessed by comparing WDs measured during the first phase baseline examination with those obtained during baseline examinations in the second phase of the study. The error in reproducibility of WD determinations was 5.3% when diameters were evaluated in the standing position and 6.4% when assessed in the supine position. The intramethod agreement was high, with a bias between readings of 0.06 ±0.18 mm and of -0.02 ±0.19 mm, respectively, in standing and supine positions. Correlation coefficients were better than 0.99 in both positions. The method appears to be sensitive enough to detect small changes in VVDs induced by treatments. The proposed technique provides a tool of potential valid use in the detection and in vivo monitoring of WD changes in patients with varicose vein disease. The method offers an innovative approach to obtain a quantitative assessment of varicose vein progression and of treatment effects, thus providing a basis for epidemiologic surveys.

Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency

The aim of this study was to evaluate the vasoprotective effects of HDL isolated from carriers of LCAT deficiency, which are characterized by a selective depletion of LpA-I:A-II particles and predominance of preβ migrating HDL. HDLs were isolated from LCAT-deficient carriers and tested in vitro for their capacity to promote NO production and to inhibit vascular cell adhesion molecule-1 (VCAM-1) expression in cultured endothelial cells. HDLs from carriers were more effective than control HDLs in promoting eNOS activation with a gene-dose-dependent effect (PTrend = 0.048). As a consequence, NO production induced by HDL from carriers was significantly higher than that promoted by control HDL (1.63 ± 0.24-fold vs. 1.34 ± 0.07-fold, P = 0.031). HDLs from carriers were also more effective than control HDLs in inhibiting the expression of VCAM-1 (homozygotes, 65.0 ± 8.6%; heterozygotes, 53.1 ± 7.2%; controls, 44.4 ± 4.1%; PTrend = 0.0003). The increased efficiency of carrier HDL was likely due to the depletion in LpA-I:A-II particles. The in vitro findings might explain why carriers of LCAT deficiency showed flow-mediated vasodilation and plasma-soluble cell adhesion molecule concentrations comparable to controls, despite low HDL-cholesterol levels. These results indicate that selective depletion of apoA-II-containing HDL, as observed in carriers of LCAT deficiency, leads to an increased capacity of HDL to stimulate endothelial NO production, suggesting that changes in HDL apolipoprotein composition may be the target of therapeutic interventions designed to improve HDL functionality.

THE USE OF ECHOCARDIOGRAPHY FOR THE NON INVASIVE EVALUATION OF CORONARY ARTERY DISEASE

Abstract In the Western world, there are now millions of patients who undergo clinical procedures that evaluate coronary artery status each year. Methods span from direct imaging using angiography, computerized tomography, to nuclear magnetic imaging as well as to functional studies, such as positron emission tomography. These techniques have provided significant information to physicians, but there is still need for an improved accessibility. Angiographic methods are expensive and expose the patient to significant amounts of radiation, undesirable in younger patients. Among the novel technologies for coronary diagnostics, transthoracic echocardiography (TTE) of coronary arteries has provided an important alternative, particularly in everyday practice. Diagnostic arterial TTE can allow determination of the coronary wall lumen in at least three major coronary segments (left main [LM], left arterial descending [LAD] and right coronary artery [RCA]). Coronary wall thickness using the LAD has been preliminarily shown to be related to the risk of coronary events. Since it is well ascertained that coronary lesions found in any location indicate that at least 80% of the coronary tree is affected, this is very important clinical information. Evaluation of coronary status by TTE is a novel technology providing important information in ischemic syndromes, in cases of coronary malformations and other coronary diseases. KEY MESSAGES Coronary evaluation can be carried out by a variety of both invasive and non-invasive methods, many requiring radiation exposure or patient immobility. Transthoracic echocardiography (TTE) of the coronaries can, in particular, evaluate the coronary wall thickness, and this may be directly related to the coronary disease risk. TTE is a useful method for the monitoring of coronary flow reserve and can allow the detection of coronary malformations.

Left main coronary wall thickness correlates with the carotid intima media thickness and may provide a new marker of cardiovascular risk

Evaluation of carotid intima media thickness (C-IMT) by ultrasound is a well-established non-invasive tool to assess cardiovascular (CV) risk. Novel equipment has made evaluation easier, although still operator-sensitive, and with normal values not always transferable outside of the cohort of origin. Parallel evaluations with coronary calcium score (CCS) by computed tomography have been carried out, but there is no consensus on which is the technique that provides the most reliable data. Visualization of coronary wall thickness is presently achievable by transthoracic echography (TTE), a procedure carried out in real time with little cost. It is repeatable, does not expose the patient to radiation risk and, in preliminary studies, correlates with coronary events over a prolonged period of time. The present report was aimed at comparing, in a continued series of 301 individuals, C-IMT with the wall thickness of the left main coronary (LMCWT), determined by TTE. All evaluated patients were individuals referred to the Lipid Clinic, in whom C-IMT measurements are routinely carried out. Of these patients, 58% were on drug treatment, predominantly statins (32%), followed by ezetimibe (11%), fibrates (8%), Proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies (2.3%) and nutraceuticals (14%). All participants signed an informed consent form and the procedures were approved by the Institutional Review Board. C-IMTs were measured with the electronic caliper of the MYLAB 70 XVG with a linear LA332 Probe (ESAOTE, Italy). The protocol requires determination of the mean C-IMTs of near and far walls of the right and left common carotids, bifurcations and internal carotids in three different projections, i.e. evaluating 36 segments per patient. C-IMTmean, an index of the extent of carotid atherosclerosis, is the average of C-IMTs at all the considered locations; conversely, C-IMTmax, representing an index of plaques, rather than of generalized wall thickening, is the single highest C-IMT. Coronary echography was carried out by the use of EPIQ 7C with an X5-1 Probe (Philips). The LMC was identified by evaluating projections from scanning, superior to the aortic valve. TTE visualization of the proximal LMCallows recording of the thickness of the LMCanterior (LMCaWT) and posterior walls (LMCpWT) together with the lumen diameter and percentage stenosis. Significant correlations for test–retest variability in the single operator were found: r1⁄4 0.81 and r1⁄4 0.85 for LMCaWT and LMCpWT, respectively. A comparative evaluation of C-IMTmax and LMCpWT in two participating patients is given in Figure 1(a) and (b). Patients were predominantly males (231 vs 70 females), women being older (median age 60 vs 51 years for males; Table 1). By assessing C-IMT variables and LMC thicknesses and widths, Spearman partial correlation coefficients, adjusted for age and body mass index (BMI), showed significant correlations (all p< 0.0001) between C-IMTmean (r1⁄4 0.31), C-IMTmax (r1⁄4 0.31) and C-IMTmean max (r1⁄4 0.33) with LMCpWT. Weaker correlations were found with the anterior wall thickness (r1⁄4 0.25, 0.23 and 0.25, respectively; all