Progression of carotid intima-media thickness as predictor of vascular events: results from the IMPROVE study.

OBJECTIVE: To investigate whether several different measures of carotid intima-media thickness (IMT) progression are associated with subsequent vascular events and whether such associations are independent of baseline carotid atherosclerotic profile and Framingham risk factors. APPROACH AND RESULTS: A longitudinal cohort study (the Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population study) was performed in 7 centers in 5 European countries (Finland, France, Italy, the Netherlands, and Sweden). Three thousand four hundred eighty-two subjects (median age 64.1 years; 47.8% men) with ≥ 3 vascular risk factors were recruited and monitored for a postprogression median follow-up of 21.5 months, during which time 129 subjects experienced a first vascular event (incidence of 20.4 per 1000 person-years). The 15th month progression of mean and maximum carotid IMT of the left and right common carotids, bifurcations, internal carotid arteries, and their composite measures, as well as the fastest IMTmax progression (Fastest-IMT(max-progr)) detected in the whole carotid tree regardless of location, were used in statistical analyses. All carotid IMT measures showed significant progression during the first 15 months (P<0.001), but only the Fastest-IMT(max-progr) was significantly associated with the risk of subsequent vascular events. The Fastest-IMT(max-progr) association persisted after Bonferroni correction for multiple comparisons and after adjustments for Framingham risk factors and pharmacological treatments (all P<0.005). The use of Framingham Risk Score in place of Framingham risk factors provided almost identical results (P=0.003). CONCLUSIONS: The Fastest-IMT(max-progr), a novel approach to assess carotid IMT progression, identifies focal increases of carotid IMT and, in contrast to other progression variables, is associated with cardiovascular risk.

Measurements of carotid intima-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events: results of the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study.

OBJECTIVES: The goal of this study was to compare the performance of several measures of carotid intima-media thickness (C-IMT) as predictors of cardiovascular events (CVEs), and to investigate whether they add to the predictive accuracy of Framingham risk factors (FRFs). BACKGROUND: Various markers of subclinical atherosclerosis have been identified as predictors of CVEs, but the most powerful variable is still under debate. METHODS: A cohort study was carried out in 5 European countries. A total of 3,703 subjects (median age 64.4 years; 48% men) were followed-up for a median of 36.2 months, and 215 suffered a first CVE (incidence: 19.9/1,000 person-years). RESULTS: All measures of C-IMT and the interadventitia common carotid artery diameter (ICCAD) were associated with the risk of CVEs, after adjustment for FRFs and therapies (all p < 0.005). The average of 8 maximal IMT measurements (IMT(mean-max)), alone or combined with ICCAD, classified events and non-events better than the common carotid mean IMT (net reclassification improvement [NRI]: +11.6% and +19.9%, respectively; both p < 0.01). Compared with classification based on FRFs alone, the NRI resulting from the combination of FRFs+ICCAD+IMT(mean-max) was +12.1% (p < 0.01). The presence of at least 1 plaque (maximum IMT >1.5 mm) performed significantly worse than composite IMTs that incorporated plaques (p < 0.001). Adjusted Kaplan-Meier curves showed that individuals with a FRS = 22.6% (cohort average), and both IMT(mean-max) and ICCAD above the median, had a 6.5% risk to develop a CVE over 3 years versus a 3.4% risk for those with the same FRS, and both IMT(mean-max) and ICCAD below the median. CONCLUSIONS: A risk stratification strategy based on C-IMT and ICCAD as an adjunct to FRFs is a rational approach to prevention of cardiovascular disease.

Estrogenic properties of six compounds derived from Eucommia ulmoides Oliv. and their differing biological activity through estrogen receptors α and ß.

Eucommia ulmoides Oliv. (Du-zhong), a well known Chinese herbal medicine, has been increasingly used as a nutraceutical supplement. The aim of this study was to identify and characterise novel estrogenic compounds in E. ulmoides. We report that six compounds, namely pinoresinol 4'-O-ß-d-glucopyranoside, pinoresinol di-O-ß-d-glucopyranoside, aucubin, wogonin, baicalein, and α-O-ß-d-glucopyranosyl-4,2',4'-trihydroxydihydrochalcone, activated estrogen receptor (ER)-dependent transcription of both transfected and endogenous target genes. Strikingly, these compounds exhibited significant difference in ER subtype (α vs. ß) selectivity. Cell proliferation and ER subcellular localisation analyses also demonstrated that they mediated the estrogenic effects by the genomic action of ERα. This study suggests that E. ulmoides is a rich source of new selective estrogen receptor modulators and evaluations of its health benefit and safety as a food additive should take into account the diverse phytoestrogen activities of the individual components.

Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study.

AIMS: The 'IMPROVE study' was designed to investigate whether cross-sectional carotid artery intima-media thickness (IMT) and overall IMT progression are predictors of new vascular events in European individuals at high risk of cardiovascular diseases. This paper reports the results of the baseline analyses aimed at identifying the major determinants of increased carotid IMT (C-IMT). METHODS AND RESULTS: IMPROVE is a prospective, multicentre, longitudinal, observational study. A total of 3711 subjects (age range 54-79 years) with at least three vascular risk factors (VRFs) were recruited in seven centres in Finland, France, Italy, the Netherlands, and Sweden. Collected variables included clinical, biochemical, genetic, socioeconomic, psychological, nutritional, and educational data, personal and family history of diseases, drug intake, and physical activity. By multiple linear regression analysis, C-IMT was positively associated with latitude, age, gender, pulse pressure, pack-years, and hypertension, and inversely with educational level (all P < 0.0001 for IMT(mean-max)). Latitude was the strongest independent determinant of C-IMT (partial r(2) for IMT(mean-max) = 0.109, P < 0.0001) and alone accounted for nearly half of the variation explained by the regression model (partial r(2) for IMT(mean-max) = 0.243, P < 0.0001). The geographical gradient for C-IMT paralleled the well-known north-to-south cardiovascular mortality gradient (r(2) for IMT(mean) = 0.96). CONCLUSION: Latitude is an important determinant of C-IMT, which is not explained by between-country differences in established VRFs. Other unknown contributory mechanisms such as heritable, nutritional, or environmental factors may be important in the genesis of this geographical gradient.

Chocolate, lifestyle, and health.

Interest in the biological activities of cocoa polyphenols is increasing steadily. In fact, the high polyphenol content of cocoa, coupled with its widespread presence in many food items, render this food of particular interest from the nutritional and "pharmacological" viewpoints. This paper summarizes the new findings and developments regarding the effects of cocoa and chocolate consumption on human health as presented at the International Conference "Chocolate, Lifestyle, and Health" (Milan, Italy, March 2, 2007) regarding the effects of cocoa and chocolate consumption on human health.

Non-pharmacological control of plasma cholesterol levels.

The importance of non-pharmacological control of plasma cholesterol levels in the population is increasing, along with the number of subjects whose plasma lipid levels are non-optimal, or frankly elevated, according to international guidelines. In this context, a panel of experts, organized and coordinated by the Nutrition Foundation of Italy, has evaluated the nutritional and lifestyle interventions to be adopted in the control of plasma cholesterol levels (and specifically of LDL cholesterol levels). This Consensus document summarizes the view of the panel on this topic, with the aim to provide an updated support to clinicians and other health professionals involved in cardiovascular prevention.

Assessment of nutritional profiles: a novel system based on a comprehensive approach.

The prevalence of non-communicable diseases (for example, cardiovascular disorders, type 2 diabetes and cancer) is rampant in Western societies, accounting for approximately 60 % of all causes of death. A large proportion of non-communicable diseases can be prevented through appropriate diets and lifestyles. Accordingly, several health authorities and regulatory bodies are assessing the nutritional profiles of food items and whole diets, to implement guidelines aimed at improving the diet of the general population. While a global approach is desirable, the need of individuals to maintain their distinct dietary habits must also be taken into account. The portion sizes of food as well as pattern of food consumption, for example during or between the main meals, are very important in determining the nutritional profile of a diet. A novel method to assess the nutritional profile of foods is being proposed and made available on-line. Its main innovative aspects are (1) the comprehensive manner with which the system analyses and computes a great range of features of individual food items and (2) the distinction among eating occasions, namely during or in-between the main meals. Moreover, this approach allows for rapid modification and great flexibility to suit individual needs and gastronomic habits.

Serum from hypercholesterolemic patients treated with atorvastatin or simvastatin inhibits cultured human smooth muscle cell proliferation.

We evaluated the pharmacological activity of whole-blood serum from atorvastatin- vs. simvastatin- (both 40 mg/day) treated hypercholesterolemic patients (n=10) on cultured smooth muscle cell (SMC) proliferation and cholesterol biosynthesis, as related to lipid-lowering effect. Patients received either single or 2-weeks repeated doses of both simvastatin and atorvastatin, following a randomised, double-blind, cross-over design. Blood samples were collected before drug administration and at the scheduled intervals after administration, and the obtained serum was separated by centrifugation, sterilized and frozen until assayed. Cultured SMC were supplemented with medium plus 15% of separate serum sampled from the patients, and grown for 72 h. Proliferation was assayed by a Coulter Counter, while cholesterol biosynthesis was measured by the incorporation of 14C-acetate into cholesterol, under the same experimental conditions. Atorvastatin was more active vs. simvastatin in reducing total- (-28.3% vs. -20.7%; p=0.045) and LDL-cholesterol (-39.8% vs. -30.1%; p=0.011) after a 2-weeks regimen. Serum from atorvastatin-treated patients inhibited SMC proliferation vs.t=0 after both single (AUC -21.6%) and repeated (AUC -26.9%) doses, while serum from simvastatin-treated patients inhibited SMC proliferation only after repeated doses (AUC -24.5%). Interestingly, in the same experimental conditions, the serum concentrations of both statins (and of their active metabolites) were constantly below the detection limits, as shown from the lack of inhibition of cholesterol biosynthesis. The absence of any significant association between the lipid-lowering effects and the inhibition of SMC proliferation, together with no detectable active statin in the serum, suggests that these effects are elicited through independent mechanisms.

Levels of the n-3 fatty acid eicosapentaenoic acid in addition to those of alpha linolenic acid are significantly raised in blood lipids by the intake of four walnuts a day in humans.

BACKGROUND AND AIMS: Ingestion of alpha linolenic acid (ALA), with the richest source among dry fruits such as walnuts, is associated with cardiovascular prevention. The aim of this study was to selectively evaluate the effects of moderate walnut consumption on the levels of ALA and its metabolic derivatives in human blood. METHODS AND RESULTS: After a 2-week run-in period, 10 volunteers consumed 4 walnuts per day (in addition to their habitual diet) for 3 weeks. Fatty acid profiles, with special attention to levels of ALA and long chain polyunsaturated fatty acids (LC-PUFA), were assessed in blood drops collected from fingertips. The data indicate that the administration of a few walnuts a day for 3 weeks significantly increases blood levels, not only of ALA (from 0.23+/-0.07 SD to 0.47+/-0.13 SD), but also of its longer chain derivative eicosapentaenoic acids (EPA) (from 0.23+/-0.37 to 0.82+/-0.41) with levels remaining elevated over basal values after washout. CONCLUSION: The findings of this pilot study indicate that plant ALA in appropriate food items favourably affects the n-3 LC-PUFA status.

Biomarkers for atherosclerosis: pathophysiological role and pharmacological modulation.

PURPOSE OF REVIEW: The aim of this article is to discuss the potential value of biomarkers for atherosclerosis in the assessment of risk for cardiovascular disease, in the pathogenesis of atherosclerosis, and in the monitoring of pharmacological treatment. RECENT FINDINGS: In an attempt to improve global cardiovascular risk prediction, considerable effort has been made in the discovery and characterization of soluble biomarkers which can go beyond the measure of total and LDL cholesterol levels. In particular, circulating molecules related to chronic inflammation have emerged as potential biomarkers for atherosclerosis. Evidence, obtained from in-vitro and in-vivo experimental models, has also documented that the majority of biomarkers play a pathological role in atherogenesis. Multiple screening of different biomarkers may therefore improve the assessment of risk, diagnosis, and prognosis for cardiovascular disease. In addition, soluble biomarkers have been shown to be modulated by hypolipidemic drugs and to be potentially useful in determining the clinical benefits of pharmacological therapies that do not alter serum lipid levels. SUMMARY: Altered levels of soluble biomarkers are associated with cardiovascular disease, and profiling of multiple biomarkers for atherosclerosis will be a useful indicator for better risk assessment, diagnosis, and prognosis, as well as monitoring pharmacological treatments for atherosclerosis.

The emerging link between nutrition, inflammation and atherosclerosis.

A number of dietary components modulate the inflammatory response in humans, thereby affecting cardiovascular risk. As basic research provides a better understanding of the molecular mechanisms of vascular function regulation by nutrients, clinical investigation and outcome studies demonstrate the relevance of dietary factors to the prevention and treatment of vascular disease. Benefits of dietary interventions may be attributable to weight loss or to more specialized mechanisms in which inflammation is targeted directly. Available evidence indicates that dietary intervention should be an integral part of therapeutic approaches for treating conditions such as the metabolic syndrome and, ultimately, for the prevention of cardiovascular disease.

Recombinant apolipoprotein A-IMilano for the treatment of cardiovascular diseases.

Apolipoprotein A-I(Milano) (apoA-I(M)) is a natural variant of apoA-I characterized by a cysteine for arginine substitution at position 173 of the primary sequence. ApoA-I(M) carriers have much less atherosclerosis than expected from their very low plasma high-density lipoprotein (HDL) cholesterol levels, suggesting that the variant might be protective. Synthetic HDL (sHDL) made with a recombinant form of the dimeric A-I(M) (A-I(M)/A-I(M)) and phospholipids given in single or multiple injections is effective in inducing the regression of atherosclerotic plaques, preventing arterial restenosis, and limiting cardiac dysfunction after ischemia/reperfusion injury. In a phase II trial in patients with acute coronary syndromes, a short-term treatment with A-I(M)/A-I(M) sHDL caused a remarkable reduction of atheroma burden. Although at early stages of drug development, A-I(M)/A-I(M) sHDL holds vast promise for the treatment of a variety of cardiovascular diseases in humans.

Activation of NF-kB and ERK1/2 after permanent focal ischemia is abolished by simvastatin treatment.

We investigated the effects of simvastatin treatment on the expression of IL-1beta and MCP-1, the activity of NF-kB, and the signaling pathways related to NF-kB activation in a rat model of permanent middle cerebral artery occlusion (pMCAO). IL-1beta and MCP-1 expression, determined using RT-PCR, was enhanced by pMCAO; this effect was inhibited by the administration of simvastatin before ischemia. Pre-treatment with simvastatin abolished the ischemia-induced activation of NF-kB observed in vehicle-treated animals. The evaluation of signal transduction pathways, including extracellular signal-regulated kinase (ERK1/2), SAPK/JNK 46/54 and p38, indicated that only ERK1/2 phosphorylation was enhanced by ischemia, and this activation was prevented by simvastatin. ERK1/2-inhibitor, U0126, reduced brain ischemia but not cytokine induction. These results provide evidence that the HMG-CoA reductase inhibitor induces its effect in the protection of ischemic brain damage with a more complex mechanism which also involve anti-inflammatory properties rather than simple inhibition of ERK1/2 signaling pathway.

Metabolic syndrome, inflammation and atherosclerosis.

The inflammatory component of atherogenesis has been increasingly recognized over the last decade. Inflammation participates in all stages of atherosclerosis, not only during initiation and during evolution of lesions, but also with precipitation of acute thrombotic complications. The metabolic syndrome is associated with increased risk for development of both cardiovascular disease and type-2 diabetes in humans. Central obesity and insulin resistance are thought to represent common underlying factors of the syndrome, which features a chronic low-grade inflammatory state. Diagnosis of the metabolic syndrome occurs using defined threshold values for waist circumference, blood pressure, fasting glucose and dyslipidemia. The metabolic syndrome appears to affect a significant proportion of the population. Therapeutic approaches that reduce the levels of proinflammatory biomarkers and address traditional risk factors are particularly important in preventing cardiovascular disease and, potentially, diabetes. The primary management of metabolic syndrome involves healthy lifestyle promotion through moderate calorie restriction, moderate increase in physical activity and change in dietary composition. Treatment of individual components aims to control atherogenic dyslipidemia using fibrates and statins, elevated blood pressure, and hyperglycemia. While no single treatment for the metabolic syndrome as a whole yet exists, emerging therapies offer potential as future therapeutic approaches.

Implications of emerging risk factors for therapeutic intervention.

Recently, the National Cholesterol Education Panel (NCEP) of the United States of America commented on the implications of new clinical trials for the Adult Treatment Panel III (ATP III) guidelines. In this commentary, new categories of "moderately high" and "very high" coronary risk were proposed with new "therapeutic options" for low-density lipoprotein (LDL) cholesterol of < or = 100 mg/dL and < or = 70 mg/dL respectively. In ATP III, these "moderately high" risk patients had been classified as moderate risk with an LDL treatment goal of < or = 130 mg/dL, while the "very high" risk patients had been classified as high risk with a treatment goal of < or = 100 mg/dL. Risk classification in the new NCEP publication is based essentially on the combination of the Framingham risk score plus counting of classical risk factors. In the present document, the International Task Force for Prevention of Coronary Heart Disease responds to this NCEP commentary and supports the suggestion of more intensive LDL cholesterol lowering in particular cases. However, the Task Force feels that a classification based on a combination of a risk score plus a count of emerging risk factors is a more logical way to identify such patients requiring lower LDL cholesterol levels than a scheme in which classical risk factors are taken into account twice, once in a count and once in a risk score.

Rosuvastatin, but not simvastatin, provides end-organ protection in stroke-prone rats by antiinflammatory effects.

OBJECTIVE: Brain abnormalities, preceded by a systemic inflammation, develop in spontaneously hypertensive stroke-prone rats (SHRSP). In this model, we investigated whether the hydrophilic statin, rosuvastatin, influences the development of inflammation associated with brain abnormalities. Because differences in hydrophilicity/hydrophobicity contribute to the differences in statin pharmacology, we also evaluated the effects of simvastatin, a lipophilic molecule METHODS AND RESULTS: SHRSP, fed a high-salt diet, were treated long-term with vehicle or rosuvastatin (1 and 10 mg/kg per day). Brain abnormalities developed after 40+/-5 days and after 60+/-5 days of salt loading, in vehicle-treated and in rosuvastatin-treated (1 mg/kg per day) SHRSP, respectively. After 100 days of treatment, no damage was detectable in 30% of the rats treated with the highest dose of the drug. In comparison with vehicle-treated SHRSP, rosuvastatin treatment attenuated the transcription of monocyte chemoattractant protein-1, transforming growth factor-beta1, IL-1beta, and tumor necrosis factor-alpha in the kidney, and of P-selectin in brain vessels and increased the transcription of endothelial nitric oxide synthase mRNA in the aorta. Urinary excretion of acute-phase proteins increased with time in vehicle-treated animals but remained negligible in drug-treated animals. These effects are independent of changes in physiological parameters. Treatment of SHRSP with simvastatin (2 to 20 mg/kg per day) did not exert any protective effect. CONCLUSIONS: Rosuvastatin attenuates inflammatory processes associated with cerebrovascular disease.