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The elastic properties of conductance arteries are one of the most important hemodynamic functions in the body, and data continue to emerge regarding the importance of their dysfunction in vascular aging and a range of cardiovascular diseases. Here, we provide new insight into the integrative physiology of arterial stiffening and its clinical consequence. We also comprehensively review progress made on pathways/molecules that appear today as important basic determinants of arterial stiffness, particularly those mediating the vascular smooth muscle cell (VSMC) contractility, plasticity and stiffness. We focus on membrane and nuclear mechanotransduction, clearance function of the vascular wall, phenotypic switching of VSMCs, immunoinflammatory stimuli and epigenetic mechanisms. Finally, we discuss the most important advances of the latest clinical studies that revisit the classical therapeutic concepts of arterial stiffness and lead to a patient-by-patient strategy according to cardiovascular risk exposure and underlying disease.

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Background The mechanisms underlying the association between obstructive sleep apnea (OSA) and cardiovascular disease may include accelerated vascular aging. The aim was to compare the magnitude of vascular aging in patients with high versus low risk of OSA. Methods and Results In 2 community-based studies, the PPS3 (Paris Prospective Study 3) and the Maastricht Study, high risk of OSA was determined with the Berlin questionnaire (a screening questionnaire for OSA). We assessed carotid artery properties (carotid intima-media thickness, Young's elastic modulus, carotid-femoral pulse wave velocity, carotid pulse wave velocity, carotid diameter using high precision ultrasound echography), and carotid-femoral pulse wave velocity (in the Maastricht Study only). Regression coefficients were estimated on pooled data using multivariate linear regression. A total of 8615 participants without prior cardiovascular disease were included (6840 from PPS3, 62% men, mean age 59.5±6.2 years, and 1775 from the Maastricht Study, 51% men, 58.9±8.1 years). Overall, high risk of OSA prevalence was 16.8% (n=1150) in PPS3 and 23.8% (n=423) in the Maastricht Study. A high risk of OSA was associated with greater carotid intima-media thickness (β=0.21; 0.17-0.26), Young's elastic modulus (β=0.21; 0.17-0.25), carotid-femoral pulse wave velocity (β=0.24; 0.14-0.34), carotid pulse wave velocity (β=0.31; 0.26-0.35), and carotid diameter (β=0.43; 0.38-0.48), after adjustment for age, sex, total cholesterol, smoking, education level, diabetes mellitus, heart rate, and study site. Consistent associations were observed after additional adjustments for mean blood pressure, body mass index, or antihypertensive medications. Conclusions These data lend support for accelerated vascular aging in individuals with high risk of OSA. This may, at least in part, underlie the association between OSA and cardiovascular disease.

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The Reference Values for Arterial Stiffness Collaboration has derived an equation using age and mean blood pressure to estimated pulse wave velocity (ePWV), which predicted cardiovascular events independently of Systematic COoronary Risk Evaluation (SCORE) and Framingham Risk Score. The study aim was to investigate the independent association between ePWV and clinical outcomes in 107 599 apparently healthy subjects (53% men) aged 19 to 97 years from the MORGAM Project who were included between 1982 and 2002 in 38 cohorts from 11 countries. Using multiple Cox-regression analyses, the predictive value of ePWV was calculated adjusting for country of inclusion and either SCORE, Framingham Risk Score, or traditional cardiovascular risk factors (age, sex, smoking, systolic blood pressure, body mass index [BMI], total and high-density lipoprotein cholesterol). Cardiovascular mortality consisted of fatal stroke, fatal myocardial infarction, or coronary death, and the composite cardiovascular end point consisted of stroke, myocardial infarction, or coronary death. Model discrimination was assessed using Harrell's C -statistic. Adjusting for country and logSCORE or Framingham Risk Score, ePWV was associated with all-cause mortality (hazard ratio, 1.23 [95% CI 1.20-1.25] per m/s or 1.32 [1.29-1.34]), cardiovascular mortality (1.26 [1.21-1.32] or 1.35 [1.31-1.40]), and composite cardiovascular end point (1.19 [1.16-1.22] or 1.23 [1.20-1.25]; all P <0.001). However, after adjusting for traditional cardiovascular risk factors, ePWV was only associated with all-cause mortality (1.15 [1.08-1.22], P <0.001) and not with cardiovascular mortality (0.97 [0.91-1.03]) nor composite cardiovascular end point (1.10 [0.97-1.26]). The areas under the last 3 receiver operator characteristic curves remained unchanged when adding ePWV. Elevated ePWV was associated with subsequent mortality and cardiovascular morbidity independently of systematic coronary risk evaluation and Framingham Risk Score but not independently of traditional cardiovascular risk factors.

Large artery stiffness is an index of vascular aging associated with cardiovascular mortality. Whereas traditional risk factors for arterial stiffness are known, the contribution of socioeconomic factors is less reported. We sought to determine the relationship between arterial stiffness and socioeconomic deprivation (at the individual and neighborhood levels) in healthy males and females. In 7803 adults, carotid stiffness was determined by high-precision carotid echo-tracking. Individual deprivation data included education, living alone, occupation, and Evaluation of the Deprivation and Inequalities of Health in Healthcare Centers score. Neighborhood deprivation was determined from commune level data (smallest administrative subdivision) available from French National Institute of Statistics and Economic Studies (2011) using principal component analysis. The separate and combined associations between individual and neighborhood deprivation (main exposures) and carotid stiffness (outcome) were quantified using linear and multilevel model adjusted for traditional risk factors. Analyses were conducted separately in males and females. Individual deprivation (lower education and occupation in males and living alone and higher Evaluation of the Deprivation and Inequalities of Health in Healthcare Centers in both populations) was adversely related to carotid stiffness, independently of potential confounders ( P<0.05). Neighborhood deprivation was adversely related to carotid stiffness in males ( P<0.05), but not in females. Socioeconomic deprivation, both at individual and, to a lesser extent, neighborhood level are associated with carotid stiffness in males. Only individual deprivation is associated with carotid stiffness in females.

Background Inflammatory bowel disease ( IBD ) is characterized by a low prevalence of traditional risk factors, an increased aortic pulse-wave velocity ( aPWV ), and an excess of cardiovascular events. We have previously hypothesized that the cardiovascular risk excess reported in these patients could be explained by chronic inflammation. Here, we tested the hypothesis that chronic inflammation is responsible for the increased aPWV previously reported in IBD patients and that anti-TNFa (anti-tumor necrosis factor-alpha) therapy reduce aPWV in these patients. Methods and Results This was a multicenter longitudinal study. We enrolled 334 patients: 82 patients with ulcerative colitis, 85 patients with Crohn disease, and 167 healthy control subjects matched for age, sex, and mean blood pressure, from 3 centers in Europe, and followed them for 4 years (range, 2.5-5.7 years). At baseline, IBD patients had higher aPWV than controls. IBD patients in remission and those treated with anti-TNFa during follow-up experienced an aortic destiffening, whereas aPWV increased in those with active disease and those treated with salicylates ( P=0.01). Disease duration ( P=0.02) was associated with aortic stiffening as was, in patients with ulcerative colitis, high-sensitivity C-reactive protein during follow-up ( P=0.02). All these results were confirmed after adjustment for major confounders. Finally, the duration of anti-TNFa therapy was not associated with the magnitude of the reduction in aPWV at the end of follow-up ( P=0.85). Conclusions Long-term anti-TNFa therapy reduces aPWV , an established surrogate measure of cardiovascular risk, in patients with IBD . This suggests that effective control of inflammation may reduce cardiovascular risk in these patients.

Carotid arterial diameter enlargement is a manifestation of arterial remodeling and may be a risk factor for cardiovascular disease (CVD). We evaluated the association between carotid artery diameter and risk of stroke, coronary heart disease, CVD, and all-cause mortality and explored whether the associations could be explained by processes involved in arterial remodeling, that is, blood pressure-related media thickening, arterial stiffness, arterial wall stress, and atherosclerosis. We included 4887 participants (mean age 67±9 years; 54% women) from 4 cohort studies: Rotterdam Study, NEPHROTEST, Hoorn Study, and a study by Blacher et al. Common carotid artery properties were measured using echotracking. Incident cases were recorded based on medical records. We used Cox proportional hazard models adjusting for cardiovascular risk factors and estimates of processes underlying arterial remodeling. During follow-up (mean, 11 years), 379 (8%) individuals had a stroke, 516 had a (11%) coronary heart disease, 807 had a (17%) CVD, and 1486 (30%) had died. After adjustment for cardiovascular risk factors, individuals in the highest tertile of carotid diameter (diameter >8 mm) compared with those in the lowest tertile (diameter <7 mm) had a higher incidence of stroke (hazard ratio, 1.5; 95% confidence interval, 1.1-2.0). From all estimates of processes underlying arterial remodeling, adjustment for carotid intima-media thickness attenuated this association (hazard ratio after adjustment for intima-media thickness, 1.2; 95% confidence interval, 0.9-1.6). Larger carotid diameter was associated with risk of CVD and mortality but not clearly with coronary heart disease risk. We showed that a larger carotid diameter is associated with incident stroke, CVD, and mortality. Carotid intima-media thickness, a measure of blood pressure-related media thickening, partially explained the association with stroke incidence., (© 2018 American Heart Association, Inc.)

Background: The recent finding that aortic pulse wave velocity (aPWV) is increased in patients with inflammatory bowel disease may explain why the cardiovascular risk is increased despite the low prevalence of traditional cardiovascular risk factors. We aimed to test whether inflammation is associated with aortic stiffening in this setting after adjustment for major confounders and to perform subgroup analyses., Methods and Results: A systematic literature search for aPWV in inflammatory bowel disease was performed using PubMed, Scopus, Web of Science, and Google Scholar databases (last accessed May 7, 2017). Inclusion criterion was peer-reviewed publications on clinical studies reporting original data. This study followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data 2015 guidelines. Data were provided for 4 cohorts in 3 countries (151 participants with ulcerative colitis, 159 with Crohn's disease, and 227 control patients). Using aPWV, cohort-specific z scores were calculated after log e -transform and combined in meta-analysis to form pooled effects using a random-effects model. Compared with controls, aPWV was increased in patients with Crohn's disease (mean difference 0.78 z score; 95% confidence interval, 0.56-1.00 z score [ P <0.001]) and ulcerative colitis (mean difference 0.75 z score; 95% confidence interval, 0.52-0.97 z score [ P <0.001]). In an outlier-robust multivariate linear regression model adjusted for prespecified confounders, aPWV was associated with disease duration (years, β=0.05 z score; 95% confidence interval, 0.02-0.08 z score [ P <0.001]) and white blood cell count (billion cells/L, β=0.07 z score; 95% confidence interval, 0.02-0.11 z score [ P =0.002]) but not with markers of acute inflammation (C-reactive protein and erythrocyte sedimentation rate), cardiovascular risk factors, and therapy., Conclusions: The increased aPWV reported in patients with inflammatory bowel disease is associated with inflammation., Clinical Trial Registration: URL: http://www.crd.york.ac.uk. Unique identifier: PROSPERO 2016: CRD42016053070., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Arterial stiffness has been accumulating evidence as an intermediate cardiovascular endpoint. It has been established as an independent risk marker for cardiovascular disease, and reflects the dissociation between chronologic and biologic age of large arteries-attributing earlier the risk that a normal vascular ageing process had installed to occur several years later. The concept of Early Vascular Ageing (EVA) is developed to establish primordial prevention, identifying individuals whose ageing path has been accelerated either by inherent features, interaction with the environment or arterial exposure to several types of insults that evolve to medial layer morphological changes. Understanding the pathophysiology of vascular ageing, its consequences and therapeutic opportunities is therefore an advantage that could be translated in time of prevention and survival free of cardiovascular disease. As the EVA construct is advancing, new features appear as interesting to better translate it into clinical practice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Background: Arterial age can be estimated from equations relating arterial stiffness to age and blood pressure in large cohorts. We investigated whether estimated arterial age (eAA) was elevated in patients with the metabolic syndrome and/or known cardiovascular disease (CVD), which factors were associated with eAA and whether eAA added prognostic information., Methods: In 1993, 2366 study participants, 41, 51, 61, and 71 years old, had traditional cardiovascular risk factors and carotid-femoral pulse wave velocity (cfPWV) measured. Risk groups were identified based on known CVD and components of metabolic syndrome, Systematic COronary Risk Evaluation, or Framingham risk score. From age, mean blood pressure, and cfPWV, eAA and estimated cfPWV (ePWV) were calculated. In 2006, the combined cardiovascular endpoint (CEP) of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for ischemic heart disease was registered., Results: cfPWV and ePWV increased with ageing and cardiovascular risk (all P < 0.001), but ePWV increased more with ageing than cfPWV. The difference between eAA and chronological age was associated with male sex (β = 0.14), higher heart rate (β = 0.16 both P < 0.001), fasting glucose (β = 0.08) soluble urokinase plasminogen activator receptor (β = 0.06, both P < 0.01), and known CVD (β = 0.06, P < 0.05) independently of age, SBP, and heart rate. Independently of Systematic COronary Risk Evaluation, eAA (hazard ratio = 1.20, P < 0.01) predicted CEP, but not as accurately as ePWV (hazard ratio = 1.58, P < 0.001) and cfPWV (hazard ratio = 1.32, P < 0.001) among apparently healthy study participants., Conclusion: Elevated eAA was associated with male sex, higher plasma glucose, and soluble urokinase plasminogen activator receptor and known CVD independently of age, SBP, and heart rate.

Introduction: Proximal aorta stiffens and dilates with aging. Aortic stiffening is a well known process, carrying prognostic implications. On the contrary, few data are available about proximal aorta dilatation. It is not known if "out of proportion" aortic remodeling, i.e. in excess for age, sex and body size, could be a marker of early vascular ageing; there is controversy on how it would be accelerated by classical risk factors or would associate with validated markers of cardiovascular organ damage., Aim: We conducted a systematic review in order to evaluate the determinants of proximal aortic dimensions, focusing on the association with arterial hypertension, cardiovascular risk factors and markers of organ damage., Determinants of Proximal Aorta Remodeling: Age, gender and body size explain 40-50% of the variability of aortic dimensions; genetic predisposition accounts for nearly 20%. Among cardiovascular risk factors obesity and hypertension seem to be associated with faster outward aortic remodeling. Arterial hypertension would account for a 0.60-0.78 mm greater diameter at the ascending aorta. Moreover, in hypertension, left ventricular mass showed a strict association with aortic diameter in nearly all studies. Other classical risk factors for atherogenesis such as dyslipidemia and smoking showed a weak influence on proximal aortic dimensions. No study reported a greater aortic remodeling in diabetics., Conclusions: "Out of proportion" proximal aortic remodeling, could represent a subclinical marker of early vascular ageing, describing the cumulative influence of genetic predisposition, arterial hypertension and obesity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The association between psychological factors and cardiovascular diseases may depend upon socio-economic status. The present cross-sectional study examined the potential moderating role of occupational status on the association between perceived stress and intima-media thickness (IMT), using baseline examination data of the Paris Prospective Study III., Methods: IMT was measured in the right common carotid artery (CCA-IMT) 1cm below the bifurcation, in a zone free of discrete plaques, using non-invasive high-resolution echotracking. Perceived stress was measured with the 4-item Perceived Stress Scale. The association between perceived stress and CCA-IMT was explored using linear regression analysis and regression coefficients (b) were given per 1-point increment., Results: The study population included 5140 participants (3539 men) in the labor force aged 55.9years on average (standard deviation: 3.9), and who were free of personal history of cardiovascular disease and not on psychotropic drugs. There was a non-significant trend between perceived stress and CCA-IMT after adjustment for socio-demographic, self-rated health and cardiovascular risk factors (b [95% CI] 1.02 [-0.08;2.12]; p=0.069). However, multivariable stratified analysis indicates a significant and robust association between perceived stress and CCA-IMT in unemployed participants (b [95% CI] 3.30 [0.44;6.17]), and an association of same magnitude in working participants with low occupational status but without reaching statistical significance., Conclusions: The association between perceived stress and CCA-IMT may depend upon employment status. These results may explain why psychological stress is more tightly linked to cardiovascular disease among individuals facing social adversity., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The growing interest in the clinical measurement of arterial aging through the noninvasive assessment of arterial stiffness is associated with important developments in novel methods and apparatus. In this review, we aimed to describe the major principles of the measurement of arterial stiffness and to critically review the advantages and limitations of the different methods. The measurement of regional stiffness is recommended by international guidelines for routine clinical practice. It is most often determined through pulse wave velocity (PWV) between 2 arterial sites. Methods using a single-site cuff-based measurement are promising. Local determination of arterial stiffness, obtained either with the well-established, high-resolution echo tracking systems or more recently with magnetic resonance imaging, is indicated for pathophysiological and pharmacologic studies. Novel apparatus that were developed for determining arterial stiffness claimed superiority over pioneering methods either through greater simplicity of use, better repeatability, or a more pertinent arterial pathway. However, the true additive value of measuring arterial aging with a given apparatus had to be translated into the predictive value of arterial stiffness as an intermediate end point, ie, the higher the arterial stiffness the higher the number of cardiovascular (CV) events. Thus, another important aim of this review was to analyze the amount of epidemiologic evidence obtained with a given method regarding the predictive value of arterial stiffness for CV events., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The mechanisms that link metabolic syndrome (MetS) to increased cardiovascular risk are incompletely understood. We examined whether MetS is associated with the neural baroreflex pathway (NBP) and whether any such associations are independent of blood pressure values.This study involved the cross-sectional analysis of data on 2835 subjects aged 50 to 75 years from the Paris Prospective Study 3. The prevalence of MetS was defined according to the American Heart Association/National Heart Blood and Lung Institute definition. NBP values were calculated from the fluctuation of the common carotid distension rate and heart rate using fast Fourier transformation and cross-spectral analysis.The prevalence of MetS was 20.1% in men and 10.4% in women. Compared with controls, subjects with MetS (≥3 components), and those at risk for MetS (1-2 components) had lower NBP (-5.3% and -2.3%, respectively) and higher carotid stiffness (+13.5% and +6.8%, respectively). The negative association between MetS components and NBP was confirmed, even after adjustment for age, sex, and carotid stiffness. After stratification for blood pressure (BP) levels, NBP was reduced only in MetS subjects and those at risk with high BP. The NBP was positively associated with carotid stiffness in controls and subjects at risk for MetS. This association was lost in subjects with MetS, regardless of BP levels.Subjects with MetS had reduced NBP values. The role of BP is fundamental in the reduction of NBP. The mechanisms that link carotid stiffness and NBP are inactive in subjects with MetS, independent of BP levels.

Introduction and Objective: Blood pressure variability (BPV) within 24 h or between visits has been found to represent an independent risk factor for cardiovascular disease. The present study was aimed at determining whether a clinical significance can be given also to the BP variations occurring within a single clinical visit., Methods: BPV was quantified as coefficient of variation and as standard deviation (SD) of the mean of three systolic SBP values within a visit in the context of a large-cross subclinical survey (BP-CARE) of treated hypertensive patients living in Eastern European countries. The study population was divided into coefficient of variation and SD quartiles and for each quartile a relationship was sought with a large number of cardiovascular risk factors based on patients' history, physical and laboratory examinations., Results: The 6425 hypertensive patients had an age of 59.2 ± 11 years (mean ± SD); they were equally distributed by sex and displayed an average SD and coefficient of variation amounting to 5.1 ± 6.2 mmHg and 3.5 ± 4.0%, respectively. Compared with the lowest coefficient of variation quartile (Q1), patients in the highest quartile (Q4) showed a significantly greater prevalence of several cardiovascular risk factors, such as age (Q1: 58.5 ± 11 vs. Q4: 60.3 ± 11 years, P < 0.001), serum total cholesterol (Q1: 213.0 ± 46 vs. Q4: 216.4 ± 51 mg/dl, P < 0.05), blood glucose (Q1: 106.2 ± 35 vs. Q4: 109.8 ± 39 mg/dl, P < 0.005), previous cardiovascular events (Q1: 57.4 vs. Q4: 63.9%, P < 0.001), and resistant hypertension (Q1: 26.3 vs. Q4: 34.1%, P < 0.001). They also showed higher office (Q1: 143.2 ± 18 vs. Q4: 154.3 ± 19 mmHg, P < 0.001) and 24-h ambulatory SBP values (Q1: 134.8 ± 17 vs. Q4: 141.2 ± 18 mmHg, P < 0.001). Similar results were obtained when BPV was expressed as SD., Conclusion: Our study provides evidence that greater within-visit BP variabilities are associated with a worse cardiovascular risk profile. This suggests that even this type of BPV may have clinical significance.

While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: By contrast with other southern European people, north Portuguese population registers an especially high prevalence of hypertension and stroke incidence. We designed a cohort study to identify individuals presenting accelerated and premature arterial aging in the Portuguese population., Method: Pulse wave velocity (PWV) was measured in randomly sampled population dwellers aged 18-96 years from northern Portugal, and used as a marker of early vascular aging (EVA). Of the 3038 individuals enrolled, 2542 completed the evaluation., Results: Mean PWV value for the entire population was 8.4  m/s (men: 8.6  m/s; women: 8.2  m/s; P < 0.02). The individuals were classified with EVA if their PWV was at least 97.5th percentile of z-score for mean PWV values adjusted for age (using normal European reference values as comparators). The overall prevalence of EVA was 12.5%; 26.1% of individuals below 30 years presented this feature and 40.2% of individuals in that same age strata were placed above the 90th percentile of PWV; and 18.7% of the population exhibited PWV values above 10  m/s, with male predominance (17.2% of men aged 40-49 years had PWV > 10  m/s). Logistic regression models indicated gender differences concerning the risk of developing large artery damage, with women having the same odds of PWV above 10  m/s 10 years later than men., Conclusion: The population PWV values were higher than expected in a low cardiovascular risk area (Portugal). High prevalence rates of EVA and noteworthy large artery damage in young ages were found.

Background: Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se - are associated with accelerated arterial ageing and with cardiovascular (CV) events. To investigate whether the distribution of clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA in the MARE (Metabolic syndrome and Arteries REsearch) Consortium., Methods: In accordance with the ATP III criteria, MetS was defined as an alteration three or more of the following five components: elevated glucose (G), fasting glucose ≥110 mg/dl; low HDL cholesterol, < 40mg/dl for men or <50 mg/dl for women; high triglycerides (T), ≥150 mg/dl; elevated blood pressure (B), ≥130/≥85 mmHg; abdominal obesity (W), waist circumference >102 cm for men or >88 cm for women., Results: MetS had a 24.3% prevalence (8468 subjects: 23.9% in men vs. 24.6% in women, p < 0.001) with an age-associated increase in its prevalence in all the cohorts. The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p < 0.0001) and in men and women (p < 0.0001). In details, the cluster TBW was observed in 12% of the subjects with MetS, but was far more common in the cohorts from the UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and the USA (2.5%). The cluster GBW accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal: 31.4, 18.4, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania: 7.6, 9.4, and 9.6% respectively)., Conclusions: The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries., (© The European Society of Cardiology 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Aims: Estimated central systolic blood pressure (cSBP) and amplification (Brachial SBP-cSBP) are non-invasive measures potentially prognostic of cardiovascular (CV) disease. No worldwide, multiple-device reference values are available. We aimed to establish reference values for a worldwide general population standardizing between the different available methods of measurement. How these values were significantly altered by cardiovascular risk factors (CVRFs) was then investigated., Methods and Results: Existing data from population surveys and clinical trials were combined, whether published or not. Reference values of cSBP and amplification were calculated as percentiles for 'Normal' (no CVRFs) and 'Reference' (any CVRFs) populations. We included 45,436 subjects out of 82,930 that were gathered from 77 studies of 53 centres. Included subjects were apparently healthy, not treated for hypertension or dyslipidaemia, and free from overt CV disease and diabetes. Values of cSBP and amplification were stratified by brachial blood pressure categories and age decade in turn, both being stratified by sex. Amplification decreased with age and more so in males than in females. Sex was the most powerful factor associated with amplification with 6.6 mmHg (5.8-7.4) higher amplification in males than in females. Amplification was marginally but significantly influenced by CVRFs, with smoking and dyslipidaemia decreasing amplification, but increased with increasing levels of blood glucose., Conclusion: Typical values of cSBP and amplification in a healthy population and a population free of traditional CVRFs are now available according to age, sex, and brachial BP, providing values included from different devices with a wide geographical representation. Amplification is significantly influenced by CVRFs, but differently in men and women., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Objectives: The goal of this study was to determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular disease (CVD) events beyond conventional risk factors., Background: Several studies have shown that aPWV may be a useful risk factor for predicting CVD, but they have been underpowered to examine whether this is true for different subgroups., Methods: We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with CVD outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects., Results: Of 17,635 participants, a total of 1,785 (10%) had a CVD event. The pooled age- and sex-adjusted hazard ratios (HRs) per 1-SD change in loge aPWV were 1.35 (95% confidence interval [CI]: 1.22 to 1.50; p < 0.001) for coronary heart disease, 1.54 (95% CI: 1.34 to 1.78; p < 0.001) for stroke, and 1.45 (95% CI: 1.30 to 1.61; p < 0.001) for CVD. Associations stratified according to sex, diabetes, and hypertension were similar but decreased with age (1.89, 1.77, 1.36, and 1.23 for age ≤50, 51 to 60, 61 to 70, and >70 years, respectively; pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor of coronary heart disease (HR: 1.23 [95% CI: 1.11 to 1.35]; p < 0.001), stroke (HR: 1.28 [95% CI: 1.16 to 1.42]; p < 0.001), and CVD events (HR: 1.30 [95% CI: 1.18 to 1.43]; p < 0.001). Reclassification indices showed that the addition of aPWV improved risk prediction (13% for 10-year CVD risk for intermediate risk) for some subgroups., Conclusions: Consideration of aPWV improves model fit and reclassifies risk for future CVD events in models that include standard risk factors. aPWV may enable better identification of high-risk populations that might benefit from more aggressive CVD risk factor management., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background/aims: Recently, we reported that small renal arteries, defined by a low reference diameter (RD) or minimal luminal diameter (MD), are independently associated with a low GFR, resistant hypertension, and onset of contrast-induced nephropathy and suggested a post-hoc analysis of CORAL trial based on RD categories. Here we hypothesized that RD and MD are markers of nontraditional cardiovascular risk factors and tested whether low RD and MD could impact the prognosis of patients with ischemic heart disease., Methods: Prospective cohort study. We used proportional hazards models to analyze the first onset of cardiovascular events in relation with RD, MD, or percentage of renal artery stenosis (RAS) in those with low-to-moderate RAS (10-70%) (n = 181)., Results: During the median follow-up of 4.5 (range, 0.1-5) years, 27.8% participants (n = 623; mean age, 64 years; 29% women) experienced a cardiovascular event (35.4% in those with RAS 10-70%). The presence of low-to-moderate RAS was associated with cardiovascular events. In these subjects, those with low MD were associated with a higher risk of cardiovascular events (MD >4.2 mm, HR: 1; MD 3.2-4.2 mm, HR: 1.66, 95% CI: 0.74-3.72, p = 0.22; MD <3.2 mm, HR: 3.72, 95% CI: 1.65-8.40, p = 0.002). When MD was added to a standard risk-factor model, risk prediction improvement was by 4.1%. Results were qualitatively similar if MD was replaced by RD or percentage of stenosis, but with smaller improvement of risk prediction and model fit., Conclusions: In patients with ischemic heart disease and low-to-moderate RAS, MD is a significant predictor of cardiovascular events, improves risk prediction, and may represent a valuable biomarker of cardiovascular disease risk., (© 2014 S. Karger AG, Basel.)

Background: Carotid-femoral pulse wave velocity (PWV), as a parameter of aortic stiffness, is an established marker of cardiovascular risk. There has been increasing use of arterial stiffness parameters combining aortic and muscular stiffness or a parameter derived from PWV - the stiffness index beta (BETA = ln(systolic/diastolic pressure) × 2 blood viscosity/pulse pressure × PWV(2)). The aim of this study was to compare different arterial stiffness parameters in a general population random sample., Methods and Results: In 809 individuals from the Czech post-MONICA study (aged 54 ± 13.5 years, 47% men), we compared the association of carotid-femoral PWV (cfPWV), carotid-ankle PWV (caPWV), and BETA with cardiovascular risk factors, parameters of subclinical organ damage, and presence of manifest cardiovascular disease. Both cfPWV and caPWV were similarly associated with blood pressure and glucose level, while cfPWV was more strongly associated with age, cholesterol level and glomerular filtration rate whereas caPWV with Sokolow-Lyon index. BETA derived from cfPWV and caPWV was less dependent on blood pressure, while it showed a closer association with coronary heart disease presence, as compared to cfPWV and caPWV., Conclusions: Addition of lower extremity to aortic stiffness has an effect on the association with cardiovascular risk factors while having no effect on the association with manifest cardiovascular disease. Beta transformation of PWV decreases its dependence on blood pressure and may increase its power in cardiovascular risk prediction., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

The ageing of the vascular tree is a fundamental reflection of biological ageing in general and a determinant of organ function. In the arterial wall this is characterized by a reduction in the elastin content, as well as by an increased content of collagen and its cross-linkages, leading to increased arterial stiffness and elevated central as well as brachial blood pressure, accompanied by increased SBP variability. In recent years a better understanding of these processes have led to the proposal of a condition named early vascular ageing (EVA) in patients with increased arterial stiffness for their age and sex. This is a condition that could increase cardiovascular risk and is associated with various degrees of cognitive dysfunction, as well as other features of biological ageing. This brief review aims to give an update on EVA and how the concept can be used in clinical practice.

While determinants of aortic pulse wave velocity (aPWV) are well known, much less is known about factors affecting lower-extremity pulse wave velocity (lePWV). Unlike aPWV, increased lePWV does not predict cardiovascular risk, but limits lower-extremity blood flow and is associated with increased left ventricular mass. The aim of this study was to compare the effect of cardiovascular risk factors on aPWV and lePWV. A total of 911 individuals from the Czech post-MONICA study (a randomly selected 1% representative population sample, mean age 54±13.5 years, 47% men) were examined. Pulse wave velocity was measured using the SphygmoCor device. Aging had a large effect on aPWV, but only a small effect on lePWV. After adjustment for covariates, we observed that hypertension, diabetes, chronic kidney disease and dyslipidemia were positively and significantly associated with aPWV. However, only hypertension had a significant effect on lePWV. Increased ankle systolic blood pressure was associated with increased aPWV independently of brachial blood pressure. Ankle systolic blood pressure was more closely related to aPWV than lePWV. Subjects with an ankle-brachial index <1.0 had higher aPWV and lower lePWV compared with individuals with a normal ankle-brachial index. Lower-extremity arterial stiffness is affected by age and cardiovascular risk factors to a lesser extent than aortic stiffness. Increased ankle systolic blood pressure is linked not only to increased lower-extremity arterial stiffness, but also increased aortic stiffness. In subjects with a low ankle-brachial index, lower-extremity arterial stiffness is spuriously decreased.

Chronic kidney disease, even at moderate stages, is characterized by a high incidence of cardiovascular events. Subclinical damage to large arteries, such as increased arterial stiffness and outward remodeling, is a classical hallmark of patients with chronic kidney disease. Whether large artery stiffness and remodeling influence the occurrence of cardiovascular events and the mortality of patients with chronic kidney disease (stages 2-5) is still debated. This prospective study included 439 patients with chronic kidney disease (mean age, 59.8 ± 14.5 years) with a mean measured glomerular filtration rate of 37 mL/min per 1.73 m(2). Baseline aortic stiffness was estimated through carotid-femoral pulse wave velocity measurements; carotid stiffness, diameter, and intima-media thickness were measured with a high-resolution echotracking system. For the overall group of patients, the 5-year estimated survival and cumulative incidence of cardiovascular events were 87% and 16%, respectively. In regression analyses adjusted on classical cardiovascular and renal risk factors, aortic stiffness remained significantly associated with all-cause mortality (for 1 SD, Cox model-derived relative risk [95% CI], 1.48 [1.09-2.02]) and with fatal and nonfatal cardiovascular events (for 1 SD, Fine and Gray competing risks model-derived relative risk [95% CI], 1.35 [1.05-1.75]). Net reclassification improvement index was significant (29.0% [2.3-42.0%]). Carotid internal diameter was also independently associated with all-cause mortality. This study shows that increased aortic stiffness and carotid internal diameter are independent predictors of mortality in patients with stages 2 to 5 chronic kidney disease and that aortic stiffness improves the prediction of the risk.

We recognize that increased systolic pressure is the most challenging form of hypertension today and that pulse pressure as an independent cardiovascular risk factor has focused attention on arterial stiffness and wave reflections as the most important factors determining these pressures. In recent years, many studies emphasized the role of arterial rigidity in the development of cardiovascular diseases, and it was shown that stiffening of arteries is associated with increased cardiovascular mortality and morbidity. Moreover,arterial stiffening is linked to decreased glomerular filtration rate, and is predictive of kidney disease progression and the patient’s cardiovascular outcome. Premature vascular aging and arterial stiffening are observed with progression of chronic kidney disease (CKD) and in end-stage renal disease(ESRD). This accelerated aging is associated with outward remodeling of large vessels, characterized by increased arterial radius not totally compensated for by artery wall hypertrophy. Arterial stiffening in CKD and ESRD patients is of multifactorial origin with extensive arterial calcifications representing a major covariate. With aging, the rigidity is more pronounced in the aorta than in peripheral conduit arteries, leading to the disappearance or inversion of the arterial stiffness gradient and less protection of the microcirculation from high-pressure transmission. Various non-pharmacological or pharmacological interventions can modestly slow the progression of arterial stiffness,but arterial stiffness is, in part, pressure dependent and treatments able to stop the process mainly include antihypertensive drugs.

Whereas vascular aging has been identified as an emerging cardiovascular risk factor, definitions of 'normal' and 'early' vascular aging (EVA) and their precise relationship with cardiovascular risk are currently equivocal. The present review discusses the concept of vascular aging; that structural and functional changes occur in the large arteries with aging; and EVA; that such age-associated changes are accelerated in individuals at increased cardiovascular risk; and their metrics; indeed, in order to provide a definition of when EVA occurs in clinical practice, reference values of normal and accelerated vascular aging are needed. Due to the complex nature of age-associated changes in the large arteries described above, there are different parameters relating to vascular aging which can be measured. These broadly include aortic and carotid stiffening; aortic and carotid lumen dilation; endothelial dysfunction (usually measured via brachial flow-mediated dilatation); and carotid intima-media thickness.

Background and Objectives: An intact endothelium is essential for adaptations between arterial vasomotor tone and shear stress (SS), i.e., flow-mediated vasodilation (FMD). Endothelial dysfunction occurs in hypertension, cardiac insufficiency, diabetes, atherosclerosis, and in end-stage renal disease (ESRD) patients, whose renal failure is associated with many of those cardiovascular diseases (CVD)., Design, Setting, Participants, & Measurements: Using a progressive hand-warming protocol and repeated measures ANOVA, we analyzed SS-mediated increase of brachial artery diameter (ΔBA) in 22 healthy controls, 18 CVD-negative ESRD patients (ESRD-CVD(-)), and 17 CVD-positive ESRD patients (ESRD-CVD(+)) to analyze the role of uremia versus CVD on FMD., Results: Hand-warming increased SS (P < 0.001) and ΔBA (P < 0.001). Negative interactions were observed between ΔBA and ESRD (P < 0.001), and between ΔBA and CVD(+) (P < 0.02), but there was no interaction between ESRD and CVD(+) (P = 0.69). For low and mild SS increases, ESRD-CVD(-) patients were characterized by similar ΔBA as controls, but it was lower than controls at higher SS (P < 0.01). In ESRD-CVD(+) patients, brachial artery diameter did not respond to mild and moderate SS increases, and showed "paradoxical" vasoconstriction at higher SS (P < 0.05). In ESRD, a positive and independent interaction was observed between ΔBA and 25(OH) vitamin D(3) insufficiency (≤15 μg/L; P < 0.02)., Conclusions: These observations indicate that, independently of each other, ESRD and CVD(+) history are associated with endothelial dysfunction. They also suggest the importance of considering the relationships between SS and endothelial function in different clinical conditions.

Aims: Limited information is available on office and ambulatory blood pressure (BP) control as well as on cardiovascular (CV) risk profile in treated hypertensive patients living in central and eastern European countries., Methods and Results: In 2008, a survey on 7860 treated hypertensive patients followed by non-specialist or specialist physicians was carried out in nine central and eastern European countries (Albania, Belarus, Bosnia, Czech Republic, Latvia, Romania, Serbia, Slovakia, and Ukraine). Cardiovascular risk assessment was based on personal history, clinic BP values, as well as target organ damage evaluation. Patients had a mean (±SD) age of 60.1 ± 11 years, and the majority of them (83.5%) were followed by specialists. Average clinic BP was 149.3 ± 17/88.8 ± 11 mmHg. About 70% of patients displayed a very high-risk profile. Electrocardiogram was performed in 99% of patients, echocardiography in 65%, carotid ultrasound in 24%, fundoscopy in 68%, and search for microalbuminuria in 10%. Ambulatory BP monitoring was performed in about one-fifth of the recruited patients. Despite the widespread use of combination treatment (87% of the patients), office BP control (<140/90 mmHg) was achieved in 27.1% only, the corresponding control rate for ambulatory BP (<130/80 mmHg) being 35.7%. Blood pressure control was (i) variable among different countries, (ii) worse for systolic than for diastolic BP, (iii) slightly better in patients followed by specialists than by non-specialists, (iv) unrelated to patients' age, and (v) more unsatisfactory in high-risk hypertensives and in patients with coronary heart disease, stroke, or renal failure., Conclusion: These data provide evidence that in central and eastern European countries office and ambulatory BP control are unsatisfactory, particularly in patients at very high CV risk, and not differ from that seen in Western Europe. They also show that assessment of subclinical organ damage is quite common, except for microalbuminuria, and that combination drug treatment is frequently used.

Arterial hypertension is often part of a constellation of anthropometric and metabolic abnormalities that occur simultaneously to a higher degree than would be expected by chance alone, supporting the existence of a discrete disorder, the so-called metabolic syndrome. It is the result of interactions among a large number of interconnected mechanisms, which eventually lead to both an increase in cardiovascular and renal risk, and the development of diabetes. Mechanisms involved in the metabolic syndrome are obesity, insulin resistance, and a constellation of independent factors, which include molecules of hepatic, vascular, and immunologic origin with pro-inflammatory properties. At each of these key points are interactions of demographics, lifestyle, genetic factors, and environmental fetal programming. Superimposing upon these are infections or chronic exposure or both to certain drugs that can also make their contribution. Skeletal muscle and the liver, not adipose tissue, are the two key insulin-response tissues involved in maintaining glucose balance, although abnormal insulin action in the adipocytes also plays a role in development of the syndrome. Factors commonly associated with and partly dependent on obesity, insulin resistance, such as overactivity of the sympathetic, stimulation of the renin-angiotensin-aldosterone systems, abnormal renal sodium handling, endothelial dysfunction, and large vessels' alterations, may play a key role in the blood pressure elevation of the syndrome.

Objectives: This study compares outcomes with drug-eluting stents (DES) versus bare metal stents (BMS) in patients with ST-elevation myocardial infarction (STEMI)., Background: DESs have been effective in elective percutaneous coronary intervention (PCI), but their safety and efficacy in patients with STEMI have not been well studied., Methods: The STENT Registry is a multicenter United States registry evaluating outcomes of DES. Our study population includes patients with STEMI treated with either a DES or BMS who completed 9-month or 2-year follow-up. Outcomes were adjusted using propensity score analysis., Results: DES patients were younger, had less prior infarction and prior bypass surgery, but had smaller vessels and longer lesions. After adjusting for differences in baseline variables, there were no significant differences between DES and BMS in death, reinfarction, or major adverse cardiac events (MACE). DES had lower rates of stent thrombosis at 9 months (1.0% vs. 2.7%, HR 0.40 [0.17-0.95]) and lower rates of target vessel revascularization (TVR) at 9 months (4.0% vs. 7.5%, HR 0.55 [0.34-0.88]) and 2 years (8.0% vs. 11.3%, HR 0.57 [0.35-0.92]). There was a nonsignificant increase in stent thrombosis with DES versus BMS from 1 to 2 years (1.1% vs. 0.3%, P = 0.28)., Conclusions: Our data suggest that DES used with primary PCI for STEMI are more effective than BMS in reducing TVR and are safe for up to 2 years. Whether DES are safe beyond 2 years and whether the reduction in TVR is enough to justify their use in STEMI will have to wait for the results of large randomized trials., (Copyright 2008 Wiley-Liss, Inc.)

Cardiovascular risk prediction relies on classical risk factors such as age, gender, lipids, hypertension, smoking and diabetes. Although the value of such scales of risk is high for populations, its value for individual is reduced and too much influenced by non-modifiable risk factors (age and gender). Biomarkers of risk have been deceiving and genome wide scan approach is too recent. Target organ damage may help in selecting patients at high risk and in determining intervention. Aortic pulse wave velocity, an index of aortic stiffness, has been widely validated as providing additional risk predictions beyond and above classical risk factors, and has now entered into official guidelines. Many interventions (dietary, behaviour, drug treatment) were shown to influence arterial stiffness positively, but little evidence of a direct effect of intervention on arterial stiffness independent of blood pressure is available. New pharmacological targets and new drugs need to be identified. To become a surrogate endpoint for drug development, there is a need to demonstrate that regression arterial stiffness is associated with improved outcome. In parallel to this demonstration, points to be improved are the homogenization and spreading of the technique of measurement, the establishment of a reference value database.

1. Cardiovascular risk prediction relies on classical risk factors such as age, gender, lipids, hypertension, smoking and diabetes. Although the value of such scales of risk is high for populations, its value for individuals is reduced and much influenced by non-modifiable risk factors (age and sex). 2. Biomarkers of risk have been deceiving and the genome-wide scan approach is too recent to have been useful. Target-organ damage may help in selecting patients at high risk and determine the necessity of intervention. 3. Aortic pulse wave velocity, an index of aortic stiffness, has been widely validated as providing additional risk prediction above and beyond classical risk factors and has now entered the 2007 guidelines for hypertension of the European Society of Hypertension. 4. We aim to show that individual prediction of cardiovascular-related death can be improved by taking aortic stiffness into account in a cohort of patients during a longitudinal follow-up. 5. Points to be improved are the homogenization and spreading of the technique of measurement, the establishment of a reference value database and the demonstration of the added value of aortic stiffness screening and stratification in interventional trials.

Objectives: Pulse pressure (PP) is a major risk factor for cardiovascular (CV) events, mainly in diabetic hypertensives. The objectives of the study were to determine which clinical characteristics could predict the fall in PP and the reduction of CV events under treatment. Design and methods. Type 2 diabetic hypertensives (n = 9379) with PP>60 mmHg (mean age 64 years) were included in a cohort study. During the 9 months follow-up, the physician in charge was asked to reinforce treatment in order to lower PP, using preferentially a fixed low-dose perindopril/indapamide combination., Results: After 9 months, PP had fallen by 9.1+/-0.2 mmHg (p<0.001). Multivariate analysis of the determinants of PP reduction showed a significant positive association with administration of fixed ACEI/diuretic combination (p<0.001) and a negative association with glycated hemoglobin (p<0.01). During the 9 months follow-up, 632 CV events occurred. In multivariate analysis, the administration of fixed perindopril/indapamide combination was associated with a lower incidence of CV events (OR = 0.64 [0.48-0.86], p<0.01), independently of CV risk factors., Conclusions: The reinforcement of therapeutic measures made possible the reduction of PP in type 2 diabetic hypertensives, under conditions of usual care. Administration of a fixed perindopril/indapamide combination therapy was associated with an independent reduction of CV events.

Measurement of arterial stiffness is assuming an increasing role in the clinical assessment of patients. Indeed, arterial stiffness and wave reflections are now well accepted as the most important determinants of increasing systolic and pulse pressure in our aging community, and thus as the cause of cardiovascular (CV) complications and events, including stroke and myocardial infarction. Carotid-femoral pulse wave velocity (PWV), which is a direct measure of arterial stiffness, is the gold standard, since it requires little technical expertise and is supported by the greatest amount of epidemiological evidence. Indeed, aortic stiffness has independent predictive value for all-cause and CV mortality, CV disease, fatal and nonfatal coronary events and fatal strokes in patients with various levels of CV risk. Carotid pulse pressure and augmentation index are only indirect, surrogate measures of arterial stiffness. However, they provide additional information concerning wave reflections. They have demonstrated their predictive value in patients with end-stage renal disease (ESRD). Carotid stiffness was predictive of CV events in a small number of patients with ESRD or following renal transplantation, but had no independent predictive value in a larger number of patients with manifest arterial disease or in the healthy elderly patients of the Rotterdam study. To be not only an intermediate end point but also a surrogate end point, aortic stiffness has to demonstrate that its attenuation has an effect on CV mortality, coronary events and stroke. This remains to be established in populations at low to medium CV risk Eth i.e., with hypertension, dyslipidemia, diabetes and moderate chronic kidney disease.

Brachial pulse pressure (PP) is now a well-established cardiovascular risk factor. Central rather than peripheral PP should be measured to determine the 'true' haemodynamic effects of antihypertensive agents on target organs. Peripheral PP, measured at the brachial artery, does not reflect central PP (either carotid or ascending aorta), because their determinants are different and pathophysiological conditions and drugs may change central PP without changing peripheral PP. Central PP (i.e. carotid artery or ascending aorta) has shown an independent predictive value for all-cause mortality in patients with end-stage renal disease and in the hypertensive patients of the CAFE study. Antihypertensive treatment has repeatedly demonstrated its ability to prevent cardiovascular events. Whether the effect on cardiovascular events in clinical trials comparing two pharmacological classes or two therapeutic strategies is, at least partly, the result of differential effects on PP remains to be demonstrated. It is therefore of major importance to determine which therapeutic strategies may differentially lower central PP, and in turn reduce cardiovascular events. In clinical practice, lowering PP is often a difficult task, particularly in diabetic hypertensive individuals. In the PARADIS study, we aimed to determine, in a population of hypertensive patients with both type 2 diabetes and PP greater than 60 mmHg, which clinical characteristics predict the fall in PP on treatment and a reduction in cardiovascular events. The reinforcement of therapeutic measures, including a fixed low-dose perindopril/indapamide combination, made possible the effective lowering of PP and cardiovascular events in type 2 diabetic hypertensive patients, under conditions of usual care by general practitioners and specialists.

Structural and functional changes in large and small arteries in hypertension, even at early stages, may affect one or several end organs such as the brain, heart, and kidneys, contributing to cardiovascular morbidity and mortality. Therefore, modern treatment strategies should not only target blood pressure (BP) reduction but also normalize vascular structure and function. The purpose of this article is to review the large body of evidence, from randomized double-blind clinical trials, that has been gathered in regard to the angiotensin-converting enzyme (ACE) inhibitor perindopril, demonstrating its efficacy in reducing BP, reversing abnormalities of vascular structure and function in patients with essential hypertension, and ultimately preventing cardiovascular events. At the site of small resistance arteries, long-term treatment with perindopril, but not atenolol, reduced arterial wall hypertrophy for a given BP reduction. The improvement in small artery function in response to structural changes is exemplified at the site of the coronary circulation. Perindopril increased coronary blood flow and coronary reserve, in parallel with the regression of periarteriolar and interstitial collagen of coronary arterioles. At the site of large arteries, long-term treatment with perindopril reduced carotid and radial artery wall hypertrophy, and reduced carotid artery internal diameter. In response to these structural changes, large artery function improved at the site of the carotid and brachial arteries, showing a higher arterial distensibility, and at the site of the coronary circulation, showing a normalized arterial dilation in response to a cold pressor test or an increase in blood flow. Moreover, in patients with end-stage renal disease, perindopril decreased pulse wave velocity independently of BP changes, resulting in a highly significant relative risk reduction in all-cause and cardiovascular mortality. The multifactorial antiatherosclerotic profile of perindopril suggests a beneficial effect not only in patients with uncomplicated hypertension but also in patients with established coronary heart disease or previous stroke, as exemplified by the EUropean trial on Reduction Of coronary events with Perindopril in stable coronary Artery disease (EUROPA) and the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS).

Blood pressure is a summation of a steady component, mean blood pressure, and a pulsatile component, pulse pressure, the latter a function of the stiffness of large arteries. Target organ damage remains a major issue in the management of hypertension. More recent evidence points to the reduction of systolic blood pressure as an important aspect of protecting the hypertensive subject from the risk of cardiovascular events, but it is not the only factor. Antihypertensive drugs which achieve similar reductions in blood pressure show differences in the degree of cardiovascular protection offered. Differences between agents may depend upon the exact mechanism by which they reduce blood pressure, for instance their effect on central or peripheral pulse pressure. Pulse pressure differs significantly between the centre and the periphery, and it is former to which the heart is subjected. It is found that central but not peripheral pulse pressure is a predictor of all-cause mortality in end-stage renal disease. A major determinant of aortic pulse pressure is arterial wall stiffness which determines how much energy is absorbed by the large arteries. Three epidemiological studies show that arterial stiffness is itself an independent predictor of the risk of all-cause mortality, cardiovascular mortality, coronary events and stroke in hypertensive subjects. Pulse pressure and arterial stiffness are therefore important targets for antihypertensive agents, which need to demonstrate efficacy not only against elevated blood pressure in brachial arteries but also on large artery stiffness in order to achieve target organ protection. Major evidence of the efficacy of antihypertensive agents in these components of blood pressure has come from a study which found that low-dose perindopril/indapamide but not atenolol reduced central pulse pressure and arterial stiffness.

Carotid intima-media thickness (IMT) measurement is a noninvasive method used for quantification of early stage of atherosclerosis. Data suggest that the combination of statin and hormone replacement therapy (HRT) might be useful in reducing the early progression of atherosclerosis in postmenopausal women. The main aim of the study is to compare the effects of 12-month therapy with atorvastatin (80 mg/day), HRT (oral 17beta-estradiol 1 or 2 mg/day, plus cyclic dydrogesterone 10 mg) alone and their combination vs. placebo on the progression of carotid IMT by using a high-definition echotracking device. The secondary objectives are to assess the effects of the treatments vs. placebo on arterial stiffness, lipid profile and C-reactive protein. The CASHMERE trial is an European randomized study with a 2 x 2-factorial design, double blinded for atorvastatin and prospective randomized, open blinded endpoint evaluation (PROBE) method applied to HRT. The investigators can adjust the dose of estradiol at any time during follow-up if necessary. A total of 800 postmenopausal women with mild hypercholesterolemia and with no previous history of cardiovascular disease will be included and followed up by their physicians [general practitioners (GPs) or gynecologists] for 1 year. The CASHMERE trial is the first randomized clinical trial to examine the effects of a statin alone or combined with HRT on the structure and the function of carotid artery as early markers of atherosclerosis in postmenopausal women with mild hypercholesterolemia. The results are expected for 2007.

This short review describes the effects of drugs and nonpharmacologic treatments on large artery stiffness in clinical trials. Arterial stiffness is generally accepted as a predictive factor for cardiovascular morbidity and mortality. The drug-induced reduction in arterial stiffness may parallel the reduction in cardiovascular work. This review summarizes the discussion of a task force that worked on the therapeutic aspects during a Consensus Conference on the 'Clinical applications of arterial stiffness," held in Paris on June 17, 2000. The effects of drugs on arterial stiffness are detailed in patients with hypertension, heart failure, and other arterial diseases. Other issues are raised, including the reversibility of arterial changes following pharmacologic treatment, and the possibility for nonpharmacologic treatment to be effective on arterial stiffness. Directions for future therapeutic trials are suggested.

Increased large artery stiffness is believed to be a cardiovascular risk factor independent from mean arterial pressure. The mechanical properties of large arteries depend not only on the amounts of their main constituents (elastin, collagen, and smooth muscle cells) but also on the spatial organization and mechanical interactions among these components. These interactions may be mediated by extracellular matrix adhesion proteins and their membrane receptors or integrins. From a mechanical viewpoint, a key element may be the dense plaque, which is composed of cytoskeletal proteins linked to matrix proteins via membrane integrin receptors. Integrin expression in normal and diseased blood vessels is currently the focus of active research. In humans, hypertension-related arterial hypertrophy is not associated with an increase in intrinsic arterial wall stiffness. Aortic fibronectin expression is increased in spontaneously hypertensive rats (SHRs). By increasing cell-matrix anchoring, fibronectin may contribute to protect arterial wall components from the increased mechanical loads associated with hypertension. In atherosclerosis, the increase in cell-matrix anchoring plays a key role in preventing atheroma plaque rupture. To determine the exact role of adhesion molecules in arterial stiffness, there is a need for studies involving use of specific anti-integrin agents and of transgenic animal models.