Vascular Function Is Improved After an Environmental Enrichment Program: The Train the Brain-Mind the Vessel Study.

Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65-89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow-mediated dilation, carotid-femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97±2.14% versus 3.73±2.06%; P=0.03) and hyperemic stimulus (shear rate area under the curve, 19.1±15.7 versus 25.7±15.1×10-3; P=0.009); only the latter remained significant after adjustment for confounders (P=0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0±4.8 to 13.1±5.5; nontraining, 12.1±3.9 to 13.2±4.8; P for interaction visit×training=0.02), flow-mediated dilation (2.82±2.19% to 3.40±1.81%, 3.05±2.08% to 2.24±1.59%; P=0.006; P=0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34+ cells and prevented the decline in carotid distensibility (18.4±5.3 to 20.0±6.6, 23.9±11.0 to 19.5±7.1 Pa-1; P=0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34+ cells, and preserved carotid distensibility. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01725178.

Ultrasound-based Pulse Wave Velocity Evaluation in Mice.

Arterial stiffness can be evaluated by calculating pulse wave velocity (PWV), i.e., the speed with which the pulse wave travels in a conduit vessel. This parameter is being increasingly investigated in small rodent models in which it is used for assessing alterations in vascular function related to particular genotypes/treatments or for characterizing cardiovascular disease progression. This protocol describes an image processing algorithm which leads to non-invasive arterial PWV measurement in mice using ultrasound (US) images only. The proposed technique has been used to assess abdominal aorta PWV in mice and evaluate its age-associated changes. Abdominal aorta US scans are obtained from mice under gaseous anesthesia using a specific US device equipped with high-frequency US probes. B-mode and Pulse-Wave Doppler (PW-Doppler) images are analyzed in order to obtain diameter and mean velocity instantaneous values, respectively. For this purpose, edge detection and contour tracking techniques are employed. The single-beat mean diameter and velocity waveforms are time aligned and combined in order to achieve the diameter-velocity (lnD-V) loop. PWV values are obtained from the slope of the linear part of the loop, which corresponds to the early systolic phase. With the present approach, anatomical and functional information about the mouse abdominal aorta can be non-invasively achieved. Requiring the processing of US images only, it may represent a useful tool for the non-invasive characterization of different arterial sites in the mouse in terms of elastic properties. The application of the present technique can be easily extended to other vascular districts, such as the carotid artery, thus providing the possibility to obtain a multi-site arterial stiffness assessment.

Impact of seasonality and air pollutants on carotid-femoral pulse wave velocity and wave reflection in hypertensive patients.

OBJECTIVE: The effects of seasonality on blood pressure (BP) and cardiovascular (CV) events are well established, while the influence of seasonality and other environmental factors on arterial stiffness and wave reflection has never been analyzed. This study evaluated whether seasonality (daily number of hours of light) and acute variations in outdoor temperature and air pollutants may affect carotid-femoral pulse wave velocity (PWV) and pressure augmentation. DESIGN AND METHOD: 731 hypertensive patients (30-88 years, 417 treated) were enrolled in a cross-sectional study during a 5-year period. PWV, central BP, Augmentation Index (AIx) and Augmentation Pressure (AP) were measured in a temperature-controlled (22-24°C) room. Data of the local office of the National Climatic Data Observatory were used to estimate meteorological conditions and air pollutants (PM10, O3, CO, N2O) exposure on the same day. RESULTS: PWV (mean value 8.5±1.8 m/s) was related to age (r = 0.467, p<0.001), body mass index (r = 0.132, p<0.001), central systolic (r = 0.414, p<0.001) and diastolic BP (r = 0.093, p = 0.013), daylight hours (r = -0.176, p<0.001), mean outdoor temperature (r = -0.082, p = 0.027), O3 (r = -0.135, p<0.001), CO (r = 0.096, p = 0.012), N2O (r = 0.087, p = 0.022). In multiple linear regression analysis, adjusted for confounders, PWV remained independently associated only with daylight hours (ß = -0.170; 95% CI: -0.273 to -0.067, p = 0.001). No significant correlation was found between pressure augmentation and daylight hours, mean temperature or air pollutants. The relationship was stronger in untreated patients and women. Furthermore, a positive, independent association between O3 levels and PWV emerged in untreated patients (ß: 0.018; p = 0.029; CI: 0.002 to 0.034) and in women (ß: 0.027; p = 0.004; CI: 0.009 to 0.045). CONCLUSIONS: PWV showed a marked seasonality in hypertensive patients. Environmental O3 levels may acutely reduce arterial stiffness in hypertensive women and in untreated patients.

Combination therapy with lercanidipine and enalapril reduced central blood pressure augmentation in hypertensive patients with metabolic syndrome.

Arterial stiffness and blood pressure (BP) augmentation are independent predictors of cardiovascular events. In a randomized, open, parallel group study we compared the effect on these parameters of combination therapy with an ACE-inhibitor plus calcium channel blocker or thiazide diuretic in 76 hypertensive patients with metabolic syndrome uncontrolled by ACE-inhibitor monotherapy. After 4weeks run-in with enalapril (ENA, 20mg), patients were randomized to a combination therapy with lercanidipine (LER, 10-20mg) or hydrochlorothiazide (HCT, 12.5-25mg) for 24weeks. Aortic stiffness (carotid to femoral pulse wave velocity, PWV), central BP values and augmentation (augmentation index, AIx) were measured by applanation tonometry. The two groups showed similar office and central BP after run-in. Office (ENA/LER: from 149.1±4.9/94.5±1.5 to 131.7±8.1/82.2±5.3; ENA/HCT: from 150.3±4.7/94.7±2.1 to 133.1±7.1/82.8±5.3mmHg) and central BP (ENA/LER 127.4±17.1/85.2±12.1 to 120.5±13.5/80.0±9.5mmHg; ENA/HCT 121.6±13.4/79.3±9.5mmHg) were similarly reduced after 24weeks. PWV was comparable after run-in and not differently reduced by the two treatments (ENA/LER from 8.6±1.5 to 8.1±1.3m/s, p<0.05; ENA/HCT from 8.5±1.2 to 8.2±1.0m/s, p<0.05). Finally, both combinations reduced AIx, but its reduction was significantly greater (p<0.05) in ENA/LER (from 26.8±10.9 to 20.6±9.1%) than in ENA/HCT arm (from 28.2±9.0 to 24.7±8.7%). In conclusion, the combination with LER caused a similar PWV reduction as compared to HCT, but a greater reduction in AIx in hypertensive patients with metabolic syndrome not controlled by ENA alone. These results indicate a positive effect of the combination of ENA/LER on central BP augmentation, suggesting a potential additive role for cardiovascular protection.

Carotid and aortic stiffness in essential hypertension and their relation with target organ damage: the CATOD study.

OBJECTIVE: The objective of the study is to investigate in the hypertensive population the possible differential association between increased aortic and/or carotid stiffness and organ damage in multiple districts, such as the kidney, the vessels, and the heart. METHODS: In 314 essential hypertensive patients, carotid-femoral pulse wave velocity (cfPWV, by applanation tonometry) and carotid stiffness (from ultrasound images analysis), together with left ventricular hypertrophy, carotid intima-media thickness, urinary albumin-creatinin ratio, and glomerular filtration rate were measured. Increased cfPWV and carotid stiffness were defined according to either international reference values or the 90th percentile of a local control group (110 age and sex-matched healthy individuals). RESULTS: When considering the 90th percentile of a local control group, increased cfPWV was associated with reduced glomerular filtration rate, either when carotid stiffness was increased [odds ratio (OR) 13.27 (confidence limits (CL) 95% 3.86-45.58)] or not [OR 7.39 (CL95% 2.25-24.28)], whereas increased carotid stiffness was associated with left ventricular hypertrophy, either when cfPWV was increased [OR 2.86 (CL95% 1.15-7.09)] or not [OR 2.81 (CL95% 1.13-6.97)]. No association between increased cfPWV or carotid stiffness and target organ damage was found when cutoffs obtained by international reference values were used. The concomitance of both increased cfPWV and carotid stiffness did not have an additive effect on organ damage. CONCLUSION: Aortic and carotid stiffness are differentially associated with target organ damage in hypertensive patients. Regional arterial stiffness as assessed by cfPWV is associated with renal organ damage and local carotid stiffness with cardiac organ damage.

Wave intensity analysis in mice: age-related changes in WIA peaks and correlation with cardiac indexes.

Mouse models are increasingly employed in the comprehension of cardiovascular disease. Wave Intensity Analysis (WIA) can provide information about the interaction between the vascular and the cardiac system. We investigate age-associated changes in WIA-derived parameters in mice and correlate them with biomarkers of cardiac function. Sixteen wild-type male mice were imaged with high-resolution ultrasound (US) at 8 weeks (T 0) and 25 weeks (T 1) of age. Carotid pulse wave velocity (PWV) was calculated from US images using the diameter-velocity loop and employed to evaluate WIA. Amplitudes of the first (W 1) and the second (W 2) local maxima, local minimum (W b) and the reflection index (RI = W b/W 1) were assessed. Cardiac output (CO), ejection fraction (EF), fractional shortening (FS) and stroke volume (SV) were evaluated; longitudinal, radial and circumferential strain and strain rate values (LS, LSR, RS, RSR, CS, CSR) were obtained through strain analysis. W 1 (T 0: 4.42e-07 ± 2.32e-07 m2/s; T 1: 2.21e-07 ± 9.77 m2/s), W 2 (T 0: 2.45e-08 ± 9.63e-09 m2/s; T 1: 1.78e-08 ± 7.82 m2/s), W b (T 0: -8.75e-08 ± 5.45e-08 m2/s; T 1: -4.28e-08 ± 2.22e-08 m2/s), CO (T 0: 19.27 ± 4.33 ml/min; T 1: 16.71 ± 2.88 ml/min), LS (T 0: 17.55 ± 3.67%; T 1: 15.05 ± 2.89%), LSR (T 0: 6.02 ± 1.39 s-1; T 1: 5.02 ± 1.25 s-1), CS (T 0: 27.5 ± 5.18%; T 1: 22.66 ± 3.09%) and CSR (T 0: 10.03 ± 2.55 s-1; T 1: 7.50 ± 1.84 s-1) significantly reduced with age. W 1 was significantly correlated with CO (R = 0.58), EF (R = 0.72), LS (R = 0.65), LSR (R = 0.89), CS (R = 0.61), CSR (R = 0.70) at T 0; correlations were lost at T 1. The decrease in W 1 and W 2 suggests a cardiac performance reduction, while that in Wb, considering unchanged RI, might indicate a wave energy decrease. The loss of correlation between WIA-derived and cardiac parameters might reflect an alteration in cardiovascular interaction.

Arsenic and subclinical vascular damage in a sample of Italian young adults: a cross-sectional analysis.

Exposure to arsenic (As) increases cardiovascular risk. The purpose of this study was to evaluate the relationship between As and intima-media thickness (IMT) in the common carotid artery and common genetic variants in genes implicated in As metabolism (ASIIIMT Met287Thr, GSTT1+/-, and GSTM1+/-) and DNA repair (hOGG1 Ser326Cys and XRCC1 Arg399Ser). Two hundred and fourteen healthy volunteers, age 20-46, were recruited in four zones polluted by As. Urine samples were tested for total As, inorganic As (iAs), monomethylarsinic (MMA), and dimethylarsinic acid (DMA). Primary and secondary methylation index (PMI, SMI) were computed as MMA/iAs and DMA/MMA. Common carotid artery scans were obtained by high-resolution ultrasound. There was no correlation between IMT and total As, iAs, iAs + MMA + DMA, PMI, or SMI. However, the increase of IMT with age was higher than that observed in the healthy population, both in males (6.25 vs. 5.20 µm/year) and, to a lesser extent, in females (5.05 vs. 4.97 µm/year). After correction for age and gender, subjects with a high urinary As level (≥3.86 µg/L) and carriers of the GSTT1-positive (+) genotype also had higher IMT than those with a low urinary level and the GSTT1-null (-) genotype (0.56 [0.48-0.64] vs. 0.53 [0.44-0.62] mm, p = 0.010). The analysis hints at faster vascular aging as compared to the healthy population. Our findings also suggested that GSTT1 and hOGG1 gene polymorphisms might play an important role in the individual risk of As-induced carotid atherosclerosis.

Time Course of Isoflurane-Induced Vasodilation: A Doppler Ultrasound Study of the Left Coronary Artery in Mice.

Isoflurane is widely used as vasodilator in studies of coronary flow reserve (CFR) in small animals, but the protocols have not been standardized. This study assessed the time course of the increase in isoflurane-induced flow in the mouse coronary artery by pulsed-wave Doppler measurements at 1% isoflurane concentration maintained for 6 min and then increased to 2.5% for 30 min. Velocity-time integral and velocity peak values were best fitted by the sigmoid model, which allowed derivation of the mean time (Tt90 = 14 min) of high-isoflurane needed to reach 90% of the hyperemic plateau value. In subsequent experiments, CFR was measured at 4 min (mean time of literature data) and 14 min of hyperemic response. The 4-min CFR was significantly lower than the 14 -min CFR, and the Bland-Altman plot revealed significant bias of the 4-min CFR against the 14-min CFR. This result suggests that measurements of flow velocity at times shorter than 14 min may be inappropriate for expressing the effective value of CFR.

Noninvasive Assessment of Carotid Pulse Pressure Values: An Accelerometric-Based Approach.

OBJECTIVE: Central pulse pressure (cPP) is increasingly investigated as possible independent predictor of cardiovascular risk and carotid pulse pressure (carPP) can be used as a surrogate of cPP. Despite its importance, carPP measurement remains challenging in clinical practice. The aim of this study was to introduce a new easier-to-use method for noninvasive carPP evaluation based on the use of a MEMS accelerometer. METHODS: carPP values (carPP(acc)) were obtained in 22 subjects (10 males, 47 ±17 years, hypertension: 50%) postprocessing and double integrating the accelerometric signals. carPP(acc) measurements were compared with tonometric assessments (carPP(ton)), and ultrasound-derived measurements (carPP(us)). Moreover, accelerometric carotid pressure waveforms (P(acc)) were contrasted in terms of shape to those obtained by tonometry (P(ton)) and ultrasound images elaboration (P(US)), calculating the root mean square error (RMSE(ton), RMSE(US)) and the regression coefficients (r(ton) and r(US)). Moreover, both the repeatability and reproducibility analyses were performed. RESULTS: carPP(acc) values (45.9 ±10.6 mmHg) were significantly correlated with carPP(ton) (47.5 ±11.3 mmHg) and carPP(US) (43.3 ±8.4 mmHg) assessments (R = 0.94, p < 0.0001 and R = 0.80, p < 0.0001, respectively). The validity of the accelerometric approach was confirmed by morphological parameters ( RMSE(ton) = 5 ±1.95 mmHg, RMSE(US) = 5.5 ±2.3 mmHg, r(ton) = 0.94 ±0.04, r(US) = 0.93 ±0.04). Coefficient of variation (CV) was equal to 6.2% for the repeatability analysis, while CV values for interoperator and intersession reproducibilities were 8.9% and 9.4%, respectively. CONCLUSION: The proposed approach, providing an easier and more available measurement, could represent a valid alternative to existing and used technique for carPP assessment.

Non-invasive assessment of pulse wave velocity in mice by means of ultrasound images.

OBJECTIVE: Pulse wave velocity (PWV) is considered as a surrogate marker of arterial stiffness and could be useful for characterizing cardiovascular disease progression even in mouse models. Aim of this study was to develop an image process algorithm for assessing arterial PWV in mice using ultrasound images only and test it on the evaluation of age-associated differences in abdominal aorta PWV. METHODS: Ultrasound scans were obtained from ten adult (mean age: 5.5 months) and nine old (mean age: 15.5 months) wild type male mice (strain C57BL6) under gaseous anesthesia. For each mouse, instantaneous values of diameter and flow velocity were obtained from abdominal aorta B-mode and PW-Doppler, respectively. Single-beat mean diameter and velocity were calculated providing the velocity-diameter (lnD-V) loop. PWV values for both the early systolic phase (aaPWV) and the late systolic one (aaPWVls) were obtained from the slope of the corresponding linear parts of the loop. Relative distension (relD) was calculated from the mean diameter signal. RESULTS: aaPWV values for adult mice (1.91 ± 0.44 m/s) were significantly lower (p < 0.01) than those obtained for older ones (2.71 ± 0.63 m/s) and the same result was found for aaPWVls (2.68 ± 0.68 vs 3.67 ± 0.95 m/s; p < 0.05). relD measurements were significantly higher (p < 0.01) in adult (22.7% ± 5.2%) compared with older animal evaluations (15.8% ± 3.9%). CONCLUSIONS: The proposed system discriminates well between age groups and supplies a non-invasive evaluation of anatomical and functional parameters of the mouse abdominal aorta. Since it provides a non-invasive PWV assessment from ultrasound (US) images only, it may offer a simple and useful system for evaluation of local vascular stiffness at other arterial site in the mouse, such as the carotid artery.

[Studies on markers of exposure and early effect in areas with arsenic pollution: methods and results of the project SEpiAs. Epidemiological surveillance in areas with environmental pollution by natural or anthropogenic arsenic]. / Studi su marcatori di esposizione ed effetto precoce in aree con inquinamento da arsenico: metodi e risultati del progetto SEpiAs. Sorveglianza epidemiologica in aree interessate da inquinamento ambientale da arsenico di origine naturale o antropica (SEpiAS CCM 2010).

INTRODUCTION: Arsenic and its inorganic compounds are classified as carcinogenic to humans. Exposures to inorganic arsenic (iAs) in drinking water are associated with both carcinogenic and non-carcinogenic effects. The risk assessment of exposures to low-moderate levels of environmental arsenic (As) is a challenging objective for research and public health. The SEpiAs study, funded by the Italian Ministry of Health (CCM), was carried out in four areas with arsenic pollution prevalently of natural origin, Amiata and Viterbo areas, or of industrial origin, Taranto and Gela. MATERIALS AND METHODS: 271 subjects (132 men) aged 20-44, were randomly sampled stratifying by area, gender and age classes. Individual data on residential history, socio-economic status, environmental and occupational exposures, lifestyle and dietary habits, were collected through interviews using questionnaire. In urine samples of recruited subjects, the concentration of inorganic arsenic (iAs) and methylated species (MMA, DMA) was measured using inductively coupled mass spectrometer (DRCICP- MS), after chromatographic separation (HPLC). Molecular biomarkers and biomarkers of DNA damage, as well as markers of cardiovascular risk were measured The distributions of iAs and iAs+MMA+DMA were described by area and gender, geometric mean (GM), percentiles and standard deviation (SD). The associations between As species and variables collected by questionnaire were evaluated by multiple regression analysis. RESULTS: Results showed a high variability of As species within and among areas. Gela and Taranto samples showed higher iAs concentration compared to Viterbo and Amiata. Subjects with iAs>1,5 µg/L or iAs+MMA+DMA>15 µg/L (thresholds suggested by the Italian Society of Reference Values), are 137 (50,6%) and 68 (25,1%), respectively. A positive association between iAs and use of drinking water emerged in the Viterbo sample, between iAs and occupational exposure in the Gela and Taranto samples. Fish consumption was associated with higher iAs concentration in the whole sample, and particularly in men of the Gela sample. Similar results were observed for iAs+MMA+DMA. Subjects with iAs or iAs+MMA+DMA values higher than the 95th percentile were 15 (6Taranto, 5 Gela, 3Viterbo, 1 Amiata). The relationships between iAs and organic species (methylation efficiency ratios) were different between sex in the four areas. The relevance of polymorphisms AS3MT Met287Thr, GST-T1, GST-M1, OGG1 was confirmed. The analysis of carotid intima-media-thickness showed normal values, but higher among man of Viterbo, Taranto and Gela areas. CONCLUSIONS: Results are informative of exposure to inorganic and organic As in large or at least non-negligible quotas of the samples. The SEpiAs results suggest a further deepening on routes of exposure to arsenic species, and support the recommendation to implement primary prevention measures to reduce population exposure.

Non-invasive assessment of carotid PWV via accelerometric sensors: validation of a new device and comparison with established techniques.

PURPOSE: Carotid pulse wave velocity (PWV) is considered as a surrogate marker for carotid stiffness and its assessment is increasingly being used in clinical practice. However, at the moment, its estimation needs specific equipment and a moderate level of technical expertise; moreover, it is based on a mathematical model. The aim of this study was to validate a new system for non-invasive and model-free carotid PWV assessment based on accelerometric sensors by comparison with currently used techniques. METHODS: Accelerometric PWV (accPWV) values were obtained in 97 volunteers free of cardiovascular disease (age 24-85 years) and compared with standard ultrasound-based carotid stiffness parameters, such as carotid PWV (cPWV), relative distension (relD) and distensibility coefficient (DC). Moreover, the comparison between accPWV measurements and carotid-femoral PWV (cfPWV) was performed. RESULTS: Accelerometric PWV evaluations showed a significant correlation with cPWV measurements (R = 0.67), relD values (R = 0.66) and DC assessments (R = 0.64). These values were also significantly correlated with cfPWV evaluations (R = 0.46). In addition, the first attempt success rate was equal to 76.8 %. CONCLUSIONS: The accelerometric system allows a simple and quick local carotid stiffness evaluation and the values obtained with this system are significantly correlated with known carotid stiffness biomarkers. Therefore, the presented device could provide a concrete opportunity for an easy carotid stiffness evaluation even in clinical practice.

Comparison of the Complior Analyse device with Sphygmocor and Complior SP for pulse wave velocity and central pressure assessment.

BACKGROUND: The Complior device (Alam Medical, France) was used in epidemiological studies which established pulse wave velocity (PWV) as a cardiovascular risk marker. Central pressure is related, but complementary to PWV and also associated to cardiovascular outcomes. The new Complior Analyse measures both PWV and central blood pressure during the same acquisition. The aim of this study was to compare PWV values from Complior Analyse with the previous Complior SP (PWVcs) and with Sphygmocor (PWVscr; AtCor, Australia), and to compare central systolic pressure from Complior Analyse and Sphygmocor. METHOD: Peripheral and central pressures and PWV were measured with the three devices in 112 patients. PWV measurements from Complior Analyse were analysed using two foot-detection algorithms (PWVca_it and PWVca_cs). Both radial (ao-SBPscr) and carotid (car-SBPscr) approaches from Sphygmocor were compared to carotid Complior Analyse measurements (car-SBPca). The same distance and same calibrating pressures were used for all devices. RESULTS: PWVca_it was strongly correlated to PWVscr (R(2) = 0.93, P < 0.001) with a difference of 0.0 ±â€Š0.7  m/s. PWVca_cs was also correlated to PWVcs (R(2) = 0.90, P < 0.001) with a difference of 0.1 ±â€Š0.7  m/s. Central systolic pressures were strongly correlated. The difference between car-SBPca and ao-SBPscr was 3.1 ±â€Š4.2  mmHg (P < 0.001), statistically equivalent to the difference between car-SBPscr and ao-SBPscr (3.9 ±â€Š5.8  mmHg, P < 0.001), whilst the difference between car-SBPca and car-SBPscr was negligible (-0.7 ±â€Š5.6  mmHg, P = NS). CONCLUSION: The new Complior Analyse device provides equivalent results for PWV and central pressure values to the Sphygmocor and Complior SP. It reaches Association for the Advancement of Medical Instrumentation standard for central blood pressure and grades as excellent for PWV on the Artery Society criteria. It can be interchanged with existing devices.

Cardiovascular effects of arsenic: clinical and epidemiological findings.

Several population studies relate exposure to high levels of arsenic with an increased incidence of ischemic heart disease and cardiovascular mortality. An association has been shown between exposure to high levels of arsenic and cardiovascular risk factors such as hypertension and diabetes mellitus, and vascular damage such as subclinical carotid atherosclerosis. The mechanisms underlying these phenomena are currently being studied and appear to indicate an alteration of vascular function. However, the effects of low levels of exposure to arsenic and their potential detrimental cardiovascular effect are less explored. The article provides an overview of the pathophysiologic mechanisms linking low-level arsenic exposure to the occurrence of cardiovascular disease and its complications, and some potential preventive strategies to implement.

Relationship between wave reflection and renal damage in hypertensive patients: a retrospective analysis.

OBJECTIVE: Arterial stiffening has harmful effects; peripheral pulse wave reflections deleteriously increase central pressure, but on the contrary they could also possibly be protective, as the pulse is transmitted to the microcirculation to a lesser extent. The aim of this study was, therefore, to explore the relationship between wave reflection and small vessel damage in the kidney. METHODS: In 216 hypertensive patients, data on renal resistive index, obtained by Doppler ultrasound sampling of the interlobar arteries, as well as augmentation index (AIx) and carotid-to-femoral pulse wave velocity (PWV), were retrospectively analyzed. Reflection magnitude was computed through a triangular flow estimate. RESULTS: AIx and reflection magnitude were positively correlated with resistive index; age, BMI, central pulse pressure, and cholesterol, but not AIx or reflection magnitude, were predictors of resistive index in multivariate analyses. Crossing tertiles of PWV and AIx, resistive index did not differ between patients with high AIx and low PWV (n=25; 0.632 (0.064)) and those with low AIx and high PWV (n=17; 0.645 (0.053)), despite a difference in reflection magnitude (74.9 (6.7) vs. 51.2 (7.3)%; P<0.001). CONCLUSION: Pressure wave reflection is positively correlated with resistive index in a hypertensive population. No negative relationship was found even adjusting for confounders or when it was examined separately from the influence of arterial stiffness. These findings do not support the hypothesis of peripheral wave reflections having a significant protective role for the microcirculation of a low resistance vascular bed such as the kidney.

Adipocytokine levels mark endothelial function in normotensive individuals.

BACKGROUND: Endothelial dysfunction is an independent risk factor for cardiovascular events. Inflammatory mediators released by the adipose tissue can lead to local insulin resistance and endothelial dysfunction. This study addressed the relationship of adipocytokines with endothelial function and blood pressure. METHODS: In 92 newly diagnosed, drug-naïve essential hypertensive patients (HT, mean age 49 yrs) without organ damage and 66 normotensive subjects (NT, mean age 47 yrs), by an automated system, we measured endothelium-dependent and -independent vasodilation as brachial artery flow-mediated dilation before and after administration of glyceryl-trinitrate. Retinol binding protein-4 (RBP4) and resistin levels were determined by ELISA and RIA, respectively. Oxidative stress was evaluated by measuring serum malondyaldehyde (MDA). RESULTS: Flow-mediated dilation was significantly (p = 0.03) lower in HT (5.3 ± 2.6%) than NT (6.1 ± 3.1%), while response to glyceryl-trinitrate (7.5 ± 3.7% vs 7.9 ± 3.4%) was similar. RBP4 (60.6 ± 25.1 vs 61.3 ± 25.9 µg/ml), resistin (18.8 ± 5.3 vs 19.9 ± 6.1 ng/ml) and MDA levels (2.39 ± 1.26 vs 2.08 ± 1.17 nmol/ml) were not different in HT and NT.RBP4 (r = -0.25; p = 0.04) and resistin levels (r = -0.29; p = 0.03) were related to flow-mediated dilation in NT, but not in HT (r = -0.03 and r = -0.10, respectively). In NT, multivariate analysis including RBP4 and confounders showed that only BMI or waist circumference remained related to flow- mediated dilation. In the multivariate model including resistin and confounders, BMI, age and resistin were significantly related to flow-mediated dilation, while only age significant correlated with this parameter when BMI was replaced by waist circumference. CONCLUSIONS: Adipocytokine levels may be independent predictors of endothelial dysfunction in the peripheral circulation of healthy subjects, providing a pathophysiological link between inflammation from adipose tissue and early vascular alterations.

Effect of mild hyperisulinemia on conduit vessel endothelial function: role of noradrenergic activation.

OBJECTIVE: The evidence that an exogenously induced modest hyperinsulinemia deteriorates conductance artery endothelial function - flow-mediated dilatation (FMD) - in healthy individuals is in contrast with in-vitro and in-vivo studies that consistently found that insulin facilitates both nitric oxide release and the endothelium-dependent dilatation. The aim of this study was to verify whether this effect is caused by the enhancement of insulin-induced adrenergic tone. METHOD: In 10 healthy male volunteers, endothelium-dependent (FMD) and endothelium-independent (glyceryl trinitrate, GTN) dilatation were evaluated by high-resolution ultrasound of the brachial artery, combined with a computerized edge detection system, at baseline (-60 and 0 min) and after 120 and 240 min during insulin infusion (INS study). In five participants, randomly selected from the initial group, the study was repeated during an isotonic saline (0.9% sodium chloride) intravenous infusion (SAL study). In an additional five participants, insulin infusion was preceded by an intravenous infusion of clonidine started 40 min before insulin and continued throughout the study (INS + CLN study). RESULTS: Plasma norepinephrine concentration increased in the INS study from 260 ±â€Š40 to 333 ±â€Š62 pg/ml (P < 0.05), whereas it remained stable throughout the INS + CLN study. In the INS study, no change in FMD was observed, whereas the response to GTN tended to decrease (P = 0.09). In the INS + CLN study, no significant changes in FMD response were observed, whereas GTN response was completely restored. CONCLUSION: Physiological hyperinsulinemia has no effect on endothelium-dependent vasodilatation in conduit vessels of healthy individuals, but it induces a slight decline in endothelium-independent vasodilatation, which is entirely explained by the insulin-induced noradrenergic activation.

Central blood pressure, arterial stiffness, and wave reflection: new targets of treatment in essential hypertension.

Central blood pressure is dependent on the stiffness of large arteries and pulse wave reflection. These parameters are very important in the development of hypertensive target organ disease. Moreover, recent clinical studies have shown their independent predictive value for cardiovascular morbidity and mortality. Therefore, 2007 guidelines for the management of hypertension inserted the evaluation of central arterial stiffness as an important component for assessing total cardiovascular risk. Differences in the way various antihypertensive drugs affect arterial stiffness and central hemodynamics may explain the greater cardio-vascular protection provided by newer drugs (eg, renin-angiotensin system blockers or calcium channel blockers) independent of peripheral blood pressure reduction, as shown by recent clinical studies. However, the predictive value of the attenuation of arterial stiffness, wave reflections, and central blood pressure still needs to be confirmed in prospective, long-term, large-scale therapeutic trials. Thus, whether these measurements should be routinely performed as a diagnostic or therapeutic indicator remains debatable.

Coronary flow reserve in idiopathic dilated cardiomyopathy: relation with left ventricular wall stress, natriuretic peptides, and endothelial dysfunction.

Studies have demonstrated impaired coronary blood flow reserve (CBFR) in idiopathic dilated cardiomyopathy (IDCM). It was the aim of this study to examine the potential underlying mechanisms for CBFR reduction in patients with IDCM by Doppler ultrasound techniques. Forty-eight clinically stable patients with heart failure caused by IDCM (New York Heart Association classes 1-3) were evaluated by echocardiographic and Doppler techniques with the assessments of CBFR and brachial artery flow-mediated dilation (FMD). CBFR was estimated as the hyperemic (dipyridamole: 0.84 mg/kg in 10 minutes, intravenously) to resting coronary diastolic peak velocities ratio. N-terminal pro-brain natriuretic peptide (Nt-pro-BNP) plasma levels were measured at the time of the index echocardiogram. Left ventricular (LV) ejection fraction was 30% +/- 8%, and wall motion score index was 2.0 +/- 0.25. The best correlation with CBFR was found with LV wall thickness-to-cavity radius (r = 0.77, P < .0001). A strong correlation of log-transformed Nt-pro-BNP levels was observed with CBFR (r = -0.64; P < .0001). No significant correlation was documented between CBFR and FMD. The stepwise regression model showed that LV wall thickness-to-cavity radius was the strongest independent predictor of CBFR followed by New York Heart Association class and log-transformed Nt-pro-BNP leading to a cumulative R value of 0.82 (P < .0001). The results of the study indicate that by measuring variables related to LV end-diastolic wall stress, such as LV wall thickness-to-cavity radius and plasma Nt-proBNP, it is possible to have information about CBFR in patients with heart failure secondary to IDCM.