Wall Cross-sectional Area Research Articles

C-Src Inhibition Improves Cardiovascular Function but not Remodeling or Fibrosis in Angiotensin II-Induced Hypertension.

c-Src plays an important role in angiotensin II (Ang II) signaling. Whether this member of the Src family kinases is involved in the development of Ang II-induced hypertension and associated cardiovascular damage in vivo remains unknown. Here, we studied Ang II-infused (400 ng/kg/min) mice in which c-Src was partially deleted (c-Src+/-) and in wild-type (WT, c-Src+/+) mice treated with a c-Src inhibitor (CGP077675; 25 mg/kg/d). Ang II increased blood pressure and induced endothelial dysfunction in WT mice, responses that were ameliorated in c-Src+/- and CGP077675-treated mice. Vascular wall thickness and cross-sectional area were similarly increased by Ang II in WT and c-Src+/- mice. CGP077675 further increased cross-sectional area in hypertensive mice. Cardiac dysfunction (ejection fraction and fractional shortening) in Ang II-infused WT mice was normalized in c-Src+/- mice. Increased oxidative stress (plasma thiobarbituric acid-reactive substances, hydrogen peroxide, and vascular superoxide generation) in Ang II-infused WT mice was attenuated in c-Src-deficient and CGP077675-treated mice. Hyperactivation of vascular c-Src, ERK1/2 (extracellular signal-regulated kinase 1/2), and JNK (c-Jun N-terminal kinase) in hypertensive mice was normalized in CGP077675-treated and c-Src+/- mice. Vascular fibronectin was increased by Ang II in all groups and further augmented by CGP077675. Cardiac fibrosis and inflammation induced by Ang II were amplified in c-Src+/- and CGP-treated mice. Our data indicate that although c-Src downregulation attenuates development of hypertension, improves endothelial and cardiac function, reduces oxidative stress, and normalizes vascular signaling, it has little beneficial effect on fibrosis. These findings suggest a divergent role for c-Src in Ang II-dependent hypertension, where c-Src may be more important in regulating redox-sensitive cardiac and vascular function than fibrosis and remodeling.

PP.12.07] EFFECTS OF AGE, BLOOD PRESSURE AND ANTIHYPERTENSIVE TREATMENTS ON RETINAL ARTERIOLES REMODELING ASSESSED BY ADAPTIVE OPTICS

Objective: In humans, adaptive optics camera enables precise large scale non-invasive retinal microcirculation evaluation to assess ageing, blood pressure (BP), and antihypertensive treatments respective roles on retinal arterioles anatomy. Retinal arteriolar remodeling comprised BP and age-driven wall thickening as well as BP-triggered lumen narrowing in younger subjects. Adaptive optics has the potential to shed light on risk factors specific remodeling mechanisms in large scale populations.Design and method: We used adaptive optics camera rtx1™ (Imagine-Eyes, Orsay, France) to measure wall thickness, internal diameter and to calculate Wall-to-Lumen Ratio (WLR) and Wall Cross Sectional Area (WCSA) of retinal arterioles. Results: In 1000 subjects, mean wall thickness, lumen diameter and WLR were 23.2 ± 3.9 μm, 78.0 ± 10.9 μm and 0.300 ± 0.054 respectively. BP and age both independently increased WLR by thickening arterial wall. In opposite, hypertension narrowed lumen in younger as compared to older subjects (73.2 ± 9.0 vs. 81.7 ± 10.2 μm; p < 0.001) while age exerted no influence on lumen diameter. In multivariate analysis, hypertension drug regimen was not an independent predictor of any retinal anatomical indices. Diabetes was associated with increased WLR by hypertrophic remodeling with WCSA increase. WLR was not different between males and females but the later exhibited harmonious elevation of both thickness and lumen. Conclusions: Retinal arteriolar remodeling comprised BP and age-driven wall thickening as well as BP-triggered lumen narrowing in younger subjects. Adaptive optics has the potential to shed light on risk factors specific remodeling mechanisms in large scale populations.

PP.04.05] ACCELERATED DEVELOPMENT OF IMMUNE CELLS IN CHILDREN WITH PRIMARY HYPERTENSION

Objective: Immune system plays a role in pathogenesis of primary hypertension (PH) and activation of immune cells is associated with subclinical hypertensive arterial injury. One of the markers of maturation of immune cells is increased number and percentage of memory cells. We hypothesized that children with PH have faster maturation of immune cells. Design and method: The distribution of peripheral T cell subsets (CD4+ and CD8+) expressing CD45 common leukocyte antigen (CD45Ag) isoforms: CD45RA (naive cells), CD45RO (memory cells) and CD31 (pecam-1, a marker of early thymic emigrants) was evaluated by three-color flow cytometry in a group of 11 PH adolescents and 16 healthy, age matched controls. Results: Hypertensive children had higher proportion of “memory” CD8 cells (CD8/CD8RO+) than their healthy counterparts (17.0 range: 11.9–23.8 vs 10.9 9.1–14.1; p = 0.03), lower of CD8/CD8RA+ cells (72.3 range: 66.5–81.9 vs 81.6 77.4–84.3; p = 0.05), and lower CD8RA/CD8RO+ ratio than the controls (5.1 range: 2.7–6.9 vs 7.4 5.5–8.9; p = 0.028). Percentage of CD4 and CD8 T bearing “naive” or “memory” phenotype correlated with brachial and aortic pulse pressure. Additionally, CD8RA/RO+ ratio was associated with pulse pressure (p = 0.03, r = −0.337) and aortic pulse pressure (p = 0.03, r = −0.384). There was also negative correlation of percentage of CD4/CD31+ with both absolute and standardized values of carotid wall cross sectional area (p = 0.01, r = −0.433 p = 0.016, r = −0.410, respectively). Conclusions: Adolescents with PH present subtle alterations in maturation of immune system manifested by: a) the decreased number of early thymic emigrants within CD4+ T cell suggesting accelerated thymic senescence, b) the increased population of more mature cells expressing “memory” markers, c) the associations with indirect indices of arterial stiffness and carotid artery remodelling and d) shift towards “memory” phenotype in T cells. Altogether these findings indicate that early stage of human primary hypertension and arterial remodelling may be related to certain defects in T cell development that result in accelerated maturation and senescence of immune system.

Retinal Arterioles in Hypo-, Normo-, and Hypertensive Subjects Measured Using Adaptive Optics.

PurposeSmall artery and arteriolar walls thicken due to elevated blood pressure. Vascular wall thickness show a correlation with hypertensive subject history and risk for stroke and cardiovascular events.MethodsThe inner and outer diameter of retinal arterioles from less than 10 to over 150 μm were measured using a multiply scattered light adaptive optics scanning laser ophthalmoscope (AOSLO). These measurements were made on three populations, one with habitual blood pressures less than 100/70 mm Hg, one with normal blood pressures without medication, and one with managed essential hypertension.ResultsThe wall to lumen ratio was largest for the smallest arterioles for all three populations. Data from the hypotensive group had a linear relationship between outer and inner diameters (r2 = 0.99) suggesting a similar wall structure in individuals prior to elevated blood pressures. Hypertensive subjects fell below the 95% confidence limits for the hypotensive relationship and had larger wall to lumen ratios and the normotensive group results fell between the other two groups.ConclusionHigh-resolution retinal imaging of subjects with essential hypertension showed a significant decrease in vessel inner diameter for a given outer diameter, and increases in wall to lumen ratio and wall cross-sectional areas over the entire range of vessel diameters and suggests that correcting for vessel size may improve the ability to identify significant vascular changes.Translational RelevanceHigh-resolution imaging allows precise measurement of vasculature and by comparing results across risk populations may allow improved identification of individuals undergoing hypertensive arterial wall remodeling.

Regular Exercise Reduces Endothelial Cortical Stiffness in Western Diet-Fed Female Mice.

We recently showed that Western diet-induced obesity and insulin resistance promotes endothelial cortical stiffness in young female mice. Herein, we tested the hypothesis that regular aerobic exercise would attenuate the development of endothelial and whole artery stiffness in female Western diet-fed mice. Four-week-old C57BL/6 mice were randomized into sedentary (ie, caged confined, n=6) or regular exercise (ie, access to running wheels, n=7) conditions for 16 weeks. Exercise training improved glucose tolerance in the absence of changes in body weight and body composition. Compared with sedentary mice, exercise-trained mice exhibited reduced endothelial cortical stiffness in aortic explants (sedentary 11.9±1.7 kPa versus exercise 5.5±1.0 kPa; P<0.05), as assessed by atomic force microscopy. This effect of exercise was not accompanied by changes in aortic pulse wave velocity (P>0.05), an in vivo measure of aortic stiffness. In comparison, exercise reduced femoral artery stiffness in isolated pressurized arteries and led to an increase in femoral internal artery diameter and wall cross-sectional area (P<0.05), indicative of outward hypertrophic remodeling. These effects of exercise were associated with an increase in femoral artery elastin content and increased number of fenestrae in the internal elastic lamina (P<0.05). Collectively, these data demonstrate for the first time that the aortic endothelium is highly plastic and, thus, amenable to reductions in stiffness with regular aerobic exercise in the absence of changes in in vivo whole aortic stiffness. Comparatively, the same level of exercise caused destiffening effects in peripheral muscular arteries, such as the femoral artery, that perfuse the working limbs.

Reduced Expression of the Extracellular Calcium-Sensing Receptor (CaSR) Is Associated with Activation of the Renin-Angiotensin System (RAS) to Promote Vascular Remodeling in the Pathogenesis of Essential Hypertension.

The proliferation of vascular smooth muscle cells (VSMCs), remodeling of the vasculature, and the renin-angiotensin system (RAS) play important roles in the development of essential hypertension (EH), which is defined as high blood pressure (BP) in which secondary causes, such as renovascular disease, are absent. The calcium-sensing receptor (CaSR) is involved in the regulation of BP. However, the underlying mechanisms by which the CaSR regulates BP are poorly understood. In the present study, the role of the CaSR in EH was investigated using male spontaneously hypertensive rats (SHRs) and rat and human plasma samples. The percentages of medial wall thickness to external diameter (WT%), total vessel wall cross-sectional area to the total area (WA%) of thoracic arteries, as well as the percentage of wall area occupied by collagen to total vessel wall area (CA%) were determined. Tissue protein expression and plasma concentrations of the CaSR, cyclic adenosine monophosphate (cAMP), renin, and angiotensin II (Ang II) were additionally assessed. WT%, WA%, and CA% were found to increase with increasing BP, whereas the plasma concentration of CaSR was found to decrease. With increasing BP, the levels of smooth muscle actin and calponin decreased, whereas those of osteopontin and proliferating cell nuclear antigen increased. The CaSR level negatively correlated with the levels of cAMP and Ang II, but positively correlated with those of renin. Our data suggest that reduced expression of the CaSR is correlated with activation of the RAS, which induces increased vascular remodeling and VSMC proliferation, and thereby associated with EH in the SHR model and in the Han Chinese population. Our findings provide new insights into the pathogenesis of EH.

Arterial Stiffening in Western Diet-Fed Mice Is Associated with Increased Vascular Elastin, Transforming Growth Factor-β, and Plasma Neuraminidase.

Consumption of excess fat and carbohydrate (Western diet, WD) is associated with alterations in the structural characteristics of blood vessels. This vascular remodeling contributes to the development of cardiovascular disease, particularly as it affects conduit and resistance arteries. Vascular remodeling is often associated with changes in the elastin-rich internal elastic lamina (IEL) and the activation of transforming growth factor (TGF)-β. In addition, obesity and type II diabetes have been associated with increased serum neuraminidase, an enzyme known to increase TGF-β cellular output. Therefore, we hypothesized that WD-feeding would induce structural modifications to the IEL of mesenteric resistance arteries in mice, and that these changes would be associated with increased levels of circulating neuraminidase and the up-regulation of elastin and TGF-β in the arterial wall. To test this hypothesis, a WD, high in fat and sugar, was used to induce obesity in mice, and the effect of this diet on the structure of mesenteric resistance arteries was investigated. 4-week old, Post-weaning mice were fed either a normal diet (ND) or WD for 16 weeks. Mechanically, arteries from WD-fed mice were stiffer and less distensible, with marginally increased wall stress for a given strain, and a significantly increased Young's modulus of elasticity. Structurally, the wall cross-sectional area and the number of fenestrae found in the internal elastic lamina (IEL) of mesenteric arteries from mice fed a WD were significantly smaller than those of arteries from the ND-fed mice. There was also a significant increase in the volume of elastin, but not collagen in arteries from the WD cohort. Plasma levels of neuraminidase and the amount of TGF-β in mesenteric arteries were elevated in mice fed a WD, while ex vivo, cultured vascular smooth muscle cells exposed to neuraminidase secreted greater amounts of tropoelastin and TGF-β than those exposed to vehicle. These data suggest that consumption of a diet high in fat and sugar causes stiffening of the vascular wall in resistance arteries through a process that may involve increased neuraminidase and TGF-β activity, elevated production of elastin, and a reduction in the size and number of fenestrae in the arterial IEL.

Phenotypes of office systolic blood pressure according to both brachial and aortic measurements: frequencies and associations with carotid hypertrophy in 1861 adults.

Aortic SBP (aSBP) associates with arterial damage more consistently than brachial SBP (bSBP). However, it is unknown how often aSBP is normal in the presence of elevated bSBP, and vice versa; if SBP phenotyping on the basis of bSBP and aSBP cut-off values improves cardiovascular risk stratification. We tested the frequency of four office SBP phenotypes: type I (both normal bSBP and aSBP); type II (high bSBP but normal aSBP); type III (normal bSBP but high aSBP), and type IV (both high bSBP and aSBP), the probability of each phenotype to be associated with increased arterial damage, using type Ia (i.e. normal bSBP and low-normal aSBP) as reference. In 1861 participants (age: 54 years, 49.1% men), we measured simultaneously bSBP, aSBP, and carotid cross-sectional wall area with ultrasound. Depending on the applied cut-off values, type II and type III phenotypes represented together 5-11% of the population (0.9-3.4 and 1.8-10.3%, respectively) and type IV around 20%. Subgroups with phenotypes, Ib (i.e. normal bSBP and high-normal aSBP), II, III, and IV had gradually significantly higher probability (by 1.37-1.91, 2.3-3.3, 3.3-8.9 times, and 4.18-6.25, respectively) to present elevated carotid artery cross-sectional wall area compared with the reference group, even after adjustment for DBP and other confounders. Type II (i.e. isolated high bSBP) and type III (i.e. isolated high aSBP) office SBP phenotypes were common and had intermediate level (between types I and IV) of arterial damage.

Estrogen therapy may counterbalance eutrophic remodeling of coronary arteries and increase bradykinin relaxation in a rat model of menopausal hypertension.

Objective:Hypertension causes adverse remodeling and vasomotor alterations in coronaries. Hormones such as estrogen may help counterbalance some of these effects. The aim of this study was to analyze the effects of ovariectomy and estrogen therapy in a rat model of menopausal hypertension induced by angiotensin II (AII).Methods:We investigated diameter, tone, and mechanics of intramural coronaries taken from ovariectomized female rats (n = 11) that received chronic AII treatment to induce hypertension, and compared the results with those found in female rats that were also given estrogen therapy (n = 11). The “hypertensive control” group (n = 11) underwent an abdominal sham operation, and received AII. After 4 weeks of AII treatment, side branches of left anterior descendent coronary (approximately 200 μm in diameter) were isolated, cannulated with plastic microcannulas at both ends, and studied in vitro in a vessel chamber. The inner and outer diameter of the arteries were measured by microangiometry, and spontenuous tone, wall thickness, wall cross-sectional area, tangential stress, incremental distensibility, circumferential incremental elastic modulus, thromboxane agonist-induced tone, and bradykinin-induced dilation were calculated.Results:In hypertension, intramural small coronaries show inward eutrophic remodeling after ovariectomy comparing with hypertensive controls. Estrogen therapy had an opposite effect on vessel diameter. Hormone therapy led to an increase in spontaneous tone, allowing for greater dilatative capacity.Conclusions:Estrogen may therefore be considered to counterbalance some of the adverse changes seen in the wall of intramural coronaries in the early stages of chronic hypertension.

Effect of Cut-Out Openings on the Axial Strength of Concrete Walls

AbstractOld structures are frequently modified to comply with current living standards and/or legislation. Such modifications may include the addition of new windows or doors and paths for ventilation and heating systems, all of which require openings to be cut into structural walls. However, effects of the required openings are not sufficiently understood. Thus, the objective of the work reported here was to analyze openings’ effects on the axial strength of large concrete wall panels. Three half-scaled walls with two opening configurations, corresponding to small and large door openings, were subjected to a uniformly distributed axial load with a small eccentricity. The results indicate that the 25 and 50% reductions in cross-sectional area of the solid wall caused by introducing the small and large openings reduced the load-carrying capacity by nearly 36 and 50%, respectively. The failure progression was captured using digital image correlation technique and the results indicated involvement of a plate...

Early regression of coronary artery remodeling with esmolol and DDAH/ADMA pathway in hypertensive rats.

Our preclinical study demonstrated that esmolol produces early regression of left ventricular hypertrophy in arterial hypertension. The aim of this study was to assess the effects of short-term esmolol therapy on the regression of left anterior descending artery remodeling in spontaneously hypertensive rats (SHRs), and to determine whether the asymmetric dimethylarginine (ADMA)/dimethylarginine dimethylaminohydrolase (DDAH) pathway, a regulator of nitric oxide (NO) bioavailability, accounted for this regression. Fourteen-month-old male SHRs were treated intravenously with vehicle (SHR, n=15) or esmolol (SHR-E, n=20) (300 μg kg-1 min-1). Age-matched, vehicle-treated male Wistar-Kyoto rats (WKY, n=15) served as controls. SHRs were also treated with nitroglycerin (SHR-N, n=5). After 48 h, the left anterior descending artery structure and morphology were assessed, and dose-response curves for 5-hydroxytryptamine (5-HT, 10-9-3 × 10-5 mol l-1) were constructed. ADMA concentrations in plasma and left ventricle and DDAH activity in tissue were analyzed. Wall thickness and cross-sectional area were significantly lower after treatment with esmolol in SHR-E than in SHR. Media thickness and smooth muscle cell count were lower in SHR-E than in SHR. Esmolol induced a significant reduction in adventitial cell count in SHR-E. The area under the concentration-response curves was significantly higher in SHR than in SHR-E, as were the esmolol normalized coronary artery contracting responses to 5-HT. We found significantly lower ADMA levels and significantly higher DDAH activity in the ventricle in SHR-E than in SHR. The protective effect of esmolol on the regression of left anterior descending artery remodeling may be related to the reduction in ADMA levels.

Effects of age, blood pressure and antihypertensive treatments on retinal arterioles remodeling assessed by adaptive optics.

In humans, adaptive optics camera enables precise large-scale noninvasive retinal microcirculation evaluation to assess ageing, blood pressure and antihypertensive treatments respective roles on retinal arterioles anatomy. We used adaptive optics camera rtx1 (Imagine-Eyes, Orsay, France) to measure wall thickness, internal diameter and to calculate wall-to-lumen ratio (WLR) and wall cross-sectional area of retinal arterioles. This assessment was repeated within a short period in two subgroups of hypertensive individuals without or with a drug-induced blood pressure drop. In 1000 individuals, mean wall thickness, lumen diameter and WLR were 23.2 ± 3.9, 78.0 ± 10.9 and 0.300 ± 0.054 μm, respectively. Blood pressure and age both independently increased WLR by thickening arterial wall. In opposite, hypertension narrowed lumen in younger as compared to older individuals (73.2 ± 9.0 vs. 81.7 ± 10.2 μm; P < 0.001), whereas age exerted no influence on lumen diameter. Short-term blood pressure drop (-29.3 ± 17.3/-14.4 ± 10.0 mmHg) induced a WLR decrease (-6.0 ± 8.0%) because of lumen dilatation (+4.4 ± 5.9%) without wall thickness changes. By contrast, no modifications were observed in individuals with stable blood pressure. In treated and controlled hypertensives under monotherapy WLR normalization was observed because of combined wall decrease and lumen dilatation independently of antihypertensive pharmacological classes. In multivariate analysis, hypertension drug regimen was not an independent predictor of any retinal anatomical indices. Retinal arteriolar remodeling comprised blood pressure and age-driven wall thickening as well as blood pressure-triggered lumen narrowing in younger individuals. Remodeling reversal observed in controlled hypertensives seems to include short-term functional and long-term structural changes.

Retinal arteriolar remodeling evaluated with adaptive optics camera: Relationship with blood pressure levels

AimTo research a retinal arterioles wall-to-lumen ratio or lumen diameter cut-off that would discriminate hypertensive from normal subjects using adaptive optics camera. Patients and methodsOne thousand and five hundred subjects were consecutively recruited and Adaptive Optics Camera rtx1™ (Imagine-Eyes, Orsay, France) was used to measure wall thickness, internal diameter, to calculate wall-to-lumen ratio (WLR) and wall cross-sectional area of retinal arterioles. Sitting office blood pressure was measured once, just before retinal measurements and office blood pressure was defined as systolic blood pressure>=140mmHg and diastolic blood pressure>=90mmHg. ROC curves were constructed to determine cut-off values for retinal parameters to diagnose office hypertension. In another population of 276 subjects office BP, retinal arterioles evaluation and home blood pressure monitoring were obtained. The applicability of retinal WLR or diameter cut-off values were compared in patients with controlled, masked, white-coat and sustained hypertension. ResultsIn 1500 patients, a WLR>0.31 discriminated office hypertensive subjects with a 0.57 sensitivity and 0.71 specificity. Lumen diameter<78.2μm discriminated office hypertension with a 0.73 sensitivity and a 0.52 specificity. In the other 276 patients, WLR was higher in sustained hypertension vs normotensive patients (0.330±0.06 vs 0.292±0.05; P<0.001) and diameter was narrower in masked hypertensive vs normotensive subjects (73.0±11.2 vs 78.5±11.6μm; P<0.005). ConclusionA WLR higher than 0.31 is in favour of office arterial hypertension; a diameter under<78μm may indicate a masked hypertension. Retinal arterioles analysis through adaptive optics camera may help the diagnosis of arterial hypertension, in particular in case of masked hypertension.

Carotid wall stress calculated with continuous intima-media thickness assessment using B-mode ultrasound

Cardiovascular risk is normally assessed using clinical risk factors but it can be refined using non-invasive infra-clinical markers. Intima-Media Thickness (IMT) is recognized as an early indicator of cardiovascular disease. Carotid Wall Stress (CWS) can be calculated using arterial pressure and carotid size (diameter and IMT). Generally, IMT is measured during diastole when it reaches its maximum value. However, it changes during the cardiac cycle and a time-dependant waveform can be obtained using B-mode ultrasound images. In this work we calculated CWS considering three different approaches for IMT assessment: (i) constant IMT (standard diastolic value), (ii) estimated IMT from diameter waveform (assuming a constant cross-sectional wall area) and (iii) continuously measured IMT. Our results showed that maximum wall stress depends on the IMT estimation method. Systolic CWS progressively increased using the three approaches (p<0.024). We conclude that maximum CWS is highly dependent on wall thickness and accurate IMT measures during systole should be encouraged.

Hypercoagulation and hyperkinetic blood pressure indicative of physiological loss-of-control despite behavioural control in Africans: The SABPA study

Objectives: A dissociation between behavioural (in-control) and physiological parameters (indicating loss-of-control) is associated with cardiovascular risk in defensive coping (DefS) Africans. We evaluated relationships between DefS, sub-clinical atherosclerosis, low-grade inflammation and hypercoagulation in a bi-ethnic sex cohort. Methods: Black (Africans) and white Africans (Caucasians) (n = 375; aged 44.6 ± 9.7 years) were included. Ambulatory BP, vascular structure (left carotid cross-sectional wall area (L-CSWA) and plaque counts), and markers of coagulation and inflammation were quantified. Ethnicity/coping style interaction was revealed only in DefS participants. Results: A hypertensive state, less plaque, low-grade inflammation, and hypercoagulation were more prevalent in DefS Africans (27–84%) than DefS Caucasians (18–41%). Regression analyses demonstrated associations between L-CSWA and 24 hour systolic BP (R2 = 0.38; β = 0.78; p < 0.05) in DefS African men but not in DefS African women or Caucasians. No associations between L-CSWA and coagulation markers were evident. Conclusion: Novel findings revealed hypercoagulation, low-grade inflammation and hyperkinetic BP (physiological loss-of-control responses) in DefS African men. Coupled to a self-reported in-control DefS behavioural profile, this reflects dissociation between behaviour and physiology. It may explain changes in vascular structure, increasing cerebrovascular disease risk in a state of hyper-vigilant coping.

CO-01: Retinal arterioles remodeling evaluated by adaptive optics camera in humans and its relationships with age, blood pressure and cardio-vascular risk factors

Background Microvascular vessels and microvascular remodeling play a major role in blood pressure (BP) regulation and peripheral tissue oxygen delivery. The adaptive optics camera (AOC), a novel technique of fundus image analysis enables the noninvasive characterization of microvascular remodeling in the retina on a large scale. Our objective was to assess the role of Blood Pressure (BP), ageing, diabetes and other risk factors on retinal arteriolar remodeling using AOC. Methods In 1.000 consecutive subjects in primary prevention with risk factors, we used the new RTX1 ® AOC (Imagine-Eyes, Orsay, France) and a semi-automated segmentation software to measure Wall Thickness (WT), Internal Diameter (ID) and to calculate Wall-to-Lumen Ratio (WLR) and Wall Cross Sectional Area (WCSA) on retinal arteriolar microvasculature. BP was assessed on standard conditions using oscillometric device during the AOC assessment. Hypertension was defined as the presence of Systolic BP>140mmHg and/or Diastolic BP>90mmHg. Standardized clinical and biological examinations were performed to assess for the presence of diabetes, dyslipidemia, obesity and current smoking which were defined according to guidelines. Results Overall, ageing was associated with an increase in WLR due to sole WT increase. Subjects with office hypertension (n = 313) had inward eutrophic remodeling with increased WLR (0.325±0.049 vs 0.292±0.056) due to higher WT, lower ID and overall stable WCSA. Diabetics (n = 180) presented with hypertrophic remodeling indicated by higher WLR due to a significant increase in WT and WCSA concomitant to a normal BP. There was no significant remodeling associated with other cardiovascular risk factors. In multivariate analysis, BP and age remained independent positive correlates of WLR and WT whereas age had no influence on ID and only BP negatively correlated to ID Abstract CO-01 – Table N Retinal Arteriolar Microvasculature Blood Pressure WLR ID.-μm WT.-μm WCSA.-μm 2 Systolic BP.-MmHg Diastolic BP.-MmHg Gender Female 489 0.301 ± .0.50 79.0 ± 10.9 23.5 ± 3.6 3386 ± 817 * 129.5 ± 21.2 72.2 ± 13.7 Male 511 0.300 ± .0.57 77.3 ± 11.1 22.89 ± 4.2 3234 ± 886 132.2 ± 19.4 71.5 ± 13.8 Hypertension Yes 313 0.325 ± .0.49 ‡ 75.6 ± 10.9 † 24.2 ± 4.0 ‡ 3392 ± 832 153.1 ± 16.1 ‡ 82.1 ± 14.8 ‡ No 687 0.292 ± .0.56 78.6 ± 10.8 22.7 ± 3.6 3249 ± 873 120.8 ± 12.4 67.1 ± 10.3 Diabetes Yes 180 0.308 ± .0.52 79.5 ± 11.2 24.2 ± 3.8 ‡ 3523 ± 861 † 134.4 ± 19.6 70.8 ± 13.6 No 820 0.299 ± .0.55 77.8 ± 11.2 23.0 ± 3.9 3256 ± 844 130.2 ± 20.5 72.1 ± 13.9 Dyslipidemia Yes 436 0.301 ± .0.57 77.6 ± 11.1 23.3 ± 4.1 3333 ± 828 130.4 ± 20.0 69.4 ± 12.2 ‡ No 564 0.301 ± .0.53 78.6 ± 11.1 23.2 ± 3.7 3281 ± 886 131.3 ± 20.6 73.7 ± 14.6 Obesity Yes 164 0.303 ± .0.55 77.0 ± 11.4 23.2 ± 3.9 3255 ± 838 136.1 ± 20.3 ‡ 76.3 ± 13.2 ‡ No 836 0.300 ± .0.55 78.2 ± 10.8 23.1 ± 3.9 3307 ± 838 129.3 ± 20.3 70.5 ± 13.7 WLR is Wall-to-Lumen Ratio, ID is internal Diameter, WT is Wall Thickness, WCSA is Wall Cross Sectionnal Area, BP is blood pressure * p † p ‡ p Conclusions Hypertension, age and diabetes are associated with increase in WLR and WT. Assessment OF WT and ID are mandatory to perform a correct interpretation of WLR increase. OAC could represent a promising tool for interventional studies on treatment-induced remodeling regression.

P4-33: Variations of retinal arteriolar wall-lumen ratio depend on mechanism of blood pressure changes

Background A recently developed non-invasive opto-electronic technology (Adaptive Optics Camera, AOC) provides a morphologic analysis of the retinal arteriolar tree. Coupled with a validated semi-automated segmentation software it allows reproducible and reliable measurements of wall thickness (WT), internal diameter (ID), wall cross sectional area (WCSA) and calculation of wall-to-lumen ratio (WLR). Our aim was to assess the determinants of WLR along the temporal retinal artery and in case of acute Blood Pressure (BP) rise or drug-induced short term BP drop. Methods We studied 3 groups of patients : 1/ We consecutively enrolled 48 patients and calculated WLR before the first bifurcation (parental vessel) and on its large and small post-bifurcation branches on the right eye temporal superior artery. 2/ In a subgroup of 10 patients WLR was measured at rest and right after exercise dynamic test. 3/ In 55 hypertensive subjects AOC assessment was repeated after a median of 49 days in 27 subjects with stable BP and 38 days in 28 subjects with a drop in BP secondary to antihypertensive drug adaptation. WT and ID were directly measured using non-invasive rtx1® AOC (ImagineEyes-Orsay, France) and a dedicated software analysis system was used to calculate WLR and WCSA. BP was measured at the time of AOC examination in standard conditions. Hypertension was defined as the presence of Systolic Blood Pressure (SBP)>140 mmHg and/or Diastolic blood pressure (DBP)>90 mmHg. Results 1/ In the first group, in both normo- and hypertensive patients, a significant decrease in ID, WT and WCSA was observed on post-bifurcation branches whereas WLR remained constant (table 1, next page). 2/ In the second group, while SBP acutely increased of 47±8 mmHg, ANOVA analysis did not show any significant changes in WLR. 3/ At 6 weeks, in the follow-up group with a short-term SBP drop (–19.3±7.7%), a decrease of WLR (–7.0±8.0 mmHg) due to ID increase (+5.6±5.9%) without significant changes in WT and WSCA were observed. No changes were observed in the group with a stable BP (see table next page). Conclusions WLR, the index of remodeling in retinal small arteries, is constant along the arterial tree despite changes in WT and ID. While WLR did not change during acute exercise-induced BP surge, it decreased due to a ID increase after a short-term drug-induced BP drop. Those results confirm the homogeneity of remodeling along the retinal arteriolar tree and that mechanisms of BP changes have different effects on remodeling. P4-33 – Tableau : Retinal arteriolar microvascular indices in parental vesse, large and small branches Parental Vessel Large Branch Small Branch p Wall to lumen ratio 0.295±0.051 0.296 ± 0.064 0.317±0.071 NS Internal diameter - μm 79.8012±9.23 71.0716±10.78¥ 54.498±8.05*† <0.001 Wall Thickness - μm 23.4015±4.12 20.7199±4.13§ 17.1838±4.31*† <0.001 Wall Cross Sectionnal Area - μm 3376.34±849.73 2680.75±775.56¥ 1891.40±1110.74*† <0.001 Small branch vs parental vessel: * p<0.001. Small branch vs large branch: † p<0.001. Large branch vs parental vessel: § p<0.05; ¥ p<0.01 Full-size table Table options View in workspace Download as CSV

CO-43: Genetic study identifies common variation in phactr1 to associate with fibromuscular dysplasia

Background Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid artery. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected. Methods We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed 25,606 common variants (MAF>0.05) using an exome-chip array. Results We followed up 13 loci ( p −4 ) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined n cases = 512, n controls = 669) confirmed this association, with an overall OR of 1.39, ( p = 7.4×10 −10 , n all cases = 1154, n all controls = 3895). The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure ( p =0.0009), increased intima media thickness ( p =0.001) and wall cross-sectional area ( p =0.003) of carotids assessed by echotracking in 3800 population-based individuals. RNA expression of PHACTR1 in primary cultured human fibroblasts is 1.7 fold higher in FMD patients ( n =20, matched to 20 controls) and we showed that FMD risk allele is an eQTL for PHACTR1 in fibroblast of 57 FMD patients ( p =0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels ( p =0.003) indicating impaired development of vasculature. Conclusions Here we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

Assessment of central blood pressure as a predictor of target organ damage in children with primary hypertension

Introduction. Central systolic blood pressure (cSBP) is assumed to be the best indicator of cardiovascular risk caused by elevated blood pressure. However, there are no data on the usefulness of cSBP measurments in the assessment of the risk of target organ damage (TOD) in hypertensive children. Aim. The aim of study was to evaluate the usefulness of noninvasive measurements of cSBP, AugP and AugInd as predictors of increased left ventricular hypertrophy (LVH) and increased carotid intima-media thickness (cIMT) in children with primary hypertension. Material and methods. 114 children (25 girls), mean age 15.2 ± 2.5 years, referred because of elevated blood pressure and with excluded secondary hypertension, were included in the study. In all patients, 24h ambulatory blood pressure monitoring (ABPM), cSBP, central pulse pressure (cPP), AugP, AugInd, cardiac index (CI), total peripheral resistance (TPR), pulse wave velocity (PWV), LVMI and cIMT were measured. Results. In 62 patients white coat hypertension was diagnosed, 9 had ambulatory hypertension and 43 had severe ambulatory hypertension. Children with severe ambulatory hypertension had greater AugP, CI and carotid wall cross sectional area (WCSA) and lower TPR. cSBP correlated with WCSA (p = 0.015; r = 0.255) and AugP with LVMI (p = 0.02; r = 0.220). ABPM had greater sensitivity and lower specificity for predicting LVH than cSBP. ABPM and cSBP had similar sensitivity and specificity as predictors of cIMT and WCSA. Conclusions. Although sensitivity and specificity of cSBP and ABPM as predictors of arterial injury were similar, ABPM performed better as a predictor of LVH. The results of our study indicate a much higher risk of TOD in children with severe ambulatory hypertension and show that the assessment of cSBP, which is also a predictor of LVH, may be a new criterion for drug therapy implementation.

Abstract 15370: Genetic Study Identifies Common Variation in PHACTR1 to Associate With Fibromuscular Dysplasia (Best of Basic Science Abstract)

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid arteries. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected. We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed ∼26K common variants (MAF&gt;0.05) using an exome-chip array. We followed up 13 loci (P&lt;10-4) in 393 cases and 2537 controls and replicated a signal on Chr6. Three additional studies (combined Ncases=512, Ncontrols=669) confirmed this association, with an overall OR of 1.39, (P=7.4х10e-10 , All Ncases=1154, All Ncontrols=3895). The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure (P=0.0009), increased intima media thickness (P=0.001) and wall cross-sectional area (P=0.003) of carotids assessed by echotracking in 3800 population-based individuals. The correlation of genotypes with the expression of PHACTR1 in primary cultured human fibroblasts showed higher expression in FMD risk allele carriers, compared to non carriers (N=57, P=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (P=0.003) indicating impaired vascular development. In conclusion, we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.