Wall Cross-sectional Area Research Articles

Protocatechuic acid attenuates isoproterenol-induced cardiac hypertrophy via downregulation of ROCK1\u2013Sp1\u2013PKC\u03b3 axis

Cardiac hypertrophy is an adaptive response of the myocardium to pressure overload or adrenergic agonists. Here, we investigated the protective effects and the regulatory mechanism of protocatechuic acid, a phenolic compound, using a mouse model of isoproterenol-induced cardiac hypertrophy. Our results demonstrated that protocatechuic acid treatment significantly downregulated the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), cardiomyocyte size, heart weight to body weight ratio, cross-sectional area, and thickness of left ventricular septum and posterior wall. This treatment also reduced the expression of isoproterenol-induced ROCK1, Sp1, and PKCγ both in vivo and in vitro. To investigate the mechanism, we performed knockdown and overexpression experiments. The knockdown of ROCK1, Sp1, or PKCγ decreased the isoproterenol-induced cell area and the expression of hypertrophic markers, while the overexpression of Sp1 or PKCγ increased the levels of hypertrophic markers. Protocatechuic acid treatment reversed these effects. Interestingly, the overexpression of Sp1 increased cell area and induced PKCγ expression. Furthermore, experiments using transcription inhibitor actinomycin D showed that ROCK1 and Sp1 suppression by protocatechuic acid was not regulated at the transcriptional level. Our results indicate that protocatechuic acid acts via the ROCK1/Sp1/PKCγ axis and therefore has promising therapeutic potential as a treatment for cardiac hypertrophy.

Pulmonary Arterial Remodeling Is Related to the Risk Stratification and Right Ventricular-Pulmonary Arterial Coupling in Patients With Pulmonary Arterial Hypertension.

BackgroundPulmonary arterial (PA) stiffness has an essential contribution to the right ventricular (RV) failure pathogenesis. A comprehensive and multiparameter risk assessment allows predicting mortality and guiding treatment decisions in PA hypertension (PAH). We characterize PA remodeling with intravascular ultrasound (IVUS) in prevalent and stable patients with PAH according to the ESC/ERS risk table and analyze the RV-PA coupling consequences.MethodsTen control subjects and 20 prevalent PAH adult patients underwent right heart catheterization (RHC) with simultaneous IVUS study. We estimated cardiac index (CI), pulmonary vascular resistance, and compliance (PVR, PAC) by standard formulas. From IVUS and RHC data, PA diameter, wall thickness/luminal diameter ratio, and indexes of stiffness (pulsatility, compliance, distensibility, incremental elastic modulus - Einc-, and the stiffness index β) were measured. We evaluated RV-PA coupling by the ratio of tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP). The individual average risk was calculated by assigning a score of 1 (low-risk -LR-), 2 (intermediate-risk -IR-), and 3 (high-risk -HR-) for each of seven variables (functional class, six-minute walking test, brain natriuretic peptide, right atrial area and pressure, CI, and PA oxygen saturation) and rounding the average value to the nearest integer.ResultsAll PA segments interrogated showed increased vessel diameter, wall cross-sectional area (WCSA), and stiffness in patients with PAH compared to control subjects. 45% corresponded to LR, and 55% corresponded to IR PAH patients. The different measurements of PA stiffness showed significant correlations with TAPSE/sPAP (r = 0.6 to 0.76) in PAH patients. The IR group had higher PA stiffness and lower relative WCSA than LR patients (P < 0.05), and it is associated with a lower PAC and TAPSE/sPAP (P < 0.05).ConclusionIn prevalent PAH patients, the severity of proximal PA remodeling is related to the risk stratification and associated with PAC and RV-PA coupling impairment beyond the indirect effect of the mean PA pressure. The concomitant assessment of IVUS and hemodynamic parameters at diagnosis and follow-up of PAH patients could be a feasible and safe tool for risk stratification and treatment response of the PA vasculopathy during serial hemodynamic measurements.

RETINAL WALL TO LUMEN RATIO IN PATIENTS WITH ANGINA AND NO CORONARY ARTERY DISEASE. AN EYE TO THE HEART

Objective: The vasculature of the eye and of the heart share several common characteristics. Therefore, the easily accessible vessels of the eye may be considered, to some extent, a “window” to the heart. Aim of this study was to evaluate retinal arterioles morphological changes in patients with angina and nonobstructive coronary artery disease. Design and method: In 19 patients (M:W 11:8, mean age 71 + 6 years) with microvascular angina (MA), confirmed by normal coronary angiography and SPECT stress hypoperfusion and in 18 controls (C) (M:W 10:8, mean age 69 ± 6 years) with normal SPECT response, direct measurement of wall to lumen of retinal arterioles (W/L) using an adaptive optics (AO) imaging system (Imagine Eyes, Orsay, France) was performed. All subjects also underwent BP measurement with an automated oscillometric device (Omron HEM 9000Ai, mean of 3 measurements). Results: No differences in demographic and hemodynamic characteristics were observed between MA patients and C, except for BMI (BMI 30 ± 4.2 vs 24 ± 4 kg/m2, in MA and C respectively, p = 0.001). Retinal arterioles wall thickness (11.75 ± 1.45 vs 13.9 ± 1.53 microm), W/L ratio (0.29 ± 0.05 vs 0.25 ± 0.03 in MA and C respectively, p = 0.008) and wall cross sectional area (WCSA) (4876 ± 976 vs 4004 ± 872 microm2, respectively in MA and C, p = 0.012) were higher in MA patients as compared with C. Differences were confirmed after adjustment for BMI. Conclusions: Our findings suggest that in patients with angina and normal coronary arteries retinal structural changes may be observed.

Hypertrophic remodelling of retinal arterioles in patients with congestive heart failure.

AimsAnalysis of microvascular parameters in the retinal circulation—known to reflect those in the systemic circulation—allows us to differentiate between eutrophic and hypertrophic remodelling of small arteries. This study aimed to examine microvascular changes in patients with congestive heart failure (CHF) and reduced as well as mid‐range ejection fraction.Methods and resultsForty subjects with CHF underwent measurement of retinal capillary flow (RCF), wall‐to‐lumen ratio (WLR), vessel and lumen diameter, wall thickness, and wall cross‐sectional area (WCSA) of retinal arterioles of the right eye by scanning laser Doppler flowmetry (SLDF). Applying a matched pair approach, we compared this group with reference values of age‐matched controls from a random sample in the population of Pilsen, Czech Republic. There was no significant difference in RCF and WLR between the groups (RCF: P = 0.513; WLR: P = 0.106). In contrast, wall thickness and WCSA, indicators of hypertrophic remodelling, were higher in CHF subjects (WT: 15.0 ± 4.2 vs. 12.7 ± 4.2 μm, P = 0.021; WCSA: 4437.6 ± 1314.5 vs. 3615.9 ± 1567.8 μm2, P = 0.014). Similarly, vessel (109.4 ± 11.1 vs. 100.5 ± 14.4 μm, P = 0.002) and lumen diameter (79.0 ± 7.9 vs. 75.2 ± 8.5 μm, P = 0.009) were increased in CHF.ConclusionsIn CHF subjects, we observed hypertrophic remodelling of retinal arterioles indicative of similar changes of small resistance arteries in the systemic circulation. Microvascular structure and function assessed by SLDF may thereby represent a useful, non‐invasive method for monitoring of microvascular damage in patients with CHF and may offer innovative treatment targets for new CHF therapies.

Correlations between Retinal Arterial Morphometric Parameters and Neurodegeneration in Patients with Type 2 Diabetes Mellitus with No or Mild Diabetic Retinopathy.

Background and Objectives: In patients with diabetes mellitus (DM), the neural retina is starting to degenerate before the development of vascular lesions. Our purpose was to investigate the correlation between the retinal arterial morphometric parameters and structural neurodegeneration in patients with type 2 DM with no or mild diabetic retinopathy (DR). Materials and Methods: This is a prospective study including 53 eyes of patients with type 2 DM and 32 eyes of healthy controls. Based on SD-OCT (spectral domain—optical coherence tomography) images, using a micro-densitometry method, we measured the outer and luminal diameter of retinal arteries and calculated the AWT (arterial wall thickness), WLR (wall-to-lumen ratio), and WCSA (wall cross-sectional area). GCL (ganglion cell layer) and RNFL (retinal nerve fiber layer) thickness were analyzed in correlation with the retinal arterial morphometric parameters mentioned above. Results: GCL was thinner in the inner quadrants in the NDR (no DR) group compared to controls (p < 0.05). RAOD (retinal artery outer diameter), RALD (retinal artery lumen diameter), AWT, WLR, and WCSA were similar between groups. A regression model considering age, gender, duration of DM, and HbA1C was carried out. Central GCL thickness was correlated positively with RAOD (coefficient 0.360 per µm, p = 0.011), RALD (coefficient 0.283 per µm, p = 0.050), AWT (coefficient 0.304 per µm, p = 0.029), and WCSA (coefficient 3.90 per µm, p = 0.005). Duration of DM was positively correlated with WCSA (coefficient 0.311 per one year duration of diabetes, p = 0.043). Conclusions: Significant GCL thinning in the inner quadrants preceded the morphological retinal arterial morphometric changes, supporting the neurodegeneration as primary pathogenic mechanism in DR.

Comparative structural analysis of polyurethane and silicone catheters of totally implantable venous access devices by micro-computed tomography

Objectives:To investigate microstructural alterations of explanted long-term central venous catheters of totally implantable venous access devices, using micro-computed tomography.Methods:A total of 16 catheters (9 made of silicone and 7 made of polyurethane), all non-fractured, have been analyzed in this study. Eight catheters were implanted for an average duration of 994 days (min–max: 98–2731 days), while the remaining eight catheters (four for each material, forming the SIref and PUref control groups) were analyzed before implant and used as a reference. X-ray micro-computed tomography was used to reconstruct the three-dimensional geometry of selected segments of each catheter (ca. 10 cm per sample).Results:Morphometric analysis of the catheters revealed increases wall thickness and section area in the polyurethane group as compared with the reference central venous catheters of the same materials (wall thickness: 403 ± 12 μm in the polyurethane (PU) group vs 382 ± 4 μm in PUref, p = 0.014; wall cross-section area: 2.04 ± 0.09 mm2 in PU vs 1.91 ± 0.03 mm2 in PUref, p = 0.04), whereas implanted silicone catheters showed a larger luminal cross section as compared with their controls (lumen cross-section area = 0.851 ± 0.020 mm2 in silicone (SI) group vs 0.811 ± 0.007 mm2 in SIref, p = 0.007). All analyzed samples in this study presented some type of alteration in the catheter walls, namely, hyperdense spots (below 0.1 mm size), air gaps/bubbles and displacements of inner and outer axes causing heterogeneous wall thickness. The incidence of air gaps showed no difference with respect to both material type and duration of implant, whereas the SI group revealed more hyperdense spots as compared to all other groups.Conclusion:Morphological change and local structural alteration can occur in both silicone and polyurethane catheters. This evidence suggests the need for further studies connecting those morphological changes with modification of mechanical robustness, which ultimately can play a role for patient safety.

Effect and mechanism of vascular endothelial growth factor-A on pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension

OBJECTIVE To study the role of vascular endothelial growth factor-A (VEGF-A) in pulmonary vascular remodeling in neonatal rats with hypoxic pulmonary hypertension (HPH) by regulating survivin (SVV). METHODS A total of 96 neonatal rats were randomly divided into three groups: HPH+VEGF-A group, HPH group, and control group. Each group was further randomly divided into 3-, 7-, 10-, and 14-day subgroups (n=8 in each subgroup). The neonatal rats in the HPH+VEGF-A and HPH groups were intratracheally transfected with adenoviral vectors with or without VEGF-A gene respectively. Those in the control group were given intratracheal injection of normal saline and were then fed under normoxic conditions. The direct measurement method was used to measure mean right ventricular systolic pressure (RVSP). Hematoxylin-eosin staining was used to observe the morphological changes of pulmonary vessels under a light microscope and calculate the percentage of media wall thickness (MT%) and the percentage of media wall cross-sectional area (MA%) in the pulmonary arterioles. Immunohistochemistry was used to measure the expression levels of VEGF-A and SVV in lung tissue. RESULTS The HPH group had a significantly higher mean RVSP than the control and HPH+VEGF-A groups at each time point (P < 0.05). Pulmonary vascular remodeling occurred in the HPH group on day 7 of hypoxia, while it occurred in the HPH+VEGF-A group on day 10 of hypoxia. On day 7 of hypoxia, the HPH group had significantly higher MT% and MA% than the control and HPH+VEGF-A groups (P < 0.05). On days 10 and 14 of hypoxia, the HPH and HPH+VEGF-A groups had significantly higher MT% and MA% than the control group (P < 0.05). The HPH and HPH+VEGF-A groups had significantly higher expression of VEGF-A than the control group at each time point (P < 0.05). On days 3 and 7 of hypoxia, the HPH+VEGF-A group had significantly higher expression of VEGF-A than the HPH group (P < 0.05). On day 14 of hypoxia, the HPH group had significantly higher expression of SVV than the control group (P < 0.05). The HPH+VEGF-A group had significantly higher expression of SVV than the control group at each time point (P < 0.05). On days 3 and 7 of hypoxia, the HPH+VEGF-A group had significantly higher expression of SVV than the HPH group (P < 0.05). CONCLUSIONS Prophylactic intratracheal administration of exogenous VEGF-A in neonatal rats with HPH can inhibit pulmonary vascular remodeling and reduce pulmonary arterial pressure by upregulating the expression of SVV in the early stage of hypoxia. This provides a basis for the interventional treatment of pulmonary vascular remodeling in neonatal HPH.

Perindopril Reduces Arterial Pressure and Does Not Inhibit Exercise-Induced Angiogenesis in Spontaneously Hypertensive Rats.

Sympathetic activity, arteriolar structure, and angiogenesis are important mechanisms modulating hypertension and this study aimed to analyze the effects of perindopril treatment, associated or not with exercise training, on the mechanisms that control blood pressure (BP) in hypertensive rats. Spontaneously hypertensive rats (SHR) were allocated into 4 groups: 1/sedentary (S); 2/perindopril (P, 3.0 mg/kg/d); 3/trained (T); and 4/trained + perindopril (TP). Wistar rats were used as normotensive sedentary control group. SHR were assigned to undergo a treadmill training (T) or were kept sedentary. Heart rate, BP, sympathetic activity to the vessels (LF-SBP), and skeletal muscle and myocardial morphometric analyses were performed. BP was significantly lower after all 3 strategies, compared with S and was accompanied by lower LF-SBP (-76%, -53%, and -44%, for P, T, and TP, respectively). Arteriolar vessel wall cross-sectional area was lower after treatments (-56%, -52%, and -56%, for P, T, and TP, respectively), and only TP presented higher arteriolar lumen area. Capillary rarefaction was present in soleus muscle and myocardium in S group and both trained groups presented higher vessel density, although perindopril attenuated this increase in soleus muscle. Although myocyte diameter was not different between groups, myocardial collagen deposition area, higher in S group, was lower after 3 strategies. In conclusion, we may suggest that perindopril could be an option for the hypertensive people who practice exercise and need a specific pharmacological treatment to reach a better BP control, mainly because training-induced angiogenesis is an important response to facilitate blood flow perfusion and oxygen uptake and perindopril did not attenuate this response.

Reference values of retinal microcirculation parameters derived from a population random sample

Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Our objective has been to establish reference values for major functional and structural parameters of retinal microcirculation in a randomly selected urban population sample.A total of 398 randomly selected individuals from an urban population aged 25 to 65 years, resident in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry (SLDF), with data evaluable in 343 patients. Of this number, complete data were available for 256 individuals free from manifest cardiovascular disease, diabetes and drug treatment for hypertension and/or dyslipidemia, constituting the reference value population.Juxtapapillary retinal capillary blood flow has increased significantly with age whereas vessel and luminal diameters have decreased. No sex differences in retinal microcirculation parameters have been found. Therefore, reference values for retinal microcirculation parameters have been established by age groups. Unattended automated office systolic BP, after adjusting for age, correlated significantly with wall-to-lumen ratio (WLR) and wall thickness (WT). Moreover, after adjusting for age and mean BP, a positive relationship has been found between carotid femoral pulse wave velocity and WT, WLR and wall cross-sectional area, indicating the interaction between micro- and macro-vasculature.In conclusion, our study is the first to provide reference values of retinal microcirculation parameters in a random Caucasian population sample. Our results have shown that, at the population level, the first structural changes in retinal microcirculation are those in lumen diameters. Of note, a close relationship between BP and vascular remodeling of retinal arterioles and between aortic stiffness and WLR of retinal arterioles suggests an interaction between micro- and macro-vasculature.

Asymmetric dimethylarginine and L-homoarginine prospectively relate to carotid wall thickness in a South African cohort.

The L-arginine derivatives asymmetric (ADMA) and symmetric dimethylarginine (SDMA), as well as L-homoarginine may have opposing effects in the pathogenesis of atherosclerosis. We aimed to investigate (i) 5-year changes in arginine derivatives, and (ii) the association between baseline arginine derivatives and follow-up measures of carotid wall thickness in South Africans. This study included men (n = 187) and women (n = 396) who took part in the 2010 and 2015 data collections of the South African arm of the Prospective Urban and Rural Epidemiology (PURE) study. Arginine derivatives were determined in plasma with liquid chromatography-tandem mass spectrometry. Carotid intima-media thickness (cIMT) and cross-sectional wall area (CSWA) were determined with B-mode ultrasonography. Mean values of arginine derivatives did not change over time. In the study group, follow-up cIMT (β = -0.10 p = 0.018) and CSWA (β = -0.12; p = 0.004) inversely associated with baseline L-homoarginine, and cIMT inversely associated with ADMA (β = -0.09; p = 0.033). In women, CSWA inversely associated with both ADMA (β = -0.11; p = 0.034) and L-homoarginine (β = -0.11; p = 0.024). No such associations were found in men. These results suggest that higher levels of L-homoarginine may play a protective role against vascular injury and delay progression of carotid wall thickening in this cohort. The role of ADMA in atherosclerosis deserves further investigation in this population.

Non-invasive evaluation of retinal vascular remodeling and hypertrophy in humans: intricate effect of ageing, blood pressure and glycaemia.

Ageing, hypertension and diabetes have an intricate effect on microvascular structure. In the retina, the respective contribution of remodeling and hypertrophy in such process is still unclear. We aimed at disentangling age, blood pressure and glycaemia effects onretinal microcirculation using the non-invasive adaptive optics ophthalmoscopy (AOO). We included 429 subjects, distributed into 4 groups according to normal (nBP) or high blood pressure (hBP) and/or normal (nGly) or high fasting glycaemia (hGly). The nBP/nGly group was stratified in age tertiles to isolate theeffect of ageing. AOO was used to measure arteriolar wall thickness (WT, µm), arteriolar (aID, µm) and venular internal diameter (vID, µm) and calculate arteriolar wall-to-lumen ratio (WLR), wall cross-sectional area (WCSA, µm2). One-way ANOVA for parametric variables and Kruskal-Wallis test for non-parametric variables were used for comparison among groups. A multivariate regression analysis including age, gender, BP, hGly and antihypertensive treatment was performed to calculate independent predictors of retinal remodeling. WT was increased with ageing (tertile1: 22.5 ± 3.2, tertile2: 24.2 ± 3.5, tertile 3: 25.2 ± 3.8, p = 0.001) and BP (hBP: 25.2 ± 4.1 vs nBP: 23.9 ± 3.7, p = 0.003). aID decreased with BP (hBP: 90.2 ± 13.4 vs nBP: 93.6 ± 11.6, p = 0.013) and increased with glycaemia (hGly: 97.7 ± 12.5 vs nGly: 93.6 ± 11.6, p = 0.002). Amultivariate analysis showed independent association of hBPwithWLR; hGly withWCSA; ageing with WLR and WCSA. AOO non-invasively identifies retinal structural changes in human confirming that microvascular remodeling is exclusively related to hypertension, whereas vascular growth is related to ageing and hyperglycaemia.

Retinal arterial remodeling in patients with pheochromocytoma or paraganglioma and its reversibility following surgical treatment.

Structural abnormalities in resistance arteries are a hallmark of patients with hypertension. In hypertensive patients with pheochromocytoma or paraganglioma (PPGL), it is still a matter of debate whether structural vascular changes are because of elevated blood pressure (BP) or to toxic effects of elevated circulating catecholamines. Hence, the aim of our study was to assess whether catecholamine excess and/or elevated BP affect the structure of small retinal arteries in patients with catecholamine-producing tumors. The study included 27 patients with PPGL and 27 hypertensive patients. All patients underwent biochemical tests for catecholamine excess, echocardiography and analyses of scanning-laser-Doppler-flowmetry (SLDF) both at baseline and 12 months following surgical resection of PPGL. Baseline retinal arterial diameter, arterial wall thickness and wall cross sectional area (WCSA) were higher in patients with PPGL as compared with subjects without PPGL (arterial diameter: 110 ± 16.5 vs. 99.5 ± 10.8 μm, wall thickness: 16.3 ± 6.0 vs. 13.5 ± 4.0 μm, WCSA: 4953.9 ± 2472.8 vs. 3784.1 ± 1446.3 μm, P < 0.05). Significant correlations were noted between wall thickness and WCSA and echocardiographic parameters assessing diastolic and systolic function of left ventricle. No correlations between retinal parameters, BP level and plasma concentrations of metanephrines were observed. In patients with PPGL, there were postoperative decreases in wall thickness (16.4 ± 15.8 vs. 14.8 ± 4.7 μm; P = 0.011) and WLR (0.42 ± 0.13 vs. 0.37 ± 0.10; P = 0.003) at 12 months after surgical removal of tumors. This is the first study to demonstrate that catecholamine excess is related to thickening of retinal arteries independent of BP and reversible after surgical cure. These data support a role of catecholamines in vascular remodeling in PPGL patients.

The histology and histomorphometry of umbilical cord cross section in preeclampsia and normal pregnancies: a comparative study

ABSTRACT The umbilical cord is the connecting link between the mother and the fetus and its morphology is an indicator of fetal well-being. Preeclampsia is a disorder of pregnancy associated with new-onset hypertension, which occurs most often after 20 weeks of gestation. There are structural differences in the umbilical cord of normotensive and hypertensive pregnant women. This research aimed to study the histology and histomorphometry of umbilical cord areas in preeclampsia and compare the parameters with normal uncomplicated pregnancies of gestational age 37–40 weeks. A total of 70 umbilical cords were studied from preeclampsia (n = 35) and normal (n = 35) pregnancies. The parameters studied included cross-sectional areas (CSA) of umbilical cord, umbilical vein lumen, umbilical vein wall, umbilical artery lumen, umbilical artery wall, and Wharton’s jelly, including the presence of edema in the vessel walls and Wharton’s jelly and basement membrane thickening. The mean umbilical cord CSA was significantly higher in preeclampsia (p = 0.014). The mean umbilical artery lumen CSA was significantly lower than the normal pregnancy cords (p = 0.006). The mean Wharton’s jelly CSA in preeclampsia was significantly higher than the normal pregnancy cords (p = 0.004). The parameters for umbilical vein lumen CSA, umbilical vein wall CSA, and umbilical artery wall CSA did not show any significant difference. Histological findings were edema (p < 0.001) and thickened basement membranes (p < 0.0001) were considered significant.

IGF-1 is an independent predictor of retinal arterioles remodeling in subjects with uncontrolled acromegaly.

Cardiovascular disease is one of the main causes of morbidity in active acromegaly due to the increased prevalence of risk factors and arterial consequences of increased growth hormone levels. No in vivo study has evaluated the consequences of acromegaly on the retinal microvasculature. The aim of this study was to identify in vivo the presence of morphological alterations of retinal arterioles in subjects with acromegaly. Single-center retrospective study of a cohort of 60 subjects with acromegaly, matched to 60 controls, who were referred for adaptive optics camera (AOC) from September 2014 to December 2016. Of the subjects with acromegaly, 19 had an active disease (AD) and 41 a controlled disease (CD) based on the IGF1 ratio (IGF1r). Retinal arteriolar remodeling was previously assessed using adaptive optics camera (AOC) in order to measure wall-to-lumen ratio (WLR), wall thickness (WT), internal diameter (ID) and wall cross sectional area (WCSA). WLR was significantly higher in AD subjects compared to CD subjects and controls (AD: 0.311 ± 0.06, CD: 0.279 ± 0.04, controls: 0.281 ± 0.04, P = 0.031). A significant positive correlation was observed between WLR and IGF-1r (R2 = 0.215, P < 0.001), even after adjustment for gender, age, systolic blood pressure (SBP) and the presence of dopamine agonist treatment (R2 = 0.406, P < 0.001). Retinal arteriolar anatomical indices were comparable between CD and controls. Active acromegaly is associated with the presence of small retinal arteriolar remodeling. These results provide new perspectives to better stratify cardiovascular risk and consequently optimize treatment in acromegaly.

Abstract 140: Vascular Structure in Brain: Lack of Small Vessel Recovery Following Hypertension

Vascular remodeling is a feature of small vessel disease (SVD), predictive of vascular events, brain injury, and cognitive decline. Hypertension alters vascular structure including diameter and cross-sectional area (CSA) of the vessel wall. While effects of hypertension on large arteries have been studied relatively widely, detailed quantification, including recovery from hypertension in microvessels, is rare. Previously, angiotensin II (Ang II)-dependent hypertension produced increased CSA but reduced internal diameter (ID) of cerebral arterioles (inward remodeling) in brain. Because cerebral arterioles are targets of SVD, we examined the hypothesis that brain microvessels can recover from hypertension after return of mean arterial pressure (MAP) to normal levels. MAP was measured using radiotelemetry in adult male C57BL6J mice at baseline, during infusion of vehicle or Ang II (1.4 mg/kg per day using osmotic mini-pumps) for 28 days, and during a 28 day recovery period (n=5 in each group). Prior to treatment, MAP was similar in both groups, with MAP remaining stable in vehicle treated mice. With Ang II treatment, MAP began to rise on day 3, steadily increasing until day 28. On day 30, MAP began to decrease, reaching levels seen with vehicle on days 46-47. In anesthetized mice, we measured pressure, diameter, and CSA of the vessel wall in maximally dilated arterioles (baseline diameter of 62±3 microns) at 1, 3, 7, 14, 28, and 56 days after pump implantation (n=7-9 in each group). At day 1, ID and CSA were similar in both groups. With vehicle, there was no significant change in CSA or ID at any time point. With Ang II, CSA increased at day 7 and was maintained at days 14 and 28 (P=0.023). ID did not change at day 3 or 7, but was reduced (by ~15%, P=0.011) at 14 and 28 days. During recovery (day 56), CSA returned 63% of the way to normal (compared to vehicle), while ID remained at day 14 and 28 values. In conclusion, CSA changed rapidly during hypertension onset and largely recovered with a reduction in MAP. Inward remodeling developed slowly and did not recover after return of MAP to control levels. The lack of recovery after hypertension has implications for the impact of SVD including hypoperfusion, impaired vasodilation, and augmented injury during ischemia.

Abstract TMP102: Sex Differences in the Structure and Function of the Middle Cerebral Artery

There are sex differences in the incidence, prevalence, and outcomes of cerebrovascular disease (CVD), including stroke and dementia. Understanding the influence of differences in cerebrovascular structure and function between males and females will provide essential insight into the rationale to identify new pharmaceutical targets to improve treatment of CVD. In the present study, we compared sex differences of the structure and function of the middle cerebral artery (MCA, M2) in young healthy SD rats. We found that female rats had a thinner vascular wall and a smaller inner diameter of MCA compared to males. However, there was no significant difference in the wall-to-lumen ratio between sexes. Female MCAs exhibited less vascular smooth muscle cell (VSMC), more elastin and less collagen I content per wall cross-sectional area than males detected by confocal microscopy using immunostaining as well as protein expression by Western blot. Female SD rats had elevated vascular tone, lower MCA distensibility, and higher wall stress. In addition, the stress/strain curves shifted to the left compared to males. Primary cerebral VSMCs isolated from females displayed lower contractile capabilities than males using a collagen-based cell contraction assay. The diameter of the MCA in males decreased by 14.7 ± 2.0% when perfusion pressure was increased from 40 to 180 mmHg. In contrast, the MCA in females failed to constrict under the same pressure changes. Female MCAs had a greater response to Ach than males. Cerebral blood flow (CBF) measured by laser Doppler flowmetry rose by 27.7 ± 4.8% and 57.4 ± 4.4% in males and females, respectively, when perfusion pressure increased from 100-180 mmHg. Functional hyperemia responses using whisker-barrel stimulation and learning and memory examined with eight-arm water maze were not different between males and females. These results demonstrate that there are intrinsic structural differences in the MCA between sexes, which lead to decreased cerebral vascular reactivity and CBF autoregulation to elevations in pressures in females. The structural differences do not alter neurovascular coupling and cognition at a young age; however, they might play a role in the development of CVD after menopause.

Ameliorated healing of biliary anastomosis by autologous adipose-derived stem cell sheets.

IntroductionCell sheets consisting of adipose-derived stem cells (ADSCs) have been reported to be effective for wound healing. We conducted this study to clarify the efficacy of ADSC sheets in wound healing at the duct-to-duct biliary anastomotic site in pigs.MethodsEleven female pigs (20–25 kg) were divided into two groups: biliary anastomosis with an ADSC sheet (n = 6) or without an ADSC sheet (n = 5). To follow the transplanted ADSCs, PKH26GL-labeled sheets were used in one of the ADSC pigs. Two weeks prior to laparotomy, ADSCs were isolated from the lower abdominal subcutaneous adipose tissue. After three passages, ADSCs were seeded on temperature-responsive culture dishes and collected as cell sheets. ADSC sheets were gently transplanted on the anastomotic site. We evaluated specimens by PKH26GL labeling, macroscopic changes, infiltration of inflammatory cells, and collagen content.ResultsLabeled ADSCs remained around the bile duct wall. In the no-ADSC group, more adhesion developed at the hepatic hilum as observed during relaparotomy. Histopathological examination showed that the diameter and cross-sectional area of the bile duct wall were decreased in the ADSC group. In the no-ADSC group, a large number of inflammatory cells and more collagen fibers were identified in the bile duct wall.ConclusionsThe present study demonstrated that autologous ADSC sheet transplantation reduced hypertrophic changes in the bile duct wall at the anastomotic site. A long-term follow-up is required to evaluate the efficacy of this mechanism in prevention of biliary anastomotic strictures.

Aortic stiffness is not only associated with structural but also functional parameters of retinal microcirculation

ObjectiveThe aim of the study was to test the hypothesis that alterations in large arteries are associated with microvascular remodelling and decreased retinal capillary blood flow. MethodsThe study group comprised of 88 patients with essential hypertension and 32 healthy controls. Retinal microcirculation was evaluated by scanning laser Doppler flowmetry. Macrovascular changes were assessed on the basis of arterial stiffness measurement (carotid-femoral pulse wave velocity), its hemodynamic consequences (central pulse pressure, augmentation pressure, augmentation index) and intima media thickness of common carotid artery. ResultsPulse wave velocity was inversely correlated to mean retinal capillary blood flow in hypertensive patients (R = −0.32, p < 0.01). This relationship remained significant in multivariate regression analysis after adjustment for age, sex, central systolic blood pressure (BP) and body mass index (β = −31.27, p < 0.001). Lumen diameter (LD) of retinal arterioles was significantly smaller in hypertensive then normotensive subjects (79.4 vs. 83.8, p = 0.03). Central and brachial systolic, diastolic and mean BPs were significantly correlated with LD and outer diameter of retinal arterioles. The relationship between LD and central BPs remained significant in multivariate analysis (β = −0.15, p = 0.03 for cSBP; β = −0.22, p = 0.04 for cDBP; β = −0.21, p = 0.03 for cMBP). Moreover, in a subgroup with cardiac damage central and brachial pulse pressure were positively associated with retinal wall thickness, wall cross sectional area, and wall to lumen ratio. ConclusionIn conclusion, the study provides a strong evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters.

Effect of A Multinutrient Complex on Retinal Microcirculation in Diabetic Patients Investigated Using an Adaptive Optics Retinal Camera.

Alimentary supplements may have beneficial effects on retinal microvasculature in diabetic patients. State-of-the-art imaging techniques were used to assess retinal microcirculation in diabetic patients in an observational study before and after 3 months treatment with a multinutrient complex including resveratrol, vitamins D3, C, E, essential fatty acids, trace elements (zinc and copper) and macular pigments (lutein and zeaxanthin)-Resvega. Fifteen subjects were included in this study. Adaptive optics ophthalmoscopy was used to measure the parameters of temporal retinal arterioles. Optical coherence tomography angiography was employed to assess foveal avascular zone and vessel densities of the superficial capillary plexus, deep capillary plexus and choricapillary plexus. After 3 months of treatment, there was a statistically significant median decrease in wall-to-lumen ratio (p=0.0001). The same tendencies were noticed for wall thickness values (p=0.008) and wall cross sectional area values (p=0.001). On the other side, no significant changes were noticed concerning the OCTA parameters. Resvega seems to have a beneficial effect on the retinal arterioles in diabetic patients.

P4993Tissue sodium concentration emerged as a determinant of hypertrophic vascular remodeling in type 2 diabetes

Abstract Background Studies describe a linkage between greater sodium intake and higher incidence of organ damage and cardiovascular end points. Sodium intake is usually assessed by measuring 24-hour urinary sodium excretion, which is prone to high fluctuation. For the assessment of tissue sodium a new technique (23Na-MRI) has been developed. We analyzed whether tissue sodium is linked to vascular remodeling of small resistance vessels in patients with type-2 diabetes. Methods In patients with type 2 diabetes we assessed tissue sodium content and vascular structural parameters of the retinal arterioles, since structural changes of resistance vessels (150–300 μm) can be non-invasively and reliably assessed in the retinal circulation by Scanning Laser Doppler Flowmetry (SLDF). Patients with antidiabetic medication were off the therapy (antihypertensives were kept constant) for 4 weeks. The structural parameters of retinal arterioles assessed were outer- and inner diameter (OD &amp; ID), wall thickness (WT), wall-to-lumen ratio (WLR) and wall cross sectional area (WCSA). Tissue sodium content was assessed non-invasively with a 3.0 T clinical MRI system in each patient. Subject placed their lower legs in the center of a 23Na knee coil and sodium content in skin and muscle (musculus triceps surae) were measured. Results In patients with type 2 diabetes (N=52) we observed a significant correlation between tissue sodium content (muscle and skin) and OD, WT and WCSA and a trend has been noticed between muscle sodium content and ID and WLR. Multiple linear regression analysis demonstrated that tissue sodium content is a significant determinant of hypertrophic vascular remodeling as indicated by increased WT and WCSA, independent of age, gender and 24-hour ambulatory diastolic blood pressure. Correlation coefficients Muscle sodium content (mmol/l) Skin sodium content (mmol/l) OD (μmol) r=0.402, p=0.003 r=0.299, p=0.033 ID (μmol) r=0.265, p=0.058 r=0.202, p=0.154 WT (μm) r=0.402, p=0.003 r=0.313, p=0.026 WLR r=0.247, p=0.078 r=0.171, p=0.230 WCSA (μm2) r=0.417, p=0.002 r=0.322, p=0.021 Conclusion With the novel 23Na-MRI technology, we could demonstrate that high tissue sodium concentration is linked to with hypertrophic vascular remodeling of retinal arterioles. Thus, the reduction of tissue sodium content may emerge as a therapeutic target.