Subcutaneous Small Arteries Research Articles

Signals From Inflamed Perivascular Adipose Tissue Contribute to Small-Vessel Dysfunction in Women With Human Immunodeficiency Virus.

People with the human immunodeficiency virus (PWH) have microvascular disease. Because perivascular adipose tissue (PVAT) regulates microvascular function and adipose tissue is inflamed in PWH, we tested the hypothesis that PWH have inflamed PVAT that impairs the function of their small vessels. Subcutaneous small arteries were dissected with or without PVAT from a gluteal skin biopsy from 11 women with treated HIV (WWH) aged < 50 years and 10 matched women without HIV, and studied on isometric myographs. Nitric oxide (NO) and reactive oxygen species (ROS) were measured by fluorescence microscopy. Adipokines and markers of inflammation and ROS were assayed in PVAT. PVAT surrounding the small arteries in control women significantly (P < .05) enhanced acetylcholine-induced endothelium-dependent relaxation and NO, and reduced contractions to thromboxane and endothelin-1. However, these effects of PVAT were reduced significantly (P < .05) in WWH whose PVAT released less adiponectin but more markers of ROS and inflammation. Moderation of contractions by PVAT were correlated positively with adipose adiponectin. PVAT from WWH has oxidative stress, inflammation, and reduced release of adiponectin, which may contribute to enhanced contractions and therefore could promote small-artery dysfunction.

Prognostic significance of the wall to lumen ratio of retinal arterioles evaluated by adaptive optics

ObjectiveMicrovascular structural alterations may be considered an important form of hypertension-mediated organ damage. An increased media-to-lumen ratio of subcutaneous small arteries evaluated with locally invasive techniques (micromyography) predicts the development of cardiovascular (CV) events. However, it is not known whether retinal arteriole structural alterations evaluated with a noninvasive approach (Adaptive Optics) may have a prognostic significance. Design and methodsTwo-hundred and thirty-seven subjects (mean age 58.7 ± 16.1 years, age range 13–89 years; 116 males) were included in the study: 65 normotensive subjects (27.4 %) and 172 patients with essential hypertension or primary aldosteronism (72.6 %). All subjects underwent a non-invasive evaluation of retinal arteriolar wall-to-lumen ratio (WLR) by Adaptive Optics. Subjects were re-evaluated after an average follow-up time of 4.55 years in order to assess the occurrence of clinical events (non CV and/or CV death or events). ResultsFifty-four events occurred in the study population:26 were cardio-cerebrovascular events (ischemic or hemorragic stroke, atrial fibrillation, heart failure, coronary artery disease, peripheral artery disease, cardiac valvular disease) while the remaining were deaths for any cause, or neoplastic diseases. Subjects with events were older and had a WLR of retinal arterioles significantly greater than those without events. The event-free survival was significantly worse in those with a baseline WLR above the median value of the population (0.28) according to Kaplan-Mayer survival curves and multivariate analysis (Cox's proportional hazard model). The evidence was confirmed after restricting the analysis to CV events. ConclusionsStructural alterations of retinal arterioles evaluated by Adaptive Optics may predict total and CV events.

RETINAL ARTERIOLAR REMODELING IN PRIMARY ALDOSTERONISM: A STUDY WITH ADAPTIVE OPTICS

Objective: Primary aldosteronism (PA) represents the most frequent form of secondary hypertension. In previous studies an hypertrophic remodeling, with smooth muscle cell growth and an increase in media to lumen ratio (MLR), has been shown in patients with primary aldosteronism (Rizzoni D et al. Hypertension 1996;28:785–790.). To date, Adaptive Optics (AO) is one of the most innovative and non-invasive methods for studying the wall-to-lumen ratio of retinal arterioles (WLR), which directly correlates with the MLR of subcutaneous small arteries (De Ciuceis C et al. J Hypertens. 2018;36(5):1154-1163.). Design and method: Therefore, the aim of this study was to evaluate microvascular structure of retinal arterioles by Adaptive Optics in PA patients, before and after pharmacological or surgical treatment, compared to essential hypertensive patients (EH). Eleven patients with PA before treatment have been matched with 11 patients with EH and 11 patients with treated PA in follow up. All patients underwent assessment of retinal microcirculation morphology with AO (RTX-1, Imagine Eyes; Orsay, FR) in order to calculate WLR and wall cross sectional area (WCSA). Results: A total of 33 patients was enrolled in the study. PA patients at the baseline showed a significant higher WLR compared to EH and to PA in follow-up (Figure 1; 0.31±0.03 vs 0.27±0.04 vs 0.275±0.03 respectively; p = 0.01). Otherwise, differences between WCSA turned out to be less relevant with no significant differences among the three groups (4500.85±879.9 vs 4195.96±553.3 vs 4278.52±836.6 respectively; p = ns). Conclusions: Our data confirm with a non-invasive technique the presence of a more evident retinal arterioles remodeling in PA patients compared to EH patients, as suggested by the increased WLR, and an improvement in WLR after PA surgical or pharmacological treatment. Further studies in a larger population are needed in order to confirm these data.

Distinct transcriptomic profile of small arteries of hypertensive patients with chronic kidney disease identified miR-338-3p targeting GPX3 and PTPRS.

Hypertension is associated with vascular injury, which contributes to end-organ damage. MicroRNAs regulating mRNAs have been shown to play a role in vascular injury in hypertensive mice. We aimed to identify differentially expressed microRNAs and their mRNA targets in small arteries of hypertensive patients with/without chronic kidney disease (CKD) to shed light on the pathophysiological molecular mechanisms of vascular remodeling. Normotensive individuals and hypertensive patients with/without CKD were recruited ( n = 15-16 per group). Differentially expressed microRNAs and mRNAs were identified uniquely associated with hypertension (microRNAs: 10, mRNAs: 68) or CKD (microRNAs: 68, mRNAs: 395), and in both groups (microRNAs: 2, mRNAs: 32) with a P less than 0.05 and a fold change less than or greater than 1.3 in subcutaneous small arteries ( n = 14-15). One of the top three differentially expressed microRNAs, miR-338-3p that was down-regulated in CKD, presented the best correlation between RNA sequencing and reverse transcription-quantitative PCR (RT-qPCR, R2 = 0.328, P < 0.001). Profiling of human aortic vascular cells showed that miR-338-3p was mostly expressed in endothelial cells. Two of the selected top nine up-regulated miR-338-3p predicted targets, glutathione peroxidase 3 ( GPX3 ) and protein tyrosine phosphatase receptor type S ( PTPRS ), were validated with mimics by RT-qPCR in human aortic endothelial cells ( P < 0.05) and by a luciferase assay in HEK293T cells ( P < 0.05). A distinct transcriptomic profile was observed in gluteal subcutaneous small arteries of hypertensive patients with CKD. Down-regulated miR-338-3p could contribute to GPX3 and PTPRS up-regulation via the canonical microRNA targeting machinery in hypertensive patients with CKD.

Vascular dysfunction and increased cardiovascular risk in hypospadias.

AimsHypogonadism is associated with cardiovascular disease. However, the cardiovascular impact of hypogonadism during development is unknown. Using hypospadias as a surrogate of hypogonadism, we investigated whether hypospadias is associated with vascular dysfunction and is a risk factor for cardiovascular disease.Methods and resultsOur human study spanned molecular mechanistic to epidemiological investigations. Clinical vascular phenotyping was performed in adolescents with hypospadias and controls. Small subcutaneous arteries from penile skin from boys undergoing hypospadias repair and controls were isolated and functional studies were assessed by myography. Vascular smooth muscle cells were used to assess: Rho kinase, reactive oxygen species (ROS), nitric oxide synthase/nitric oxide, and DNA damage. Systemic oxidative stress was assessed in plasma and urine. Hospital episode data compared men with a history of hypospadias vs. controls. In adolescents with hypospadias, systolic blood pressure (P = 0.005), pulse pressure (P = 0.03), and carotid intima-media thickness standard deviation scores (P = 0.01) were increased. Arteries from boys with hypospadias demonstrated increased U46619-induced vasoconstriction (P = 0.009) and reduced acetylcholine-induced endothelium-dependent (P < 0.0001) and sodium nitroprusside-induced endothelium-independent vasorelaxation (P < 0.0001). Men born with hypospadias were at increased risk of arrhythmia [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.4–5.6, P = 0.003]; hypertension (OR 4.2, 95% CI 1.5–11.9, P = 0.04); and heart failure (OR 1.9, 95% CI 1.7–114.3, P = 0.02).ConclusionHypospadias is associated with vascular dysfunction and predisposes to hypertension and cardiovascular disease in adulthood. Underlying mechanisms involve perturbed Rho kinase- and Nox5/ROS-dependent signalling. Our novel findings delineate molecular mechanisms of vascular injury in hypogonadism, and identify hypospadias as a cardiovascular risk factor in males.

Abstract MP60: Down-regulated Mir-338-3p In Subcutaneous Small Arteries Of Hypertensive Patients With Chronic Kidney Disease Targets Protein Tyrosine Phosphatase Receptor Type S And Glutathione Peroxidase 3

Background: Hypertension (HTN) causes vascular injury identified by endothelial dysfunction, vascular stiffening, and remodeling, which contributes to kidney damage leading to chronic kidney disease (CKD). MicroRNAs (miRNAs) repress/degrade target mRNAs. Their role in vascular injury in HTN remains unclear. We aimed to identify differentially expressed (DE) miRNAs in gluteal subcutaneous arteries of patients with HTN associated or not with CKD to shed light on the pathophysiological molecular mechanisms. Methods: Normotensive subjects and patients with HTN associated or not with CKD grades 3-4 were studied (n=15-16). Small arteries were isolated from gluteal subcutaneous biopsies, RNA extracted and small and total RNA sequencing performed by Illumina HiSeq-2500. DE genes were identified with a P &lt;0.05 and fold change (FC) &gt;1.3. Top 3 DE miRNAs ( P &lt;0.001, FC&gt;2, mean read count number (MRCN) &gt;3,000 in all groups and having predicted mRNA targets) were selected for validation by reverse transcription-quantitative PCR (RT-qPCR). The mRNA targets of the top selected miRNA were predicted by TargetScan with P &lt;0.01, FC&gt;1.5 and MRCN&gt;150 and the top 9 targets were validated by RT-qPCR using gain- and loss-of-function in human aortic endothelial cells (HAECs). Gene ontology enrichment analysis (GOEA) was done in Cytoscape. Results: DE miRNAs and mRNAs were identified uniquely associated with HTN (miRNAs: 10, mRNAs: 68), CKD (miRNAs: 68, mRNAs: 395), and in both groups (miRNAs: 2, mRNAs: 32). miR-338-3p presented the best correlation between RNA sequencing and RT-qPCR (R 2 =0.328, P &lt;0.001) among the top 3 DE miRNAs. Two of the selected top 9 miR-338-3p predicted targets were validated in HAECs. Protein tyrosine phosphatase receptor type S ( PTPRS , FC: 0.80±0.08 vs 1.00±0.00) and glutathione peroxidase 3 ( GPX3 , FC: 0.88±0.04 vs 1.00±0.00) were down-regulated in HAECs transfected with miR-338-3p mimics ( P &lt;0.05). GOEA showed association of GPX3 with oxidative stress detoxification ( q &lt;0.05), and of PTPRS with the immune system, neuronal system and developmental process ( q &lt;0.001). Conclusion: Down-regulated miR-338-3p in gluteal subcutaneous small arteries of hypertensive patients with CKD targets PTPRS and GPX3 that may play a role in vascular injury in HTN.

Abstract P3003: miR-338-3p Down-Regulation Caused Up-Regulation of Alkaline Ceramidase 2 and Glutathione Peroxidase 3 mRNAs in Subcutaneous Small Arteries of Hypertensive Patients With Chronic Kidney Disease

Background: Hypertension (HTN) and chronic kidney disease (CKD) are associated with vascular damage characterized by vascular remodeling and stiffening and endothelial dysfunction. miRNAs are small non-coding RNA that regulate gene expression by binding to their target messenger RNAs (mRNAs), leading to mRNA degradation or translational repression. Their implication in vascular injury remains unclear. We aimed to identify differentially expressed (DE) miRs in small arteries of HTN and CKD human subjects to gain insight into pathophysiological molecular mechanisms in these conditions. Methods: Normotensive, HTN [systolic blood pressure (BP) &gt;135 mmHg or diastolic BP of 85-115 mmHg with BpTRU] and CKD subjects (estimated glomerular filtration rate &lt;60mL/min/m 2 ) (n=15-16) were studied. Small arteries were isolated from subcutaneous gluteal biopsies and RNA extracted for small and total RNA sequencing using Illumina HiSeq-2500 and further studied using a systems biology approach. Differentially expressed (DE) genes were identified with fold change &gt;1.5 and fold discovery rate &lt;0.1. Results: DE miRs were identified ( P &lt;0.05) uniquely associated with HTN (3↑ and 6↓) or CKD (42↑ and 39↓) or both groups (2↓). Correlation between RNA-sequencing and RT-qPCR data was demonstrated for 3 of 14 tested miRs. Among them, the first-ranked, miR-338-3p ( r =0.91, P &lt;10 -16 ), uniquely associated with CKD, was studied further. miR-338-3p and some of its predicted targets were highly expressed in human aortic endothelial cells (HAECs). Two of them, alkaline ceramidase 2 ( ACER2 ) and glutathione peroxidase 3 (GPX3), were up-regulated by ~36% and ~60% in HAECs transfected with anti-miR-338-3p, respectively ( P &lt;0.05). miR-338-3p mimic co-transfection decreased by 30% luciferase activity of reporter vectors containing the conserved wild-type but not mutated ACER2 or GPX3 3’ untranslated transcribed region miR-338-3p-5p binding sites ( P &lt;0.05). Conclusion: miR-338-3p was down-regulated in small arteries, which was uniquely associated with CKD. ACER2 and GPX3 , identified as miR-338-3p targets, may play a role in vascular injury in CKD.

Calciphylaxie dans un contexte de maladie de Basedow : à propos d’un cas

BackgroundCalciphylaxis or calcific uremic arteriolopathy (CUA) is a cutaneous disease with ulcerations secondary to calcification of cutaneous and subcutaneous small arteries and arterioles. It is a rare but severe disease with significant morbidity and mortality affecting 1 to 4% of dialysis patients. The circumstances of occurrence are multiple. CaseWe report the case of a severe bilateral lower limb calciphylaxis in a 69-year-old, obese, hemodialysis patient with a recent diagnosis of Graves’ disease complicated with hypercalcemia and cardiac arrhythmia requiring the use of vitamin K antagonist. Complex and multidisciplinary therapeutic management (daily hemodialysis, sodium thiosulfate therapy, treatment of hypercalcemia by denosumab, hyperbaric oxygen therapy, meshed skin autograft) allowed complete healing of the lesions. ConclusionThis is the first description of AUC secondary to hyperthyroidism in a dialysis patient. Multidisciplinary care is essential to achieve clinical improvement in those critical situations.

Abstract P120: Mir-338-3p is Down-regulated in Subcutaneous Small Arteries of Hypertensive Patients With Chronic Kidney Disease

Background: Hypertension (HTN) and chronic kidney disease (CKD) are among the most prevalent global health conditions that cause millions of deaths per year. They are associated with vascular damage characterized by vascular remodeling, stiffening and endothelial dysfunction. miRNAs (miRs) are a class of small non-coding RNA that regulate gene expression by binding to their target messenger RNAs (mRNAs), thereby leading to mRNA degradation or translational repression. Their implication in vascular injury remains unclear. We aimed to identify differentially expressed (DE) miRs in small arteries of HTN and CKD human subjects to gather insight into pathophysiological molecular mechanisms in these conditions. Methods and Results: Normotensive, HTN [systolic blood pressure (BP) &gt;135 mmHg or diastolic BP of 85-115 mmHg with BpTRU] and CKD subjects (eGFR&lt;60mL/min/m 2 ) (n=15-16) were studied. Small arteries were isolated from subcutaneous gluteal biopsies and RNA extracted for small and total RNA sequencing using Illumina HiSeq-2500. EdgeR identified DE miRs ( P &lt;0.05) uniquely associated with HTN (3 up and 6 down) or CKD (42 up and 39 down) or with both groups (2 down). Reverse transcription-quantitative PCR (RT-qPCR) was used to confirm miRNA differential expression. Correlation between RNA sequencing and RT-qPCR data was demonstrated for 3 miRs from 14 tested: mir-146a-5p (r=0.56, P &lt;10 -4 ), miR-338-3p (r=0.91, P &lt;10 -16 ) and mir-374a-3p (r=0.57, P &lt;10 -4 ). The best correlated DE miRNA, miR-338-3p was down-regulated by 76% ( P &lt;10 -4 ) and uniquely associated with CKD. TargetScan predicted that the up-regulated mRNA encoding glutathione peroxidase 3 ( GPX3 , 1.57 fold, P &lt;0.001) to be a miR-338-3p target. Both miR-338-3p and GPX3 were found to be highly expressed in human aortic endothelial cells (HAECs) by RT-qPCR. Target prediction was validated by showing using RT-qPCR that GPX3 expression was up-regulated 1.73±0.28 fold in HAECs transfected with anti-miR-338-3p ( P &lt;0.05). Conclusion: miR-338-3p down-regulation was found in small arteries, uniquely associated with CKD. GPX3 , which may be important for preservation of endothelial function, is a miR-338-3p potential target. miR-338-3p and associated target may play a role in vascular remodeling in CKD.

Changes in extracellular matrix in subcutaneous small resistance arteries of patients with essential hypertension

Background: In the development of hypertensive microvascular remodeling, a relevant role may be played by changes in extracellular matrix proteins. Aim of this study was the to evaluate some extracellular matrix components within the tunica media of subcutaneous small arteries in 9 normotensive subjects and 12 essential hypertensive patients, submitted to a biopsy of subcutaneous fat from the gluteal or the anterior abdominal region.Patients and Methods: Subcutaneous small resistance arteries were dissected and mounted on an isometric myograph, and the tunica media to internal lumen ratio was measured. In addition, fibronectin, laminin, transforming growth factor-beta-1 (TGF-β1) and emilin-1 contents within the tunica media were evaluated by immunofluorescence and relative immunomorphometrical analysis (immunopositivity % of area). The total collagen content and collagen subtypes within the tunica media were evaluated using both Sirius red staining (under polarized light) and immunofluorescence assay.Results: Normotensive controls had less total and type III collagen in respect with hypertensive patients. Fibronectin and TGF-β1 tunica media content was significantly greater in essential hypertensive patients, compared with normotensive controls, while laminin and emilin-1 tunica media content was lesser in essential hypertensive patients, compared with normotensive controls. A significant correlation was observed between fibronectin tunica media content and media to lumen ratio.Conclusions: Our results indicate that, in small resistance arteries of patients with essential hypertension, a relevant fibrosis may be detected; fibronectin and TGF-β1 tunica media content is increased, while laminin and emilin-1 content is decreased; these changes might be involved in the development of small resistance artery remodeling in humans.

New Methods to Study the Microcirculation.

Essential hypertension is associated with structural alterations in the microvessels; in particular, an increase in the media thickness to internal lumen ratio of small resistance arteries (MLR) and a reduction in capillary density have been observed. The evaluation of the morphological characteristics of small resistance arteries in humans is challenging. The gold-standard method is generally considered to be the measurement by wire or pressure micromyography of MLR of subcutaneous small vessels obtained by local biopsies. However, noninvasive techniques for the evaluation of retinal arterioles were recently proposed; in particular, 2 approaches, scanning laser Doppler flowmetry (SLDF) and adaptive optics (AO), seem to provide useful information. Both of them provide an estimation of the wall to lumen ratio (WLR) of retinal arterioles. Moreover, a noninvasive measurement of basal and total capillary density may be obtained by videomicroscopy/capillaroscopy. It has been recently demonstrated that AO has a substantial advantage over SLDF in terms of evaluation of microvascular morphology, since WLR measured with AO is more closely correlated with the M/L of subcutaneous small arteries. The possibility to noninvasively assess in a reliable way, microvascular morphology in a clinical setting may represent a major advancement, since micromyography has substantial limitations in its application due to the local invasiveness of the procedure.

Abnormal Remodeling of Subcutaneous Small Arteries Is Associated With Early Diastolic Impairment in Metabolic Syndrome

BackgroundSmall artery pathophysiology is frequently invoked as a cause of obesity‐related diastolic heart failure. However, evidence to support this hypothesis is scant, particularly in humans.Methods and ResultsTo address this, we studied human small artery structure and function in obesity and looked for correlations between vascular parameters and diastolic function. Seventeen obese patients with metabolic syndrome and 5 control participants underwent echocardiography and subcutaneous gluteal fat biopsy. Small arteries were isolated from the biopsy and pressure myography was used to study endothelial function and wall structure. In comparison with the control group, small arteries from obese participants exhibited significant endothelial dysfunction, assessed as the vasodilatory response to acetylcholine and also pathological growth of the wall. For the obese participants, multiple regression analysis revealed an association between left atrial volume and both the small artery wall thickness (β=0.718, P=0.02) and wall‐to‐lumen ratio (β=0.605, P=0.02). Furthermore, the E:E′ ratio was associated with wall‐to‐lumen ratio (β=0.596, P=0.02) and inversely associated with interleukin‐6 (β=−0.868, P=0.03). By contrast, endothelial function did not correlate with any of the echocardiographic parameters studied.ConclusionsAlthough the small arteries studied were not cardiac in origin, our results support a role for small artery remodeling in the development of diastolic dysfunction in humans. Further direct examination of the structure and function of the myocardial resistance vasculature is now warranted, to elucidate the temporal association between metabolic risk factors, small artery injury, and diastolic impairment.

Relationship Between Different Subpopulations of Circulating CD4+ T-lymphocytes and Microvascular Structural Alterations in Humans.

Different components of the immune system, including innate and adaptive immunity (T-effector lymphocytes and T-regulatory lymphocytes-TREGs) may be involved in the development of hypertension. In addition, it was demonstrated in animal models that TREGs may prevent angiotensin II-induced hypertension and vascular injury/inflammation. However, no data are presently available in humans about possible relationships between T-lymphocyte subtypes and microvascular structural alterations. For this purpose, in the present study, we enrolled 24 normotensive subjects and 12 hypertensive patients undergoing an elective surgical intervention. No sign of local or systemic inflammation was present. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph and the media to lumen ratio (M/L) was calculated. In addition, retinal arteriolar structure was evaluated noninvasively by scanning laser Doppler flowmetry. Capillary density in the nailfold, dorsum of the finger, and forearm were evaluated by videomicroscopy. A peripheral blood sample was obtained before surgery for assessment of T-lymphocyte subpopulations by flow cytometry. Significant negative correlations were observed between indices of microvascular structure (M/L of subcutaneous small arteries and wall to lumen ratio of retinal arterioles) and circulating TREG lymphocytes. A direct correlation was observed between M/L of subcutaneous small arteries and circulating Th17 lymphocytes. In addition, total capillary density was correlated with a TREG effector memory subpopulation. Our data suggest that some lymphocyte subpopulations may be related to microvascular remodeling, confirming previous animal data, and opening therapeutic possibilities.

Insulin-increased endothelial l-arginine/no signalling pathway requires A2B adenosine receptors activation in human umbilical vein endothelium from late-onset preeclampsia

OBJECTIVE: The aim of the study was to investigate bradykinin-mediated vasodilator function in small arteries from normotensive pregnant and nonpregnant women and from women with preeclampsia. STUDY DESIGN: Small subcutaneous arteries (approximately 250 μm luminal diameter) were dissected from biopsy specimens obtained at cesarean section from 24 normotensive pregnant women and 6 women with preeclampsia and during abdominal surgery in 15 nonpregnant women. Vascular function was assessed after arteries were mounted on a small vessel myograph. RESULTS: Preconstricted arteries from normotensive pregnant women demonstrated enhanced relaxation to bradykinin compared with those from nonpregnant women (p < 0.05), whereas arteries from women with preeclampsia showed blunted responses compared with those from normotensive pregnant women (p < 0.01). Relaxation in all groups was attenuated in the presence of the nitric oxide synthase inhibitor Nω-nitro-l-arginine so that it became similar in the three groups. Indomethacin had a small but significant inhibitory effect on bradykinin-induced relaxation, but this component of relaxation was no different among groups. Sensitivity of arteries to norepinephrine and sodium nitroprusside showed no significant differences in the three groups of women. CONCLUSION: This study provides evidence for an increase in bradykinin-mediated nitric oxide synthesis from the vascular endothelium of small arteries from the peripheral circulation of normotensive pregnant women and a relative reduction in women with preeclampsia. In turn, these changes may contribute to vasodilation in normal pregnancy and elevation of the blood pressure in preeclampsia. (Am J Obstet Gynecol 1996;175:1668-74.)

Effects of a long-term treatment with aliskiren or ramipril on structural alterations of subcutaneous small-resistance arteries of diabetic hypertensive patients.

Structural alterations of subcutaneous small-resistance arteries are associated with a worse clinical prognosis in hypertension and non-insulin-dependent diabetes mellitus. The effects of the direct renin inhibitor aliskiren on microvascular structure were never previously evaluated. Therefore, we investigated the effects of aliskiren in comparison with those of an extensively used angiotensin-converting enzyme inhibitor, ramipril, on peripheral subcutaneous small-resistance artery morphology, retinal arteriolar structure, and capillary density in a population of patients with non-insulin-dependent diabetes mellitus. Sixteen patients with mild essential hypertension and with a previous diagnosis of non-insulin-dependent diabetes mellitus were included in the study. Patients were then randomized to 1 of the 2 active treatments (aliskiren 150 mg once daily, n=9; or ramipril 5 mg once daily, n=7). Each patient underwent a biopsy of the subcutaneous fat from the gluteal region, an evaluation of retinal artery morphology (scanning laser Doppler flowmetry), and capillary density (capillaroscopy), at baseline and after 1 year of treatment. Subcutaneous small arteries were dissected and mounted on a pressurized micromyograph, and the media-to-lumen ratio was evaluated. A similar office blood pressure-lowering effect and a similar reduction of the wall-to-lumen ratio of retinal arterioles were observed with the 2 drugs. Aliskiren significantly reduced media-to-lumen ratio of subcutaneous small-resistance arteries, whereas ramipril-induced reduction of media to lumen ratio was not statistically significant. No relevant effect on capillary density was observed. In conclusion, treatment with aliskiren or ramipril was associated with a correction of microvascular structural alterations in patients with non-insulin-dependent diabetes mellitus.

Blood pressure and retinal small arteries

Blood pressure and retinal small arteries

Relationship between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles evaluated noninvasively by scanning laser Doppler flowmetry

Structural alterations of subcutaneous small resistance arteries, as indicated by an increased media-to-lumen ratio, are frequently present in hypertensive and/or diabetic patients, and may represent the earliest alteration observed. Furthermore, media-to-lumen ratio of small arteries evaluated by micromyography has a strong prognostic significance; however, its extensive evaluation is limited by the invasivity of the assessment, since a biopsy of subcutaneous fat is needed. Noninvasive measurement of wall-to-lumen of retinal arterioles using scanning laser Doppler flowmetry (SLDF) has recently been introduced. However, this new technique has not yet been compared to micromyographic measurement, generally considered the gold standard approach. We investigated 40 individuals and patients, 24 of them were hypertensive patients and 16 normotensive individuals. All patients underwent a biopsy of subcutaneous fat during an elective surgical intervention. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, and media-to-lumen ratio was measured. In addition, an evaluation of wall-to-lumen ratio of retinal arterioles by SLDF was performed (Heidelberg Retina Flowmeter, Heidelberg Engineering). A close correlation was observed between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles (r = 0.76, P < 0.001; P < 0.001, r(2) = 0.57). A noninvasive and easily repeatable procedure (intraobserver and interobserver variation coefficient <13%) such as an evaluation of the arterioles in the fundus oculi by SLDF may provide similar information regarding microvascular morphology compared with an invasive, accurate and prognostically relevant micromyographic measurement of media-to-lumen ratio of subcutaneous small arteries.

Wall-to-lumen ratio of retinal arterioles

Wall-to-lumen ratio of retinal arterioles

Vascular Remodeling in Hypertension

Over the past few years noninvasive and invasive techniques have allowed a better appreciation of vascular changes in hypertensive humans and experimental animals.1 Large arteries undergo outward hypertrophic remodeling and increased stiffness with aging,2–4 and in hypertension there may be an acceleration of this process leading to enhanced pulse pressure. A reduced aortic diameter in middle-aged hypertensive subjects may also play a role in increases in pulse pressure through increased specific impedance,5 contradicting the classic hypertensive aortic phenotype characterized by vascular wall degeneration and calcification and increased aortic diameter. In advanced hypertension, however, the elastic laminae undergo duplication and fragmentation, with increased deposition of collagen and fetal (EIIIA) fibronectin, contributing to increased stiffness. Classically the remodeling of small arteries in hypertension has been associated with increased media thickness, but recent studies have demonstrated that 2 types of remodeling are found, inward eutrophic or inward hypertrophic remodeling, depending on whether the media cross-sectional area is enlarged (true hypertrophy).6–9 Although eutrophic remodeling is usually found in essential (primary) hypertension in humans and spontaneously hypertensive rats (SHRs); in secondary hypertension such as in renovascular hypertension, primary aldosteronism, or in pheochromocytoma10; in hypertension associated with diabetes mellitus11,12; and in acromegaly,13 hypertrophic remodeling has been described. In mineralocorticoid hypertension in rodents14,15 and in salt-sensitive Dahl rats,16 in both of which the endothelin (ET) system is activated, remodeling of small arteries is also hypertrophic (see below). Thus, when the renin-angiotensin system is even mildly activated (primary hypertension and SHRs), remodeling is usually eutrophic. In salt-dependent hypertension, diabetes mellitus, and malignant hypertension, all conditions in which the ET system is activated, remodeling is hypertrophic.17 Hyperplasia of vascular smooth muscle cells (VSMCs) is found in small arteries of …

Investigation of the effects induced on endothelial function by the human T2238C ANP gene molecular variant

s 153 Clinica Medica, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy Clinica Chirurgica, Department of Medical and Surgical Sciences, University of Brescia, Brescia, Italy Chair of Ophthalmology, University of Brescia, Brescia, Italy Chair of Ophthalmology, University of Molise, Campobasso, Italy Chair of Ophthalmology, University of Ferrara, Ferrara, Italy Structural alterations of subcutaneous small resistance arteries, as indicated by an increased media to lumen (M/L) ratio, are frequently present in hypertensive and/or diabetic patients, and may represent the earliest alteration observed. In addition, M/L of small arteries evaluated by micromyography has a strong prognostic significance; however its extensive evaluation is limited by the invasivity of the assessment, since a biopsy of subcutaneous fat is needed. Non-invasive measurement of wall to lumen (W/L) of retinal arterioles using scanning laser doppler flowmetry (SLDF) has been recently introduced (Harazny J et al, Hypertension 2007; 50:623-629). However, this new technique was never compared with micromyographic measurement, considered the gold standard approach. Methods and Results: We have investigated 37 subjects and patients. Twenty-three of them were hypertensives and 14 normotensives. Blood pressure values were 139/88 17/10 mmHg and 125/71 17/12 mm Hg, respectively (p<0.05). All patients underwent a biopsy of subcutaneous fat during an elective surgical intervention. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, and M/L was measured. In addition, an evaluation of W/L of retinal arterioles by SLDF was performed (Heidelberg Retina Flowmeter, Heidelberg Engineering). A close correlation was observed between M/L of subcutaneous small arteries and WL of retinal arterioles: rZ0.77, p<0.001 (see Figure). Conclusion: A non invasive and easily repeatable procedure (intraobserver and interobserver variation coefficient around 10%) such as an evaluation of the arterioles in the fundus oculi by SDLF may provide similar information regarding microvascular morphology compared in respect with an invasive, accurate and prognostically relevant micromyographic measurement of M/L. y = 6,5298x 0,234 R2 = 0,5902 0,00 0,10 0,20 0,30 0,40 0,50 0,60 0,70 0,80 0,04 0,06 0,08 0,10 0,12 0,14 0,16