Early Vascular Alterations Research Articles

Abstract 4136025: Establishing normal values for central systolic blood pressure and augmentation index in healthy young people

Background: The process of cardiovascular disease (CVD), a leading cause of death worldwide, commences in childhood. Increasing evidence indicates that early exposure to CVD risk factors in childhood is associated with impaired arterial distensibility and other vascular alterations, suggesting that vascular ageing biomarkers, that capture the deterioration in vascular structure and function, can be used to identify children at risk. However, the identification of early vascular alterations in the young is hampered by the lack of a recognized, vascular biomarker that can be used in clinical practice. The Youth Vascular Consortium, an international collaborative open resource has been established to answer these gaps by analysing different biomarkers, including central systolic blood pressure (cSBP) and augmentation index (AIx). These two non-invasive measures are related to CVD and end-organ damage, however, their assessment in clinical practice is limited by the lack of established normal values. Aims: We aimed to establish cSBP and AIx normal values in a young, healthy, international population. Methods: The Consortium collected data on 36,973 participants from 24 countries. We included 14,476 and 5,047 subjects respectively for the cSBP and AIx populations. Subjects were free of any CVD or cardiovascular risk factors. Data were collected from participants aged from 1 to 40 years. Normal values of cSBP and AIx were calculated as percentiles stratified by age and sex. Percentiles curves were generated using generalised additive models. Results: The cSBP percentile curves increase with the same trend for both males and females until age 13 years. Over this age, males experience greater cSBP than females. This is in contrast to AIx, which decreases with the same trend in both sexes until 15 years of age, after which females experience increased AIx. Conclusion: Normal values of cSBP and AIx in healthy young are now available according to age and sex with a wide geographical representation. Incorporating these values into clinical practice for young could facilitate their utilization as targets for the introduction and monitoring of interventions.

SPECTRUM AND CHARACTERISTICS OF THE ELECTROCARDIOGRAPHIC CHANGES IN CHILDREN WITH TYPE I DIABETES MELLITUS

Introduction. Type I diabetes mellitus (T1D) is one of the most widespread and socially significant diseases. Well-known as a co-occurring condition with youth-onset type 1 diabetes mellitus, cardiovascular disease manifests early after initial diagnosis as signs of cardiovascular remodeling. Growing data indicates that type 1 diabetic children and young adults experience subclinical heart dysfunction, central aortic stiffening, and accelerated peripheral vascular disease. Increased morbidity and mortality in adults have been linked to peripheral artery, heart, and cerebrovascular diseases, and early vascular alterations have been demonstrated to exist since childhood. Little is known to date concerning the development of early cardiac structural and functional problems in children with T1D. Early diagnostic is of high importance. Aim. To assess the frequency and spectrum of electrocardiography (ECG) abnormalities in children with type 1 diabetes. Materials and methods. Records of 60 patients with type I diabetes included into the analysis. ECG data, main anamnestic, clinical and laboratory data analyzed. Results. So-called "small ECG abnormalities" were found. Incomplete left/right blockade bundle branch block found in 22.5% of children, shortened PQ interval in 15%, extrasystoles, tachycardia, bradycardia in 52.5%, T wave amplitude decrease in 60%. 87.5% of the examinees have a combination of 2–3 of the above changes on the ECG. Only 12% of the examined children had an ECG without pathological changes. All children with newly diagnosed type 1 DM had at least 1 of the described ECG abnormalities. Correlation analysis done. Substantial positive correlations between Hb1Ac levels and number of ECG changes, serum cholesterol levels and number of ECG changes were found. Conclusions. The results of the study indicate that the majority of children with type I diabetes have so-called "small ECG abnormalities." According to the type of disturbances, they can be classified as rhythm and conduction disturbances and combined changes. These findings are promising in terms of management tactics for children with type I diabetes, early detection and timely therapeutic correction of ECG abnormalities.

Early remodeling and loss of light-induced dilation of retinal small arteries in CADASIL

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1–2 μm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity.

The Assessment of Radial Peripapillary Capillary Vessel Density in Adult Children of Patients With Primary Open Angle Glaucoma.

The observed decrease in radial peripapillary capillary vessel density among adult children of individuals with primary open angle glaucoma, in comparison to controls, suggests the possibility of early microvascular alterations in the eyes of these at-risk individuals. To compare the radial peripapillary capillary vessel density (RPCVD) and peripapillary retinal nerve fiber layer (RNFL) thickness values of eyes between healthy adults with a maternal or paternal history of primary open angle glaucoma (POAG) and age-matched healthy controls without a family history of POAG. RPCVD values and RNFL thicknesses in the peripapillary region and 4 quadrants (superior, inferior, nasal, and temporal) were evaluated using optical coherence tomography angiography among 30 adult children of patients with POAG and 30 age-matched healthy controls without a family history of POAG. The mean whole image RPCVD (51.6±1.7% vs. 49.8±1.7%, P =0.0006) and average RPCVD (54.7±1.7% vs. 53.2±2.1%, P =0.006) values were significantly lower in the adult children of patients with POAG compared with age-matched healthy controls without a family history of POAG. There was no difference in terms of RNFL thickness values in any region. Despite having similar RNFL thickness values to the control group, the observation of lower RPCVD in the eyes of adult children of POAG patients may indicate potential early vascular alterations. The result of the present study encourages further longitudinal studies to determine the potential importance of the underlying vascular alterations in these high-risk individuals.

Effect of repeatedly applied cold water immersion on subclinical atherosclerosis, inflammation, fat accumulation and lipid profile parameters of volunteers.

Significant acute cardiovascular, metabolic, and endocrine changes have been traced to short-lasting cold water immersion (CWI); however, the long-term impact of recurrent CWI on atherogenesis, lipid parameters, and fat distribution has not yet been studied. The goal of this study was to investigate the alleged protective effect. A total of 35 healthy volunteers were monitored for a period of 5 months during which the CWI was performed under standardized conditions (three times per week for 7-10 min, without neoprene equipment). Volunteers with measured weight or muscle mass increases of more than 5% were ineligible. An analogous control group (N = 30) was included. At the onset and completion of the study, blood samples were obtained, and clinical assessments took place. PCSK9 and hsCRP levels were measured together with other lipid-related and non-lipid-related indicators. Carotid intima-media thickness test (cIMT) and echo-tracking for the identification of arterial stiffness (PWV, AI, and β) were used to identify early vascular alterations. Hepatorenal index (HRI) calculations served to quantify liver steatosis, while changes in subcutaneous and visceral fat thickness were used to quantify fat distribution. The given protocol was successfully completed by 28volunteers. Long-term repeated CWI resulted in asignificant decline in cIMT (p = 0.0001), AI (p = 0.0002), Beta (p = 0.0001), and PWV (p = 0.0001). PCSK9 (p = 0.01) and hsCRP (p = 0.01) showed asignificant decrease when compared to initial values. In comparison to the starting values, liver fat accumulation decreased by 11% on average (HRI p = 0.001). LDL, TC, TG, and VLDL levels all significantly decreased as well. We suggest that repeated CWI may have beneficial impact on lipid, non-lipid, and lipid-related indices, as well as atherogenesis and liver fat storage.

Unveiling the Silent Danger of Childhood Obesity: Non-Invasive Biomarkers Such as Carotid Intima-Media Thickness, Arterial Stiffness Surrogate Markers, and Blood Pressure Are Useful in Detecting Early Vascular Alterations in Obese Children.

Obese children present a higher cardio-metabolic risk. Measuring vascular biomarkers that assess the evolution of arterial stiffness, subclinical atherosclerosis, and hypertension in such patients could be helpful in the long term. We studied 84 children, aged from 6 to 18 years: 50 obese subjects, versus 34 of normal weight. Clinical examination involved: BMI, waist circumference, waist-to-height ratio, and detection of the presence of acanthosis nigricans and irregular menstrual cycles (the latter in adolescent girls). The carotid intima-media thickness (CIMT) was measured with the Aixplorer MACH 30 echography device. The pulse wave velocity (PWV), augmentation index (AIx), and peripheral and central blood pressures (i.e., SBP, DBP, cSBP, cDBP, and cPP) were acquired through a Mobil-O-Graph device. Obese subjects underwent body composition analysis with a Tanita BC-418. Blood tests were: HOMA-IR, lipid panel, uric acid, and 25-OH vitamin D. All vascular biomarkers presented increased values in obese subjects versus controls. The following cut-off values were significant in detecting obesity: for PWV > 4.6 m/s, cSBP > 106 mmHg for the <12-year-olds, PWV > 4.5 m/s and cSBP > 115 mmHg for the 12-15-year-olds, and PWV > 5 m/s, cSBP > 123 mmHg for the >15-year-olds. AIx is higher in obese children, regardless of their insulin resistance status. Waist circumference and waist-to-height ratio correlate to all vascular parameters. HOMA-IR is an independent predictor for all vascular parameters except CIMT. Cut-off values for PWV of >4.8 m/s, SBP > 125 mmHg, and a cSBP > 117 mmHg predicted the presence of acanthosis nigricans. Obese girls with irregular menses displayed significantly higher PWV, SBP, and DPB. Elevated levels of uric acid, LDL-c, non-LDL-c, triglycerides, and transaminases, and low levels of HDL-c and 25-OH vitamin D correlated with higher arterial stiffness and CIMT values. We conclude that CIMT and the markers of arterial stiffness are useful in the early detection of vascular damage in obese children.

Investigating the correlation between early vascular alterations and cognitive impairment in Alzheimer's disease in mice with SD-OCT.

Vascular alterations have recently gained some attention with their strong association with Alzheimer's disease (AD). We conducted a label-free in vivo optical coherence tomography (OCT) longitudinal imaging using an AD mouse model. We achieved the tracking of the same individual vessels over time and conducted an in-depth analysis of temporal dynamics in vasculature and vasodynamics using OCT angiography and Doppler-OCT. The AD group showed an exponential decay in both vessel diameter and blood flow change with the critical timepoint before 20 weeks of age, which precedes cognitive decline observed at 40 weeks of age. Interestingly, for the AD group, the diameter change showed the dominance in arterioles over venules, but no such influence was found in blood flow change. Conversely, three mice groups with early vasodilatory intervention did not show any significant change in both vascular integrity and cognitive function compared to the wild-type group. We found early vascular alterations and confirmed their correlation with cognitive impairment in AD.

Cardiac Mitochondria Dysfunction in Dyslipidemic Mice.

Dyslipidemia triggers many severe pathologies, including atherosclerosis and chronic inflammation. Several lines of evidence, including our studies, have suggested direct effects of dyslipidemia on cardiac energy metabolism, but details of these effects are not clear. This study aimed to investigate how mild dyslipidemia affects cardiac mitochondria function and vascular nucleotide metabolism. The analyses were performed in 3- and 6-month-old knock-out mice for low-density lipoprotein receptor (Ldlr−/−) and compared to wild-type C57Bl/6J mice (WT). Cardiac isolated mitochondria function was analyzed using Seahorse metabolic flux analyzer. The mechanical function of the heart was measured using echocardiography. The levels of fusion, fission, and mitochondrial biogenesis proteins were determined by ELISA kits, while the cardiac intracellular nucleotide concentration and vascular pattern of nucleotide metabolism ecto-enzymes were analyzed using reverse-phase high-performance liquid chromatography. We revealed the downregulation of mitochondrial complex I, together with a decreased activity of citrate synthase (CS), reduced levels of nuclear respiratory factor 1 and mitochondrial fission 1 protein, as well as lower intracellular adenosine and guanosine triphosphates’ pool in the hearts of 6-month Ldlr−/− mice vs. age-matched WT. The analysis of vascular ecto-enzyme pattern revealed decreased rate of extracellular adenosine monophosphate hydrolysis and increased ecto-adenosine deaminase activity (eADA) in 6-month Ldlr−/− vs. WT mice. No changes were observed in echocardiography parameters in both age groups of Ldlr−/− mice. Younger hyperlipidemic mice revealed no differences in cardiac mitochondria function, CS activity, intracellular nucleotides, mitochondrial biogenesis, and dynamics but exhibited minor changes in vascular eADA activity vs. WT. This study revealed that dysfunction of cardiac mitochondria develops during prolonged mild hyperlipidemia at the time point corresponding to the formation of early vascular alterations.

Early Abnormal Placentation and Evidence of Vascular Endothelial Growth Factor System Dysregulation at the Feto-Maternal Interface After Periconceptional Alcohol Consumption.

Adequate placentation, placental tissue remodeling and vascularization is essential for the success of gestation and optimal fetal growth. Recently, it was suggested that abnormal placenta induced by maternal alcohol consumption may participate in fetal growth restriction and relevant clinical manifestations of the Fetal Alcohol Spectrum Disorders (FASD). Particularly, periconceptional alcohol consumption up to early gestation can alter placentation and angiogenesis that persists in pregnancy beyond the exposure period. Experimental evidence suggests that abnormal placenta following maternal alcohol intake is associated with insufficient vascularization and defective trophoblast development, growth and function in early gestation. Accumulated data indicate that impaired vascular endothelial growth factor (VEGF) system, including their downstream effectors, the nitric oxide (NO) and metalloproteinases (MMPs), is a pivotal spatio-temporal altered mechanism underlying the early placental vascular alterations induced by maternal alcohol consumption. In this review we propose that the periconceptional alcohol intake up to early organogenesis (first trimester) alters the VEGF-NO-MMPs system in trophoblastic-decidual tissues, generating imbalances in the trophoblastic proliferation/apoptosis, insufficient trophoblastic development, differentiation and migration, deficient labyrinthine vascularization, and uncompleted remodelation and transformation of decidual spiral arterioles. Consequently, abnormal placenta with insufficiency blood perfusion, vasoconstriction and reduced labyrinthine blood exchange can be generated. Herein, we review emerging knowledge of abnormal placenta linked to pregnancy complications and FASD produced by gestational alcohol ingestion and provide evidence of the early abnormal placental angiogenesis-vascularization and growth associated to decidual-trophoblastic dysregulation of VEGF system after periconceptional alcohol consumption up to mid-gestation, in a mouse model.

Non-Invasive Detection of Fetal Vascular Endothelial Function in Gestational Diabetes Mellitus.

ObjectivesEndothelial dysfunction in the fetuses of women with gestational diabetes mellitus (GDM) is associated with their subsequent cardiovascular events. Prenatal assessment of endothelial function in fetuses exposed to intrauterine hyperglycemic environment remains challenging. The aim of this study was to assess the fetal vascular endothelial function in GDM patients using color M-mode derived aortic propagation velocity (APV) and evaluate the correlation of APV with endothelial function biomarkers.MethodsThis observational cross-sectional study included 31 gestational diabetic mothers and 30 healthy pregnant mothers from August 2019 to January 2020. Clinical data were compared between the groups. Fetal APV was measured using color M-mode echocardiography at late gestation. Concentrations of endothelial biomarkers including von Willebrand Factor (vWF), vascular endothelial-cadherin and endothelin-1 in umbilical cord serum were assessed. Measurements between diabetic group and controls were compared.ResultsvWF was the only endothelial functional marker that differed between the two groups. Fetuses in the GDM group had significantly lower APV levels and higher vWF levels compared with the healthy controls (P < 0.05). There was a moderate but significant correlation between APV and vWF (r =−0.58, P < 0.001). There were no associations between APV and ventricular wall thickness or umbilical artery pulsatility index.ConclusionsColor M-mode propagation velocity of aorta is a non-invasive, practical method that correlates well with GDM and fetal endothelial function. This novel metric could contribute to recognizing early vascular functional alterations and hence represents a potential strategy for early risk factor surveillance and risk modification.

Sectorwise analysis of peripapillary vessel density and retinal nerve fiber layer thickness in exfoliation syndrome

This cross-sectional study compared the peripapillary vessel density and retinal nerve fiber layer (RNFL) thickness in patients with exfoliation syndrome (XFS) and healthy controls for evaluation of the early structural and vascular alterations in XFS. One eye was included from 75 patients with XFS and 54 healthy controls. The patients with XFS were matched the controls for age, intraocular pressure and axial length. The vascular density of the radial peripapillary capillaries (RPCs) and the peripapillary RNFL thickness were evaluated with optical coherence tomography angiography. The mean peripapillary RNFL thicknesses of the groups were similar in all sectors (p > 0.05 for all). However, eyes with XFS demonstrated lower mean peripapillary vessel densities in all areas (p < 0.05 for all) except for the nasal sector (p = 0.68) compared to the controls. The gradual age correlated decline in the peripapillary RNFL thickness and the RPC vessel density observed in the healthy eyes was absent in XFS (r = - 0.14 p = 0.65 and r = - 0.23 p = 0.05). Alterations in the peripapillary vascular density despite a preserved RNFL thickness in XFS supports the hypothesis that vascular alterations may precede structural alterations and have an important role in the pathogenesis of XFS. XFS may have different effects on the microvasculature of different peripapillary areas, with the nasal sector being mostly preserved.

Acromegaly: Cardiovascular risk factors, cardiovascular manifestations and early vascular alterations in relation to disease activity

Acromegaly is associated with increased cardiovascular morbidity and mortality. 49 acromegaly patients were evaluated for presence of cardiovascular risk factors and manifestations using 2D-Echocardiography, strain, strain-rate, carotid intima media thickness (CIMT) and flow mediated dilatation (FMD) and correlated with disease activity. 32 patients with growth hormone (GH) level >1 ng/ml were considered active. Patients with active disease have more LV dysfunction as assessed by strain(p-0.031) and strain rate(p-0.001); trend towards lower ejection fraction(p-0.11) with significant correlation to GH(cc −0.252,p-0.05). Patient with active disease have reduced FMD(p- 0.042); with no difference in prevalence of cardiovascular risk factors and CIMT inrelation to disease activity.

Metabolic risk factors, but not vascular lesions and β‐amyloid, are associated with functional connectivity across the Alzheimer’s disease spectrum

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disease, characterized not only by pathological protein aggregation (Ab and tau), but also by early vascular dysfunctions and functional connectivity alterations (Iturria‐Medina 2016; van der Kant 2019). The study objective was to investigate the association between different markers of vascular health as well as brain β‐amyloid burden and brain network functional connectivity across the AD spectrum.MethodThe sample included 131 participants with normal cognition, subjective cognitive decline, mild cognitive impairment and clinical AD from the IMAP cohort (Caen, France). Vascular risk factors comprised mean arterial pressure, body‐mass‐index (BMI), glycemia and HbA1c levels. White matter hyperintensities (WMH) were segmented from FLAIR‐MRI using the “lesion‐segmentation‐tool” (Schmidt, 2017). Brain β‐amyloid burden was measured by the mean of AV45‐SUVR in an AD‐related neocortex mask (LaJoie 2012). Resting‐state functional connectivity (RSFC) was determined within seven predefined functional networks (Schaefer 2018, Verfaillie 2018). Partial correlation analyses were run to assess associations of vascular risk factors, total WMH load and β‐amyloid burden with RSFC. Additionally, we tested for interaction effects with β‐amyloid status in linear regression analyses. All models were age‐ and sex‐adjusted.ResultParticipant characteristics are presented in Figure 1. Across all participants, higher BMI and higher glycemia were associated with lower RSFC within the default‐mode, salience/ventral‐attention, fronto‐parietal and dorsal‐attention networks (Figure 2 and 3). Results remained significant after correction for diagnostic group status. No associations were found between RSFC and total WMH load or β‐amyloid burden (p≥0.05). There were no significant moderation effects by β‐amyloid positivity (p≥0.05).ConclusionThese findings demonstrate that metabolic‐related vascular risk factors, but not cerebrovascular or β‐amyloid pathologies, are associated with functional connectivity specifically within cognition‐related functional networks. Our study further highlights that connectivity alterations associated with metabolic risk, previously shown in diabetes patients (Musen 2012; Chen 2015), are also present in a non‐diabetic aging and AD cohort. Given that functional connectivity supports reserve capacity, connectivity failure within higher‐order networks may limit resilience against aging and pathological processes.

Proteoglycan/glycosaminoglycan and collagen content in the arterial wall of patients with end-stage renal disease: new indicators of vascular disease.

The prevalence of cardiovascular (CV) comorbidity in patients with chronic kidney disease (CKD) is high, particularly in end‑stage renal disease (ESRD). There is an ongoing search for novel biomarkers of CV disease in this population. We aimed to investigate the associations of matrix proteoglycans (PGs) and glycosaminoglycans (GAGs), collagen, and arterial calcifications with selected serum and plasma markers of endothelial dysfunction, inflammation, oxidative stress, and bone turnover in patients with ESRD. We enrolled 47 adult patients (32 men) with stage 5 CKD. The following parameters were investigated: fibrinogen, soluble thrombomodulin (sTM), plasminogen activator inhibitor 1 (PAI‑1), stromal cell‑derived factor 1α (SDF‑1α), calcium (Ca), phosphate (Pi), intact parathormone, interleukin 6, high‑sensitivity C‑reactive protein (hs‑CRP), ferric reducing ability of plasma, 2,2‑diphenyl‑1‑picrylhydrazyl scavenging, ferric reducing ability of ascorbate in plasma, fetuin‑A, fibroblast growth factor 23, osteopontin, osteoprotegerin, osteocalcin, transforming growth factor β (TGF‑β), hepatocyte growth factor, secreted protein acidic and rich in cysteine, as well as matrix metalloproteinase 2. Radial artery specimens were stained with alizarin red for calcifications, alcian blue for PGs and GAGs, and sirius red for collagen. We observed positive correlations between PG and GAG, collagen, and calcification staining. The most intense (grade 3) alcian blue staining was significantly correlated with diabetes as well as higher levels of Ca × Pi product, hs‑CRP, fibrinogen, SDF‑1α, PAI‑1, and sTM. However, PAI‑1 was the only significant predictor of grade 3 alcian blue staining in a multiple logistic regression model adjusted for hemodialysis, Ca× Pi product, and hs‑CRP levels. Coagulation disorders and endothelial dysfunction are the hallmarks of ESRD. The levels of SDF‑1α, PAI‑1, sTM, and fibrinogen may be novel predictors of early vascular wall alterations and may serve as CV risk markers.

Association of nuts and unhealthy snacks with subclinical atherosclerosis among children and adolescents with overweight and obesity

BackgroundThe process of atherosclerosis begins early in childhood and usually remains asymptomatic until later in life. Carotid intima-media thickness (cIMT) as a marker of subclinical atherosclerosis could identify early vascular alterations. Unhealthy snacks consumption is associated with obesity and other CVD risk factors in children and adolescents. The aim of this study is to investigate the association of different snack substitution and cIMT among overweight and obesity children and adolescents.MethodsA total of 339 participants aged 6 to 13 years with the body mass index Z score ≥ 1 based on WHO criteria enrolled in this study. We measured food intakes of participants by validate and reliable food frequency questionnaire (FFQ). Carotid intima media thickness was measured in the common carotid artery with high-resolution ultrasonography.ResultsAfter controlling for confounders, intake of nuts had a negative relationship with cIMT (β = 0.135 mm P value = 0.009). Moreover, participants in the last tertile of nuts intake had 59% lower risk of high cIMT in comparison with those who consumed less than 0.64 serving/wk./1000Kcal of nuts (P for trend = 0.010). Substituted of nuts intake with sweet unhealthy snacks had a negative relationship with cIMT (β = 0.15 mm). There was no other significant association between energy-dense nutrient-poor solid snacks and cIMT.ConclusionsOur findings emphasize the impact of nuts consumption as a healthy snack on subclinical stages atherosclerosis. Clinical trial studies could examine the effect of different kinds of nuts consumption on cIMT and complications of CVD risk factors.

Indoxyl Sulfate and p-Cresyl Sulfate Promote Vascular Calcification and Associate with Glucose Intolerance.

Protein-bound uremic toxins indoxyl sulfate (IS) and p-cresyl sulfate (PCS) have been associated with cardiovascular morbidity and mortality in patients with CKD. However, direct evidence for a role of these toxins in CKD-related vascular calcification has not been reported. To study early and late vascular alterations by toxin exposure, we exposed CKD rats to vehicle, IS (150 mg/kg per day), or PCS (150 mg/kg per day) for either 4 days (short-term exposure) or 7 weeks (long-term exposure). We also performed unbiased proteomic analyses of arterial samples coupled to functional bioinformatic annotation analyses to investigate molecular signaling events associated with toxin-mediated arterial calcification. Long-term exposure to either toxin at serum levels similar to those experienced by patients with CKD significantly increased calcification in the aorta and peripheral arteries. Our analyses revealed an association between calcification events, acute-phase response signaling, and coagulation and glucometabolic signaling pathways, whereas escape from toxin-induced calcification was linked with liver X receptors and farnesoid X/liver X receptor signaling pathways. Additional metabolic linkage to these pathways revealed that IS and PCS exposure engendered a prodiabetic state evidenced by elevated resting glucose and reduced GLUT1 expression. Short-term exposure to IS and PCS (before calcification had been established) showed activation of inflammation and coagulation signaling pathways in the aorta, demonstrating that these signaling pathways are causally implicated in toxin-induced arterial calcification. In CKD, both IS and PCS directly promote vascular calcification via activation of inflammation and coagulation pathways and were strongly associated with impaired glucose homeostasis.

Endothelial edema precedes blood-brain barrier breakdown in early time points after experimental focal cerebral ischemia

In the setting of stroke, ischemia-related blood-brain barrier (BBB) dysfunction aggravates the cerebral edema, which critically impacts on the clinical outcome. Further, an impaired vascular integrity is associated with the risk of intracranial bleeding, especially after therapeutic recanalization. Therefore, the present study was aimed to investigate early vascular alterations from 30 min to 4 h after experimental middle cerebral artery occlusion (MCAO) in mice. Here, an extravasation of the permeability marker FITC-albumin was detectable in animals 2 and 4 h after MCAO. Thereby, BBB breakdown correlated with alterations of the endothelial surface, indicated by a discontinuous isolectin-B4 staining, while tight junction strands remained detectable using electron and immunofluorescence microscopy. Noteworthy, already 30 min after MCAO, up to 60% of the ischemia-affected vessels showed an endothelial edema, paralleled by edematous astrocytic endfeet, clearly preceding FITC-albumin extravasation. With increasing ischemic periods, scores of vascular damage significantly increased with up to 60% of the striatal vessels showing loss of endothelial integrity. Remarkably, comparison of permanent and transient ischemia did not provide significant differences 4 h after ischemia induction. As these degenerations also involved penumbral areas of potentially salvageable tissue, adjuvant approaches of endothelial protection may help to reduce the vasogenic edema after ischemic stroke.

Evaluation of vascular and kidney injury biomarkers in Mexican children exposed to inorganic fluoride

Exposure to inorganic fluoride (F) has been implicated in cardiovascular and kidney dysfunction mainly in adult populations. However, limited epidemiological information from susceptible populations, such as children, is available. In this study we evaluated the relationship of F exposure with some vascular and kidney injury biomarkers in children. A cross-sectional study was conducted in 374 Mexican schoolchildren. Dental fluorosis and F concentrations in the water and urine were evaluated. The glomerular filtration rate (eGFR) and the urinary concentrations of kidney injury molecule 1 (KIM-1) and cystatin-C (uCys-C) were examined to assess kidney injury. The carotid intima media thickness (cIMT) and serum concentrations of vascular adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), endothelin 1(ET-1) and cystatin-C (sCys-C) were measured to assess vascular alterations. High proportions of children exposed to F were observed (79.7% above 1.2 ppm F in urine) even in the low water F exposure regions, which suggested additional sources of F exposure. In robust multiple linear regression models, urinary F was positively associated with eGFR (β = 1.3, p = 0.015), uCys-C (β = −8.5, p = 0.043), VCAM-1 (β = 111.1, p = 0.019), ICAM-1 (β = 57, p = 0.032) and cIMT (β = 0.01, p = 0.032). An inverse association was observed with uCys-C (β = −8.5, p = 0.043) and sCys-C (β = −9.6, p = 0.021), and no significant associations with ET-1 (β = 0.069, p = 0.074) and KIM-1 (β = 29.1, p = 0.212) were found. Our findings revealed inconclusive results regarding F exposure and kidney injury. However, these results suggest that F exposure is related to early vascular alterations, which may increase the susceptibility of cardiovascular diseases in adult life.

Decreased Retinal Thickness in Type 1 Diabetic Children with Signs of Nonproliferative Diabetic Retinopathy.

The retina functions as a neurovascular unit. How early vascular alterations affect neuronal layers remains controversial; early vascular failure could lead to edema increasing retinal thicknesses, but alternatively neuronal loss could lead to reduced retinal thickness. Objective. To evaluate retinal thickness in a cohort of pediatric patients with type 1 diabetes mellitus (PwT1DM) and to analyze differences according to the presence or absence of nonproliferative diabetic retinopathy (NPDR), poor metabolic control, and diabetes duration. Patients and Methods. We performed retinographies and optical coherence tomography (OCT) (TOPCON 3D1000®) to PwT1DM followed at our center and healthy controls. Measurements of the control group served to calculate reference values. Results. 59 PwT1DM (age 12.51 ± 2.59) and 22 healthy controls (age 10.66 ± 2.51) volunteered. Only two PwT1DM, both adolescents with poor metabolic control, presented NPRD. Both showed decreased thicknesses and retinal volumes. The odds ratio of having decreased retinal thickness when signs of NPDR were present was 11.72 (95% IC 1.16–118.28; p = 0.036). Conclusions. PwT1DM with NPDR have increased odds of decreased retinal thicknesses and volumes. Whether these changes are reversible by improving metabolic control or not remains to be elucidated.

X-Ray Phase Contrast Tomography Reveals Early Vascular Alterations and Neuronal Loss in a Multiple Sclerosis Model

The degenerative effects of multiple sclerosis at the level of the vascular and neuronal networks in the central nervous system are currently the object of intensive investigation. Preclinical studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapy in experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis, but the neuropathology of specific lesions in EAE and the effects of MSC treatment are under debate. Because conventional imaging techniques entail protocols that alter the tissues, limiting the reliability of the results, we have used non-invasive X-ray phase-contrast tomography to obtain an unprecedented direct 3D characterization of EAE lesions at micro-to-nano scales, with simultaneous imaging of the vascular and neuronal networks. We reveal EAE-mediated alterations down to the capillary network. Our findings shed light on how the disease and MSC treatment affect the tissues, and promote X-ray phase-contrast tomography as a powerful tool for studying neurovascular diseases and monitoring advanced therapies.