Marker Of Vascular Dysfunction Research Articles

Inorganic nitrate attenuates endothelial dysfunction consequent to systemic inflammation

Abstract Introduction Chronic cardiovascular diseases are characterised by low-grade systemic inflammation and attenuated nitric oxide (NO) bioavailability resulting in endothelial dysfunction. Inorganic nitrate augments NO bioavailability and improves markers of vascular dysfunction in patients with cardiovascular risk factors. However, the exact mechanism of this effect is uncertain. Purpose To determine whether inorganic nitrate supplementation alters systemic inflammation-induced endothelial dysfunction. Methods 62 healthy male volunteers were randomised 1:1 to receive ∼8–10 mmol of dietary inorganic nitrate in beetroot juice or nitrate-free beetroot juice (placebo) once daily for 6 days. Measures of brachial artery flow-mediated dilatation (FMD), brachial blood pressure (BP), pulse wave analysis and carotid-femoral pulse wave velocity (PWV) by Vicorder were taken prior to and at 8 hours after a typhoid vaccine (to induce mild systemic inflammation). Plasma, urine and saliva samples were also collected. Clinicaltrials.gov: NCT02715635. Results Baseline characteristics were similar between the two groups. Inorganic nitrate significantly elevated plasma nitrite (placebo = Δ0.02±0.5 μM, inorganic nitrate = Δ0.63±1.2 μM; p=0.01) and nitrate levels (p<0.0001) compared to placebo. There were significant increases in urine nitrite (p<0.0001) and nitrate (p<0.0001) in addition to salivary nitrite (p<0.0001) and nitrate (p<0.0001) compared to placebo. After 8 hours, typhoid vaccine induced an increase in circulating white cells (placebo = Δ3.34±3.37x109/L, inorganic nitrate = Δ2.9±2.78x109/L; p=0.58) that was similar in in both arms. However, there was a significant reduction in the FMD response in the placebo group at 8-hours post vaccine; an effect that was absent in volunteers treated with inorganic nitrate (placebo = Δ−1.33±1.53%, inorganic nitrate = Δ−0.07±1.84%, p=0.005). Importantly, there were no statistically significant differences in baseline vessel diameter (p=0.78), time to peak diameter in response to flow (p=0.87) and peak shear rate (p=0.57) between the groups. When comparing change from baseline to 8 hours after the vaccine, there were no significant differences in brachial systolic BP (p=0.12), central systolic BP (p=0.12) and PWV (p=0.60) between groups, but a significant reduction in brachial diastolic BP in the inorganic nitrate group (p=0.048). Conclusions Inflammation-induced endothelial dysfunction was prevented in those receiving dietary inorganic nitrate suggesting that elevating circulating nitrite and delivering NO to the blood vessel wall, through dietary approaches may offer potential therapeutic benefit in those cardiovascular diseases which typically exhibit low grade inflammation and deficiencies in bioavailable NO. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): British Heart Foundation

Abstract 03: Ablation Of Endothelial Dysfunction Improves Blood Pressure And Fetal Growth Restriction In A Mouse Model Of Preeclampsia-like Hyperleptinemia

Placental ischemia, an initiating event of preeclampsia (PE), increases plasma leptin levels. We recently developed a model of midgestation (gestation day (GD)11-18) leptin infusion mimicking the midgestation rise in leptin levels of PE patients. Our previous work demonstrates that deletion of endothelial mineralocorticoid receptors (ECMR) improves markers of vascular dysfunction in leptin-infused female mice. We hypothesized vascular function improvement with ECMR deletion ablates hypertension and fetal growth restriction in pregnant leptin-infused mice. Pregnant ECMR +/+ (WT) and ECMR -/- (KO) mice were infused with vehicle or leptin by osmotic pump (lep, 0.9mg/kg/day, s.c.) on GD11-18 while implanted with radiotelemeters for conscious blood pressure (BP) measurement and wire myography of thoracic aorta and 2 nd order mesenteric arteries at GD18 (*=P<0.05). Leptin infusion did not decrease maternal weight in any groups. Leptin decreased pup weight (0.86±0.04g WT vs 0.52±0.11 WT+lep*) and placental efficiency (pup/placenta ratio) (9.7±0.7 WT vs 7.9±0.6 WT+lep*) in WT pregnant mice. ECMR deletion prevented leptin-mediated decreases in pup weight (0.91±0.06g KO vs 1.0±0.07 KO+lep) and placental efficiency (9.6±0.5 KO vs 9.4±1.2 KO+lep). Mean arterial pressure (BP) increased in leptin-infused WT (102±3mmHg WT vs 120±12 WT+lep*), but not KO (107±2 KO vs 106±8 KO+lep), mice from GD11-18. Leptin infusion reduced acetylcholine-mediated relaxation in both aorta and mesenteric arteries of WT* and constriction to KCl in mesenteric arteries in WT*, but not KO, pregnant mice (2-way ANOVA, repeated measures). Leptin increased plasma endothelin-1 (ET-1, 1.1±0.3 pg/ml WT vs 4.4±1.8 WT+lep*), placental mRNA expression of prepro-ET-1 (1.9±0.3-fold change from WT*) and ET-1 converting enzyme-1 (1.6±0.3-fold change from WT*) in pregnant WT mice. Leptin infusion also increased adrenal aldosterone-synthase protein (1.4±0.4 WT ratio/β actin vs 3.2±0.3 WT+lep*) and angiotensin II type 1 receptor b (3.5±0.8-fold change from WT*) mRNA in pregnant mice. Collectively, these data indicate that leptin infusion induces hypertension and fetal growth restriction in pregnant mice due to vascular dysfunction and increased ECMR activation in pregnant mice.

Visit-to-visit blood pressure variability and regional cerebral perfusion decline in older adults

Blood pressure variability (BPV) is linked to dementia risk, possibly through cerebral hypoperfusion. We investigated BPV over 1 year and concurrent regional cerebral perfusion decline in older adults without dementia. Participants underwent 4 blood pressure measurements across 12 months, ASL-MRI at baseline and 12-months, and baseline FDG-PET. Regional perfusion was normalized to precentral gyrus. A subset had cerebral spinal fluid Alzheimer's disease biomarker abnormalities. For every SD increase in BPV, perfusion decreased in medial orbitofrontal cortex (ß = -.36; p = 0.008), hippocampus (ß = -.37; p = 0.005), entorhinal cortex (ß = -.48; p < 0.001), precuneus (ß = -.31; p = 0.02), inferior parietal cortex (ß = -.44; p < 0.001), and inferior temporal cortex (ß = -.46; p < 0.001). Similar patterns emerged in subsets with biomarker abnormalities. Older adults with elevated BPV exhibit concurrent regional perfusion decline in areas vulnerable to Alzheimer's disease, independent of cerebral hypometabolism. BPV may be an early marker of vascular dysfunction in aging.

Are Advanced Glycation End Products in Skin Associated with Vascular Dysfunction Markers? A Meta-Analysis.

Evidence exists regarding the association between advanced glycation end products and different cardiovascular disease subclinical processes, such as arterial stiffness and atherosclerosis. With this systematic review and meta-analysis, we aimed to provide a synthesis of the evidence regarding the association of arterial stiffness measured by pulse wave velocity and atherosclerosis measured by carotid intima media thickness with skin autofluorescence. A systematic search was performed using: MEDLINE (PubMed), SCOPUS, and Web of Science, until 30 March 2020. Cross-sectional studies or baseline data from prospective longitudinal studies were considered. The DerSimonian and Laird method was used to calculate the pooled estimates of correlation coefficients and the corresponding 95% confidence intervals (CI) for the association of pulse wave velocity and carotid intima media thickness with skin autofluorescence. Twenty-five studies were included in the systematic review and meta-analysis, including 6306 subjects. The pooled correlation coefficient was 0.25 (95% CI: 0.18, 0.31) for pulse wave velocity and skin autofluorescence, and 0.31 (95% CI: 0.25, 0.38) for carotid intima media thickness and skin autofluorescence. This systematic review and meta-analysis provide a synthesis of the evidence showing a positive weak association of pulse wave velocity and carotid intima media thickness with skin autofluorescence.

Cold extremities in migraine: a marker for vascular dysfunction in women.

Background and purposeMigraine is recognized as a vascular risk factor, especially in women. Presumably, migraine, stroke and cardiovascular events share pathophysiological mechanisms. Self‐reported cold extremities were investigated as a marker for vascular dysfunction in migraine. Secondly, it was hypothesized that suffering from cold extremities affects sleep quality, possibly exacerbating migraine attack frequency.MethodsIn this case–control study, a random sample of 1084 migraine patients and 348 controls (aged 22–65 years) from the LUMINA migraine cohort were asked to complete questionnaires concerning cold extremities, sleep quality and migraine.ResultsA total of 594 migraine patients and 199 controls completed the questionnaires. In women, thermal discomfort and cold extremities (TDCE) were more often reported by migraineurs versus controls (odds ratio 2.3, 95% confidence interval 1.4–3.7; P < 0.001), but not significantly so in men (odds ratio 2.5, 95% confidence interval 0.9–6.9; P = 0.09). There was no difference in TDCE comparing migraine with or without aura. Female migraineurs who reported TDCE had higher attack frequencies compared to female migraineurs without TDCE (4 vs. 3 attacks per month; P = 0.003). The association between TDCE and attack frequency was mediated by the presence of difficulty initiating sleep (P = 0.02).ConclusionWomen with migraine more often reported cold extremities compared with controls, possibly indicating a sex‐specific vascular vulnerability. Female migraineurs with cold extremities had higher attack frequencies, partly resulting from sleep disturbances. Future studies need to demonstrate whether cold extremities in female migraineurs are a predictor for cardiovascular and cerebrovascular events.

Annexin V+ Microvesicles in Children and Adolescents with Type 1 Diabetes: A Prospective Cohort Study

Background Type 1 diabetes is a chronic disease including hyperglycemia and accelerated atherosclerosis, with high risk of micro- and macrovascular complications. Circulating microvesicles (cMVs) are procoagulant cell fragments shed during activation/apoptosis and discussed to be markers of vascular dysfunction and hypercoagulability. Limited knowledge exists on hypercoagulability in young diabetics. We aimed to investigate cMVs over a five-year period in children/adolescents with type 1 diabetes compared with controls and any associations with glycemic control and cardiovascular risk factors. We hypothesized increased shedding of cMVs in type 1 diabetes in response to vascular activation. Methods The cohort included type 1 diabetics (n = 40) and healthy controls (n = 40), mean age 14 years (range 11) at inclusion, randomly selected from the Norwegian Atherosclerosis and Childhood Diabetes (ACD) study. Citrated plasma was prepared and stored at -80°C until cMV analysis by flow cytometry. Results Comparable levels of Annexin V (AV+) cMVs were observed at inclusion. At five-year follow-up, total AV+ cMVs were significantly lower in subjects with type 1 diabetes compared with controls; however, no significant differences were observed after adjusting for covariates. In the type 1 diabetes group, the total AV+, tissue factor-expressing AV+/CD142+, neutrophil-derived AV+/CD15+ and AV+/CD45+/CD15+, and endothelial-derived AV+/CD309+ and CD309+/CD34+ cMVs were inversely correlated with HbA1c (r = ‐0.437, r = ‐0.515, r = ‐0.575, r = ‐0.529, r = ‐0.416, and r = ‐0.445, respectively; all p ≤ 0.01), however, only at inclusion. No significant correlations with cardiovascular risk factors were observed. Conclusions Children/adolescents with type 1 diabetes show similar levels of AV+ cMVs as healthy controls and limited associations with glucose control. This indicates that our young diabetics on intensive insulin treatment have preserved vascular homeostasis and absence of procoagulant cMVs.

Circulating Argonaute-Bound MicroRNA-126 Reports Vascular Dysfunction &amp;amp; Response to Treatment in Acute &amp;amp; Chronic Kidney Disease

Vascular and kidney dysfunction commonly co-exist. There is an unmet need for biomarkers of vascular health. Circulating microRNAs (miRs) are disease biomarkers; miR-126 is endothelial cell-enriched. We measured circulating miR-126 in rats with nephrotoxic nephritis (NTN) and humans with acute endothelial and renal injury (vasculitis associated with autoantibodies to neutrophil cytoplasm antigens (ANCA)). We then compared these findings to those from patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) and explored the relationship between miR-126 and markers of vascular dysfunction. In rats, NTN was induced with nephrotoxic serum. Samples were prospectively collected from 70 patients with ANCA vasculitis (at presentation and once in treatment-induced remission), healthy subjects (n=60), patients with CKD (n=30) and ESRD before and after dialysis (n=15). In humans and rats, miR-126 and miR-122 (liver-specific control) were measured and correlated with vascular function. In NTN rats, miR-126 was selectively reduced. In ANCA vasculitis, pre-treatment circulating miR-126 was reduced compared to health (88-fold reduction, ROC-AUC 0.87 (0.80-0.94)). miR-126 increased 3.4-fold post-treatment but remained lower than in health (~26-fold). There was no change in miR-122. Plasma fractionation demonstrated that argonaute 2-bound miR-126 increased with treatment of ANCA vasculitis. Urinary miR-126 decreased post-treatment. miR-126 did not differ between CKD and health but its concentration significantly correlated with measures of endothelial dysfunction. miR-126 was substantially reduced in ESRD (~350 fold compared to health and CKD). miR-126 may be a marker of vascular inflammation and has the potential to aid in clinical decision-making.

The Vasculopathy in the Bone Marrow Microenvironment of Humanized Sickle Cell Mice Is Reversible By Blood Transfusion

Sickle cell disease (SCD) is a monogenic red cell disorder with high morbidity and mortality due to significant end-organ disease. Here we investigated for the first time the impact of SCD on the bone marrow (BM) vascular niche, which is critical for hematopoiesis. In SCD mice, we find a disorganized and structurally abnormal BM vasculature with highly tortuous arterioles and fragmented sinusoidal vessels, the latter filled with aggregates of sickle erythroid and myeloid cells. By in vivo imaging, sickle and control red blood cells exhibit significantly slow intravascular flow speeds in sickle cell BM but not in control BM. These abnormalities lead to increased ROS production in expanded erythroblast populations, and to up-regulation in the BM of HIF-1a and key growth factors required to support angiogenesis, e.g. VEGF-A, Ang1, Ang2. Moreover, increased levels of VCAM-1, a marker for vascular dysfunction, are detected. SCD also impacts the BM perivascular niche, i.e. the number of CXCL12-abundant reticular cells, is markedly decreased, and is associated with mobilization of hematopoietic stem/progenitor cells as well as mature leukocytes to the periphery. Strikingly, the distorted vascular network is completely reversed by blood transfusion, which highlights the plasticity of the BM vascular niche. Thus, we provide molecular and cellular features of the pathologic BM microenvironment, which suggest that the local hypoxia-induced angiogenic network combined with inflammatory vascular dysfunction is responsible for the vasculopathy. In addition, the findings may serve to develop new biomarkers and therapeutic targets of BM end-organ damage. Figure Disclosures No relevant conflicts of interest to declare.

Targeted transcriptional profiling of the tumor microenvironment reveals lymphocyte exclusion and vascular dysfunction in metastatic osteosarcoma

ABSTRACTOsteosarcoma (OS) is the most common bone tumor in pediatric and adolescent/young adult patients yet little is known about the microenvironment that supports this aggressive disease. We have used targeted gene expression profiling and immunohistochemistry to characterize the microenvironment of metastatic and non-metastatic OS specimens from pediatric patients exhibiting poor histologic response to chemotherapy. Our results indicate that metastatic specimens exhibit lymphocyte exclusion as T cells are confined to the periphery of the pulmonary lesions. Furthermore, our data provides evidence of vascular dysfunction in metastatic OS indicated by increased expression of VEGFA, an increased ANGPT2:ANGPT1 gene expression ratio, and decreased expression of SELE, the gene encoding the adhesion molecule E-selectin. Moreover, correlation analyses show an inverse relationship between lymphocyte abundance and markers of vascular dysfunction exclusively in the metastatic specimens. Together, our data shows that the non-metastatic OS specimens demonstrate increased expression of various immunotherapeutic targets in comparison metastatic specimens and identifies vascular dysfunction and lymphocyte exclusion as important processes for therapeutic intervention in metastatic disease.

MicroRNA‐126 is a Marker of Vascular Dysfunction in Human ANCA Vasculitis

Vascular dysfunction and kidney disease commonly co‐exist and their presence substantially increases the risk of cardiovascular disease. There is an unmet clinical need for biomarkers that specifically report vascular health and injury. MicroRNAs (miRs) change in disease states and some are tissue specific which makes them an attractive reservoir for circulating biomarker discovery. MiR‐126 is endothelial cell‐enriched and present throughout the vasculature. Antineutrophil cytoplasmic antibody (ANCA) vasculitis is a rare disease, primarily affecting the vasculature, which often injures the kidneys resulting in rapidly progressive glomerulonephritis. It represents a tractable model of acute vascular and kidney injury in humans. We examined the relationship between miR‐126 and vascular dysfunction in patients with ANCA vasculitis.Patients presenting with ANCA vasculitis were recruited at the Royal Infirmary of Edinburgh, UK. Inclusion criteria were seropositivity for ANCA and organ‐threatening disease requiring immunosuppression. The study was approved by the local research ethics committee and performed in accordance with the Declaration of Helsinki. Plasma samples were collected from patients with vasculitis at initial disease presentation (pre‐treatment), and at disease remission (post‐treatment) (n=70 paired). Samples were also collected from patients with chronic kidney disease (CKD), a group known to have chronic vascular dysfunction (n=37), and healthy subjects (n=56). The concentration of a panel of circulating microRNAs were measured by qRT‐PCR and absolute quantification was performed using a standard curve. Results were correlated with clinical parameters currently used to assess vascular function. Statistical significance was determined by Mann‐Whitney U test or Wilcoxon matched‐pairs signed rank test.In ANCA vasculitis, pre‐treatment circulatory miR‐126 was reduced compared to post‐treatment: pre‐treatment median 0.08fM (IQR 0.03–0.32fM), post‐treatment median 0.30fM (IQR 0.06–1.12fM), P=0.0015. In patients with CKD, the concentration of miR‐126 was higher than in patients with ANCA vasculitis pre‐treatment, median 1.96fM (IQR 0.81–4.66fM), P&lt;0.0001. MiR‐126 was substantially higher in healthy subjects than in pre‐treatment vasculitis patients, median 8.46fM (IQR 1.90–185.10fM), P&lt;0.0001 and CKD patients (P=0.0011). MicroRNA species that are not expressed in the vasculature did not differ across the groups. The increase in the circulating concentration of miR‐126 from pre‐treatment to post‐treatment correlated with estimated glomerular filtration rate (eGFR), a key clinical indicator of kidney function (r=0.60, P&lt;0.0001).MicroRNA‐126 is a novel circulating biomarker that might report vascular injury and response to treatment in patients with vasculitis. With further development and refinement, microRNA‐126 could prove to be a valuable marker for diagnosis and tracking disease progression to ensure effective treatment.Support or Funding InformationSupported by the British Heart Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Multispecies Probiotic Supplementation Favorably Affects Vascular Function and Reduces Arterial Stiffness in Obese Postmenopausal Women-A 12-Week Placebo-Controlled and Randomized Clinical Study.

Obesity in the postmenopausal period is associated with an increased risk of cardiovascular diseases in women. One of the key drivers of cardiovascular risk is endothelial dysfunction; thus, this is also a crucial point for studies on new therapeutic methods of cardioprotective properties. The aim of the current study was to evaluate the effect of two doses of multispecies probiotic Ecologic® Barrier supplement on functional (primary endpoint) and biochemical parameters (secondary endpoint) of endothelial dysfunction in obese postmenopausal women in a 12-week randomized, placebo-controlled clinical trial. A total of 81 obese Caucasian women participated in the trial. The subjects were randomly assigned to three groups that received a placebo, a low dose (LD) (2.5 × 109 colony forming units (CFU) per day), or a high dose (HD) (1 × 1010 CFU per day) of lyophilisate powder containing live multispecies probiotic bacteria. The probiotic supplement was administered each day for 12 weeks in two equal portions. A high dose probiotic supplementation for 12 weeks decreased systolic blood pressure, vascular endothelial growth factor, pulse wave analysis systolic pressure, pulse wave analysis pulse pressure, pulse wave analysis augmentation index, pulse wave velocity, interleukin-6, tumor necrosis factor alpha, and thrombomodulin. Low doses of probiotic supplementation decreased the systolic blood pressure and interleukin-6 levels. The mean changes in the estimated parameters, compared among the three groups, revealed significant differences in the vascular endothelial growth factor, the pulse wave analysis systolic pressure, the pulse wave analysis augmentation index, the pulse wave velocity, the tumor necrosis factor alpha, and thrombomodulin. The post hoc tests showed significant differences for all parameters between HD and the placebo group, and HD and LD (besides pulse wave analysis augmentation index). We show for the first time that supplementation with multispecies probiotic Ecologic® Barrier favorably modifies both functional and biochemical markers of vascular dysfunction in obese postmenopausal women.

Soluble receptor for advanced glycation end products as a vasculopathy biomarker in sickle cell disease.

Soluble forms of RAGE (sRAGE) have been found circulating in plasma and tissues. Evidence is accruing in human subjects linking levels of sRAGE to oxidative stress in many disorders. Because sickle cell disease (SCD) is a state of oxidative stress, we tested the hypothesis that circulating sRAGE levels may be involved in the vascular pathology of SCD. To determine the sRAGE levels in children and adolescents with SCD and investigate their association with markers of hemolysis, iron overload, and SCD-related organ complications. The level of sRAGE was measured in 40 children and adolescent with SCD compared with 40 healthy controls using enzyme-linked immunosorbent assay (ELISA). sRAGE was significantly higher in patients compared with controls (p < 0.001) and was elevated in patients with history of stroke, acute lung syndrome, and frequency of sickling crisis or serum ferritin > 2500 (p < 0.05). Patients with high sRAGE levels are candidates for chelation. sRAGE was positively correlated with HbS% (r = 0.422, p = 0.007), LDH (r = 0.329, p = 0.038), and serum ferritin levels (r = 0.516, p = 0.001). Multivariable regression analysis proved that both HbS% and serum ferritin were significant independent factors affecting sRAGE level (p < 0.05). Our findings suggest that sRAGE may be considered as a marker for vascular dysfunction in SCD patients.

Phosphodiesterase type 5 inhibitors improve microvascular dysfunction markers in pulmonary arterial hypertension associated with congenital heart disease.

Ideally, vasodilator therapies for pulmonary arterial hypertension (PAH) should have a favorable impact on markers of vascular dysfunction, in addition to their known effects on hemodynamics, cardiac function, and patient's physical capacity. We analyzed circulating (plasma) markers of endothelial and platelet activation/dysfunction (enzyme-linked immunoassays) in the specific setting of advanced PAH associated with congenital heart disease, during the course of sildenafil and tadalafil therapies. Thirty-one patients were enrolled (age 10-54years), most of them with chronic hypoxemia and elevated hematocrit. Drugs were administered orally for 6months (sildenafil [n=16], 20mg t.i.d.; tadalafil [n=15], single daily dose of 40mg). Measurements were performed at baseline, and 90 and 180days. Compared to controls, patients had elevated baseline β-thromboglobulin (β-TG, P=.002), P-selectin (P=.027), tissue-type plasminogen activator (t-PA, P=.009), and von Willebrand factor antigen (VWF:Ag, P=.010). Thrombomodulin was importantly reduced (TM, P<.001), while soluble CD40 Ligand was not changed (P=.320). Tadalafil administration was associated with improvement of β-TG (P=.004), t-PA (P=.003) and TM (P=.046) levels, while P-selectin was improved by sildenafil treatment only (P=.034). VWF:Ag improved transiently in the sildenafil group (P=.019). Both therapies were associated with improvement of the physical capacity (functional class and distance walked during the 6-minute test, P<.05), hematocrit and hemoglobin level (P<.05), and health-related quality of life (physical and mental components, P<.05). In PAH associated with congenital heart disease, phosphodiesterase 5 inhibitors seem to have beneficial actions at microcirculatory level, beyond the proposed effects as vasodilators.

Detectable levels of eHSP72 in plasma are associated with physical activity and antioxidant enzyme activity levels in hypertensive subjects

Previous studies reported that extracellular HSP72 (eHSP72) correlates with poor prognosis, markers of vascular dysfunction, and the severity of cardiovascular diseases, associated with a systemic oxidative and inflammatory profile. On the other hand, eHSP72 may represent immune-regulatory signaling that is related to exercise benefits, but the association between physical activity levels and eHSP72 levels is not established. Thus, since regular physical activity may avoid oxidative stress and inflammation, we investigate whether detectable levels of eHSP72 in plasma are associated with physical activity and antioxidant enzyme activity levels in hypertensive subjects. Physical activity levels of hypertensive subjects (n = 140) were measured by tri-axial movement sensor pedometer for 24h during 5 consecutive days. One day after, blood was collected into heparinized tubes for oxidative stress analyses (catalase-CAT and superoxide dismutase-SOD activities and malondialdehyde levels) or in disodium EDTA tubes for eHSP72 assays. Thus, hypertensive subjects were classified as physically inactive (< 10,000 footsteps/day) or active (> than 10,000 footsteps/day) and according detectable or not detectable eHSP72 levels in plasma, performing the inactive/eHSP72-, active/eHSP72-, inactive/eHSP72+, and active/eHSP72+ groups. We found that detectable levels of eHSP72 in plasma were associated with physical activity levels and low oxidative stress profile (Higher CAT and SOD activities and low malondialdehyde levels). eHSP72 levels can be used as a biomarker of the amount of physical activity necessary to improve antioxidant defense and thus cardiovascular health in hypertensive subjects.

Effects of a cluster-randomized school-based prevention program on physical activity and microvascular function (JuvenTUM 3)

Background and aimsIt is unknown whether a school-based prevention program has the potential to improve microvascular health in children. This study investigates the impact of the school-based lifestyle intervention program JuvenTUM 3 on physical activity, physical fitness, serum biomarkers and microvascular function. MethodsWe studied 434 children (10–11 years) in a cluster-randomized setting (8 intervention schools, IG; 7 control schools, CG) over 18 months. The school-based prevention program included weekly lifestyle lessons for children with the aim to increase physical activity in and outside of school, physical fitness as well as health behavior. Anthropometric measurements and blood sampling were conducted using standard protocols, physical activity by use of a questionnaire and physical fitness by a 6-item-test battery. Central retinal arteriolar (CRAE) and venular (CRVE) vessel diameters as early marker of vascular dysfunction, as well as the arteriolar-to-venular diameter ratio (AVR), were investigated with a non-mydriatic vessel analyser. ResultsSchool-based physical activity increased in 41% of children in IG (19% in CG, p = 0.038). Improvements in vascular parameters were observed for AVR (increase in 83% of children in IG versus 50% in CG; p < 0.001) and for CRVE (43% of children with retinal venular widening in IG versus 58% in CG, p = 0.019). These vascular improvements were also seen in overweight children for CRAE (p = 0.021) and AVR (p < 0.001). ConclusionsThe school-based prevention program JuvenTUM 3 increased physical activity at school inducing favourable effects on retinal microvasculature function. These findings underline the importance of early lifestyle interventions in children for primary prevention of cardiovascular disease.

Altered dynamics of neurovascular coupling in CADASIL.

Background and ObjectiveNeurovascular coupling is the complex biological process that underlies use‐dependent increases in blood flow in response to neural activation. Neurovascular coupling was investigated at the early stage of CADASIL, a genetic paradigm of ischemic small vessel disease.MethodsFunctional hyperemia and evoked potentials during 20‐ and 40‐sec visual and motor stimulations were monitored simultaneously using arterial spin labeling‐functional magnetic resonance imaging (ASL‐fMRI) and electroencephalography.ResultsCortical functional hyperemia differed significantly between 19 patients and 19 healthy individuals, whereas evoked potentials were unaltered. Functional hyperemia dynamics, assessed using the difference in the slope of the response curve between 15 and 30 sec, showed a time‐shifted decrease in the response to 40‐sec neural stimulations in CADASIL patients. These results were replicated in a second cohort of 10 patients and 10 controls and confirmed in the whole population.InterpretationAlterations of neurovascular coupling occur early in CADASIL and can be assessed by ASL‐fMRI using a simple marker of vascular dysfunction.

Serum cystatin C is an independent biomarker associated with the renal resistive index in patients with chronic kidney disease.

Cystatin C is a cysteine protease inhibitor that is produced by nearly all human cells. The serum level of cystatin C is a stronger predictor of the renal outcome and the risk of cardiovascular events than the creatinine level. The resistive index (RI) on renal Doppler ultrasonography is a good indicator of vascular resistance as well as the renal outcomes in patients with chronic kidney disease (CKD). However, it is unclear whether serum cystatin C is associated with signs of vascular dysfunction, such as the renal RI. We measured the serum cystatin C levels in 101 CKD patients and investigated the relationships between cystatin C and markers of vascular dysfunction, including the renal RI, ankle-brachial pulse wave velocity (baPWV), intima-media thickness (IMT), and cardiac function. The renal RI was significantly correlated with the serum cystatin C level (p < 0.0001, r = 0.6920). The serum cystatin C level was found to be a significant determinant of the renal RI (p < 0.0001), but not the baPWV, in a multivariate regression analysis. The multivariate odds ratio of the serum cystatin C level for a renal RI of more than 0.66 was statistically significant (2.92, p = 0.0106). The area under the receiver-operating characteristic curve comparing the sensitivity and specificity of cystatin C for predicting an RI of more than 0.66 was 0.882 (cutoff value: 2.04 mg/L). In conclusion, the serum cystatin C level is an independent biomarker associated with the renal RI in patients with CKD.

Gender Difference in the Relationship of Albuminuria and Arterial Stiffness in Chinese Adults - a 6.6-Year Follow-Up Longitudinal Study

Background/Aims: Brachial–ankle pulse wave velocity (baPWV) reflects the stiffness of muscular arteries. Albuminuria is recognized as a marker of vascular dysfunction. We assessed the association between arterial stiffness and albuminuria in a population-based longitudinal study. Methods: 1116 adults aged ≥ 40 years in the Taichung Community Health Study (TCHS) in 2004 attended a follow-up visit in 2011. Albuminuria was defined as an urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g. Arterial stiffness was defined as BaPWV ≥ 1540 cm/sec in males and BaPWV ≥ 1480 cm/sec in females, respectively. ∆baPWV was calculated as baPWV at follow-up minus baPWV at baseline, while ∆UACR was calculated as UACR at follow-up minus UACR at baseline. Multiple linear and logistic regression analyses were used to explore the relationship between albuminuria and arterial stiffness. Results: Among 652 subjects without arterial stiffness at baseline, 209 (32%) subjects developed incident arterial stiffness after an average of 6.6 years. In male subjects, baseline albuminuria was associated with development of arterial stiffness (odds ratio: 4.47, 95% confidence interval [CI]: 1.04–19.31) and ∆baPWV was modestly positively associated with ∆UACR. Conclusion: Our results indicated that male adults with albuminuria had an increased risk for developing arterial stiffness.

4.52 Preserved Coronary Distensibility Index Is Associated With Reduced Adulthood Posttraumatic Stress Disorder in Youth With Adverse Childhood Experience

Impaired coronary distensibility index (CDI) is a marker of vascular dysfunction, measures an endothelial-dependent process, is associated with vulnerable plaque composition, and predicts major adverse cardiovascular event (MACE). We previously reported that impaired CDI is strongly associated with the severity of adverse childhood experiences’ (ACE) symptoms and predicts an increased risk of MACE in subjects with ACE. This study investigated the relationship between ACE and adulthood PTSD in youth with and without preserved CDI.

HIV-positive youth who are perinatally infected have impaired endothelial function.

Evaluating cardiovascular disease risk in children and youth 13 to 24 years old who are facing a life time exposure to both HIV and antiretroviral therapy is a research priority. This study compares endothelial function measured by peripheral arterial tonometry in HIV-positive youth infected perinatally and behaviorally as well as HIV-negative controls. Three groups of participants aged 8-30 year were enrolled; HIV-positive perinatally infected, HIV-positive behaviorally infected on antiretroviral therapy with HIV-1 RNA less than 1000 copies/ml, and HIV-negative controls. We measured the reactive hyperemic index, a measure of endothelial function, using endoPAT (Caesarea, Israel). Markers of systemic inflammation, monocyte activation, and gut integrity were also assessed. Spearman correlations and regression analyses were used to explore relationships between endothelial function measures and other measured variables. Overall, 119 participants were enrolled: 53 HIV-positive behaviorally infected, 18 HIV-positive perinatally infected, and 48 controls. Overall, 71% were men; 77% African Americans and median age was 22 years old. Median (interquartile range) reactive hyperemic index was lower in the HIV-positive perinatally infected group [1.34 (1.20, 1.42)], compared with the behaviorally infected group [1.52 (1.34, 1.75)] and the control group [1.52 (1.27, 1.80; P < 0.01)]. Soluble CD14, a marker of monocyte activation, intestinal fatty acid-binding protein, a marker of gut integrity and soluble vascular cell adhesion molecule, a marker of vascular dysfunction, were different among the three groups (P ≤ 0.01). HIV-positive youth infected perinatally appear to have higher levels of endothelial dysfunction and immune activation when compared with behaviorally infected youth. Further longitudinal studies are needed to determine whether perinatally infected youth have higher risks of cardiovascular disease.