Marker Of Vascular Dysfunction Research Articles

The Relationship of Mitral Annular Calcification and Aortic Valve Sclerosis to Endothelial Dysfunction.

Calcific aortic valve disease (CAVD) and mitral annular calcification (MAC) are associated with various cardiovascular diseases and may influence systemic vascular pathologies. However, their relationship with endothelial dysfunction and carotid intima-media thickness (CIMT) remains poorly elucidated. This research aims to explore the associations between MAC, aortic valve sclerosis (AVS), and markers of vascular dysfunction, specifically CIMT and endothelial function. This prospective observational study included 200 patients undergoing routine echocardiographic evaluation at the National Heart Institute between May 2022 and April 2023. Patients were stratified into four groups namely isolated MAC (38 patients), isolated AVS (72 patients), combined MAC and AVS (50 patients), and a control group without MAC or AVS (40 patients). All participants underwent comprehensive cardiovascular evaluation, including transthoracic echocardiography (TTE) and carotid duplex ultrasonography. Endothelial function was determined by measuring reactive hyperemia-induced alterations in brachial artery diameter. The mean age of participants was 60.6±8.4 years, with a predominance of male subjects (64%). No significant differences were noted in baseline demographic and clinical characteristics across the groups. Patients with isolated AVS, isolated MAC, and both conditions demonstrated increased CIMT compared to controls, with significant differences noted in the combined MAC and AVS group compared to controls (p-value=0.031). Endothelial dysfunction was observed in 14.8% of the AVS group and 21.1% in the combined group, but no significant differences existed when compared to controls. The study also revealed that patients with AVS are more likely to exhibit increased CIMT (p-value=0.008). Both MAC and AVS are connected to increased CIMT, suggesting a link with systemic atherosclerotic processes. Although the existence of endothelial dysfunction was not significantly higher in patients with valvular calcifications, the findings support the need for further research into the cardiovascular implications of CAVD and MAC.

Neuroinflammation in post-acute sequelae of COVID-19 (PASC) as assessed by [11C]PBR28 PET correlates with vascular disease measures

The COVID-19 pandemic caused by SARS-CoV-2 has triggered a consequential public health crisis of post-acute sequelae of COVID-19 (PASC), sometimes referred to as long COVID. The mechanisms of the heterogeneous persistent symptoms and signs that comprise PASC are under investigation, and several studies have pointed to the central nervous and vascular systems as being potential sites of dysfunction. In the current study, we recruited individuals with PASC with diverse symptoms, and examined the relationship between neuroinflammation and circulating markers of vascular dysfunction. We used [11C]PBR28 PET neuroimaging, a marker of neuroinflammation, to compare 12 PASC individuals versus 43 normative healthy controls. We found significantly increased neuroinflammation in PASC versus controls across a wide swath of brain regions including midcingulate and anterior cingulate cortex, corpus callosum, thalamus, basal ganglia, and at the boundaries of ventricles. We also collected and analyzed peripheral blood plasma from the PASC individuals and found significant positive correlations between neuroinflammation and several circulating analytes related to vascular dysfunction. These results suggest that an interaction between neuroinflammation and vascular health may contribute to common symptoms of PASC.

Two novel cerebrospinal fluid markers for vascular injury are associated with CSF markers of AD, neurodegeneration, and gliosis

AbstractBackgroundVascular dysfunction often occurs concurrently with Alzheimer’s disease (AD). Breakdown of the blood–brain barrier (BBB) and vascular injury may be related to amyloid and tau pathology. In preliminary analyses, we examined the relationship between cerebrospinal fluid (CSF) biomarkers of AD, neurodegeneration, and glial activation, and two novel CSF markers of vascular dysfunction: soluble platelet‐derived growth factor receptor beta (sPDGFRβ) a marker of BBB integrity, and angiopoietin‐2 (Ang2), a marker of vascular injury.MethodCSF samples from participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP) or the Wisconsin Alzheimer’s Disease Research Center (WADRC) studies were assayed for markers of AD, neurodegeneration, and gliosis, using Roche NeuroToolKit® immunoassays (Roche Diagnostics International Ltd, Switzerland). A subset of serially sampled participants (N = 209, Nob s = 531) who spanned the AD clinical spectrum (cognitively unimpaired, MCI, dementia) underwent sPDGFRβ measurement (ELISA); a sample of N = 121 (Nobs = 276) was also assayed for Ang2 (ELISA) (Table 1). Pearson correlations were calculated for all CSF biomarkers. Linear mixed‐effects models with random intercepts, age‐at‐lumbar‐puncture as the measure of time, and CSF vascular biomarker as the outcome were used to test associations with tau positivity (>24.8 pg/mL), and cognitive status.ResultsPDGFRβ correlated with all CSF biomarkers (rs range .18 to .45, ps<.001, Figure 1A) except AB42/40. Ang2 correlated with all CSF biomarkers (rs range .21 to .45 ps <.001, Figure 1B) except AB42/40, and S100B. sPDGFRβ and Ang2 correlated most strongly with Aβ40 and biomarkers of synaptic function (neurogranin and α‐synuclein). Tau positivity was associated with sPDGFRβ in the whole sample (estimate = 64.5, p<.001) and excluding participants with MCI/dementia (estimate = 77.7, p<.001). Tau positivity was associated with Ang2 (estimate = 18.1, p = .007), however the association was not significant after excluding participants with MCI/dementia. There was no difference in sPDGFRβ across the AD clinical spectrum. Ang2 was higher among participants with MCI than cognitively unimpaired participants (estimate = 21.0, p = .037, Figure 2).ConclusionCSF markers of vascular injury were elevated in MCI and were moderately related to tau pathology and markers of neuronal injury and neuroinflammation, but not amyloid pathology, providing insight into the association of of vascular injury to AD related disease

SPDGFRβ and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study.

There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants. Adults (45-65 years) with a parental history of AD were enrolled (n=82). CSF and blood biomarkers were collected at baseline and year 2. CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aβ)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor β (sPDGFRβ) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aβ40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRβ and tau were significantly lower in B/AA than NHW. Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships. Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.

Towards high-resolution quantitative assessment of vascular dysfunction

Neurovascular alterations are increasingly recognized as a key feature of many brain diseases. They can manifest as a reduction in resting cerebral blood flow or cerebrovascular reactivity (CVR) in the whole brain or in specific regions, depending on the underlying condition. Neurovascular impairment is observed in hypertension, Alzheimer’s disease, stroke, multiple sclerosis and cerebral small vessel disease. Magnetic resonance imaging (MRI)-derived CVR mapping is a reliable marker of vascular dysfunction and has been performed mainly at standard functional MRI (fMRI) resolutions of 2–3 mm using the blood oxygen level dependent (BOLD) contrast. However, vascular alterations may occur at a finer scale (i.e., in the capillary bed) which would be better characterized with smaller voxel sizes. Capillaries in gray matter deliver oxygen and glucose to neural tissue and are arranged in a mesh structure, with variable density across the cortical depth. Given that the human cortex is, on average, 2.5 mm thick, submillimetric voxel sizes are effective in increasing the spatial specificity of measurements of hemodynamic and metabolic changes. Novel MRI sequences offer the possibility to map physiological parameters at high resolution with relatively simple experimental setups. In particular, pairing the BOLD acquisition with a contrast sensitive to blood volume changes, while administering a mild hypercapnic challenge, allows for simultaneous mapping of CVR, cerebral metabolic rate of oxygen consumption and other relevant parameters at a high resolution and can be performed at the clinical field strength of 3 T. We propose that this approach will help provide crucial insights into vascular impairment.

High sensitivity c-reactive protein and circulating biomarkers of endothelial dysfunction in patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of patients with chronic myelogenous leukemia (CML); however, they may cause cardiovascular (CV) toxicities. In this cross-sectional study, we explored whether high-sensitivity C-reactive protein (hsCRP) and novel markers of vascular dysfunction were associated with exposure to specific TKIs, in 262 CML patients. Hs-CRP level was not associated with CML disease activity or treatment with a specific TKI. Body mass index (OR: 1.15, 95% CI: 1.108–1.246; p < 0.001) and CML duration (OR: 1.004, 95% CI: 1.001–1.008; p = 0.024) were independently associated with higher hs-CRP. In exploratory analyses, novel endothelial-centric markers (e.g. ET-1 and VCAM-1) were differential across the various TKIs, particularly amongst nilotinib- and ponatinib-treated patients. While Levels of hs-CRP do not appear to be correlated with specific TKIs, circulating markers of vascular dysfunction were altered in patients treated with specific TKIs and should be explored as potential markers of TKI-associated CV risk.

Glycyrrhizic Acid Inhibits High-Mobility Group Box-1 and Homocysteine-Induced Vascular Dysfunction.

Hyperhomocysteinemia (HHcy) worsens cardiovascular outcomes by impairing vascular function and promoting chronic inflammation via release of danger-associated molecular patterns, such as high-mobility group box-1 (HMGB-1). Elevated levels of HMGB-1 have recently been reported in patients with HHcy. Therefore, targeting HMGB-1 may be a potential therapy to improve HHcy-induced cardiovascular pathologies. This study aimed to further elucidate HMGB-1's role during acute HHcy and HHcy-induced atherogenesis and to determine if inhibiting HMGB-1 with glycyrrhizic acid (Glyz) improved vascular function. Male New Zealand White rabbits (n = 25) were placed on either a standard control chow (CD; n = 15) or atherogenic diet (AD; n = 10) for 4 weeks. Rabbit serum and Krebs taken from organ bath studies were collected to quantify HMGB-1 levels. Isometric tension analysis was performed on abdominal aorta (AA) rings from CD and AD rabbits. Rings were incubated with homocysteine (Hcy) [3 mM] for 60 min to induce acute HHcy or rhHMGB-1 [100 nM]. Vascular function was assessed by relaxation to cumulative doses of acetylcholine. Markers of vascular dysfunction and inflammation were quantified in the endothelium, media, and adventitia of AA rings. HMGB-1 was significantly upregulated in serum (p < 0.0001) and Krebs (p < 0.0001) after Hcy exposure or an AD. Incubation with Hcy (p < 0.0001) or rhHMGB-1 (p < 0.0001) and an AD (p < 0.0001) significantly reduced relaxation to acetylcholine, which was markedly improved by Glyz. HMGB-1 expression was elevated (p < 0.0001) after Hcy exposure and AD (p < 0.0001) and was normalized after Glyz treatment. Moreover, markers of vascular function, cell stress and inflammation were also reduced after Glyz. These results demonstrate that HMGB-1 has a central role during HHcy-induced vascular dysfunction and inhibiting it with Glyz could be a potential treatment option for cardiovascular diseases.

Serum endocan levels in patients with habitual abortion.

The aim of this study was to investigate whether there is a new factor in the etiology of recurrent loss of pregnancy. For this purpose, serum malondialdehyde (MDA) and nitric oxide (NO) levels as indicators of oxidative stress, and endocan levels, a marker of vascular dysfunction, were investigated in patients diagnosed with habitual abortion. The research was conducted as a prospective case-control study. Patients aged 18-40 years with two or more consecutive pregnancy losses revealed by ultrasonographic or histopathological examination, and with no pathology capable of causing habitual abortion were included in the study group. Patients with no history of abortion, with at least one healthy pregnancy, who were planning pregnancies, and who presented to the outpatient clinic for routine prepregnancy tests were selected as the control group. Two groups were established-habitual abortion (n = 30) and control (n = 29). At the end of the menstrual cycle, blood samples were collected and centrifuged. Serum NO, MDA, and endocan levels were studied. Serum endocan, NO, and MDA levels were higher in women with habitual abortion compared to healthy controls. Pearson's correlation analysis revealed a positive correlation between serum endocan levels and NO and MDA levels. A positive correlation was also observed between serum MDA and NO levels. Multiple regression was run to predict serum endocan levels from MDA and NO levels. These variables emerged as statistically significant predictors of endocan. These findings suggest the presence of vascular endothelial dysfunction in patients with habitual abortion.

Diabetes and Sexual Dysfunction

Type 2 diabetes can produce various sexual dysfunctions in both men and women. Prevalence of sexual dysfunction is 25~75% in type 2 diabetes, which is three times that of the general population. As hyperglycemia persists, atherosclerosis progresses, and macrovascular and microvascular complications can occur. Autonomic neuropathy and hypogonadism are principal causes of various sexual dysfunctions such as erectile dysfunction, retrograde ejaculation, and premature ejaculation in males and loss of libido, vaginal dryness, anorgasmia, and dyspareunia in females. Although erectile dysfunction is reversible in early stages, it is more difficult to control as diabetes and associated autonomic dysfunction and microvascular complications progress. Sexual dysfunction can decrease quality of life in type 2 diabetes patients and is a marker of vascular dysfunction. Sexual dysfunction has prognostic value for cardiovascular events in type 2 diabetes. This illustrates the importance of sexual function evaluation in type 2 diabetes patients.

Endothelin-1 gene polymorphism (G8002A) and endothelial monocyte-activating polypeptide II: Role in vascular dysfunction in pediatric patients with β-thalassemia major.

Endothelin-1 (ET-1), a potent endogenous vasoconstrictor, stimulates production of reactive oxygen species. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional polypeptide. To assess ET-1 gene polymorphism (G8002A) in pediatric patients with β-thalassemia major (β-TM) as a potential genetic marker for vascular dysfunction and its possible relation to EMAP II, oxidative stress and vascular complications. β-TM patients (n=95) without symptomatic cardiac or renal disease were compared with 95 healthy controls. Markers of hemolysis, serum ferritin, urinary albumin-to-creatinine ratio, serum EMAP II, malondialdehyde (MDA) and antioxidant enzymes; superoxide dismutase (SOD), glutathione peroxidase (GPx), reduced glutathione (GSH), glutathione reductase and catalase were measured. ET-1 gene polymorphism (G8002A) was determined using polymerase chain reaction‑restriction fragment length polymorphism. β-TM patients had significantly higher EMAP II than healthy controls. EMAP II was significantly higher among patients with cardiac disease, pulmonary hypertension (PH) risk, nephropathy, poor compliance to therapy and ferritin≥2500μg/L. There were significant correlations between EMAP II and transfusion index, LDH, ferritin and oxidative stress markers. The AA genotype of ET-1 gene polymorphism (G8002A) was significantly higher among β-TM patients than controls. The number of patients with cardiac disease, PH risk or nephropathy was significantly higher among AA genotype compared with GG and GA genotypes. Lactate dehydrogenase (LDH), serum ferritin, EMAP II, MDA, SOD and GPx were significantly higher in AA genotype. ET-1 gene polymorphism (G8002A) could be a possible genetic marker for prediction of increased susceptibility to cardiopulmonary and renal complications among pediatric patients with β-TM.

Relationship between the Soluble F11 Receptor and Annexin A5 in African Americans Patients with Type-2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is characterized by endothelial dysfunction, increased thrombogenicity, and inflammation. The soluble human F11 receptor (sF11R) and annexin A5 (ANXA5) play crucial roles in inflammatory thrombosis and atherosclerosis. We examined the relationship between circulating sF11R and ANXA5 and their impact on endothelial function. The study included 125 patients with T2DM. Plasma levels of sF11R and ANXA5 were quantified by ELISA. Microvascular function was assessed using the vascular reactivity index (VRI). Large artery stiffness was assessed by carotid-femoral pulse wave velocity (PWV). Carotid intima-media thickness (CIMT) was assessed by B-mode ultrasound imaging. The mean age of patients in the study was 59.7 ± 7.8 years, 78% had hypertension, 76% had dyslipidemia, and 12% had CKD. sF11R correlated positively with ANXA5 levels (β = 0.250, p = 0.005), and correlated inversely with VRI and total nitic oxide (NO), (β = −0.201, p = 0.024; β = −0.357, p = 0.0001, respectively). Multivariate regression analysis revealed that sF11R was independently associated with ANXA5 in the total population and in patients with HbA1c > 6.5% (β = 0.366, p = 0.007; β = 0.425, p = 0.0001, respectively). sF11R and ANXA5 were not associated with vascular outcome, suggesting that they may not be reliable markers of vascular dysfunction in diabetes. The clinical significance of sF11R/ANXA5 association in diabetes warrants further investigation in a larger population.

Early life body mass index trajectories and albuminuria in midlife: A 30-year prospective cohort study

SummaryBackgroundAlbuminuria is a marker of vascular dysfunction and is associated with chronic renal and cardiovascular diseases. Data on the association between the longitudinal patterns of weight change early in life and albuminuria later in life are limited. We aimed to identify the body mass index (BMI) trajectory across a 30-year span and evaluate its association with middle-age albuminuria.MethodsOf the 4623 participants aged 6–18-year-old recruited by Hanzhong Adolescent Hypertension Study cohort in northern China from March 10, 1987 to June 3, 2017, a total of 1,825 participants followed up with 6 visits over 30 years were enrolled. Group-based trajectory modeling was used to identify distinct BMI trajectories in longitudinal analyses. Albuminuria was defined as a urinary albumin-to-creatinine ratio (uACR) ≥ 30 mg/g.FindingsThree distinct BMI trajectories were identified: low-increasing (n = 671, 36.8%), moderate-increasing (n = 940, 51.5%), and high-increasing (n = 214, 11.7%); male participants exhibited a steeper increase in BMI than females. The uACR was increased linearly from the low- to high-increasing group. A total of 201 individuals developed albuminuria, with an incidence of 11.0%. Compared with the low-increasing group, the odds ratio (OR) of albuminuria in middle age was 2.13(95% confidence interval [CI]: 1.26 to 3.61) for the high-increasing group after full adjustment for age, sex, smoking, alcohol consumption, marital status, systolic blood pressure, diabetes, and hyperlipidemia. The unadjusted ORs of the high-increasing BMI group were 5.08 (2.76–9.37) for males and 3.45 (1.78–6.69) for females, and the association remained significant in males in the fully adjusted models.InterpretationHigher BMI trajectories are associated with higher uACR and an increased risk of albuminuria in middle age, especially in males. Identifying long-term BMI trajectories from an early age may assist in predicting the risk of renal diseases and cardiovascular disease later in life.FundingThis work was supported by the National Natural Science Foundation of China (81600327, 82070437, 81870319, 82070549, and 82170437), Natural Science Basic Research Program of Shaanxi Province (2021JM-257 and 2021JM-588), Institutional Foundation of the First Affiliated Hospital of Xi'an Jiaotong University (2019QN-06 and 2021ZXY-14), the Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University of China (XJTU1AF-CRF-2019-004, XJTU1AF2021CRF-021, and XJTU1AFCRF-2017-021), Research Incubation Fund of Xi'an People's Hospital (FZ-61), Grants from the Major Chronic Non-communicable Disease Prevention and Control Research Key Project of the Ministry of Science and Technology of China (2017YFC1307604 and 2016YFC1300104).

Angiogenic content of microparticles in patients with diabetes and coronary artery disease predicts networks of endothelial dysfunction

BackgroundElevated endothelial microparticles (EMPs) levels are surrogate markers of vascular dysfunction. We analyzed EMPs with apoptotic characteristics and assessed the angiogenic contents of microparticles in the blood of patients with type 2 diabetes (T2D) according to the presence of coronary artery disease (CAD).MethodsA total of 80 participants were recruited and equally classified as (1) healthy without T2D, (2) T2D without cardiovascular complications, (3) T2D and chronic coronary artery disease (CAD), and (4) T2D and acute coronary syndrome (ACS). MPs were isolated from the peripheral circulation, and EMPs were characterized using flow cytometry of CD42 and CD31. CD62E was used to determine EMPs’ apoptotic/activation state. MPs content was extracted and profiled using an angiogenesis array.ResultsLevels of CD42- CD31 + EMPs were significantly increased in T2D with ACS (257.5 ± 35.58) when compared to healthy subjects (105.7 ± 12.96, p < 0.01). There was no significant difference when comparing T2D with and without chronic CAD. The ratio of CD42-CD62 +/CD42-CD31 + EMPs was reduced in all T2D patients, with further reduction in ACS when compared to chronic CAD, reflecting a release by apoptotic endothelial cells. The angiogenic content of the full population of MPs was analyzed. It revealed a significant differential expression of 5 factors in patients with ACS and diabetes, including TGF-β1, PD-ECGF, platelet factor 4, serpin E1, and thrombospondin 1. Ingenuity Pathway Analysis revealed that those five differentially expressed molecules, mainly TGF-β1, inhibit key pathways involved in normal endothelial function. Further comparison of the three diabetes groups to healthy controls and diabetes without cardiovascular disease to diabetes with CAD identified networks that inhibit normal endothelial cell function. Interestingly, DDP-IV was the only differentially expressed protein between chronic CAD and ACS in patients with diabetes.ConclusionOur data showed that the release of apoptosis-induced EMPs is increased in diabetes, irrespective of CAD, ACS patients having the highest levels. The protein contents of MPs interact in networks that indicate vascular dysfunction.

Pulse Wave Velocity as a Marker of Vascular Dysfunction and Its Correlation with Cardiac Disease in Children with End-Stage Renal Disease (ESRD).

One of the main markers of arterial stiffness is pulse wave velocity (PWV). This parameter is well studied as a marker for end-organ damage in the adult population, being considered a strong predictor of major cardiovascular events. This study assessed PWV in children with chronic kidney disease (CKD) as a marker of cardiovascular risk. We conducted a prospective observational single-center cohort study of 42 consecutively pediatric patients (9–18 years old) with terminal CKD and dialysis, at the Hemodialysis Department of the “M. S. Curie” Hospital, Bucharest. We measured PWV by echocardiography in the ascending aorta (AscAo) and the descending aorta (DescAo), and we correlated them with left ventricular hypertrophy (LVH). Fifteen patients (35.7%) presented vascular dysfunction defined as PWV above the 95th percentile of normal values in the AscAo and/or DescAo. Cardiac disease (LVH/LV remodeling) was discovered in 32 patients (76.2%). All patients with vascular damage also had cardiac disease. Cardiac damage was already present in all patients with vascular disease, and the DescAo is more frequently affected than the AscAo (86.6% vs. 46.9%). Elevated PWV could represent an important parameter for identifying children with CKD and high cardiovascular risk.

Relationship between platelet derived growth factor receptor‐β and Alzheimer’s biomarkers in a racially diverse, high‐risk cohort

AbstractBackgroundWith the increasing prevalence of Alzheimer’s disease (AD), there is an increased need for systematic research targeting preclinical pathophysiologic mechanisms of AD development for high‐risk, racially diverse, populations. Neurovascular dysfunction and blood brain barrier (BBB) breakdown likely occur early in AD pathology, however their relationship to AD biomarkers in preclinical populations are not well known. Soluble platelet derived growth factor receptor‐β (sPDGFRβ), a novel CSF biomarker of BBB‐associated capillary pericyte damage, is shed from injured human pericytes and is associated with AD pathology. Here we tested the hypothesis that sPDGFRβ is related to CSF AD biomarkers and CSF markers of vascular dysfunction in a cohort of Black/African American (B/AA) and non‐Hispanic White (NHW) participants.MethodCognitively unimpaired, middle‐aged (45‐65 years) adults with a parental history of AD were enrolled. CSF was collected at baseline and 2 years for measurement of sPDGFRβ, AD biomarkers (Aβ and tau), and markers of vascular dysfunction (ACE activity, and VCAM‐1).ResultParticipants (N=70) were mostly female (69%), well educated (81% college or greater), and 34% identified as B/AA. Forty‐eight percent were ApoEε4 positive. At both baseline and 2 years sPDGFRβ was positively correlated with P‐tau (r=.380, p=.003; r=.356, p=.008), T‐tau (r=.466, p&lt;.001; r=.485, p&lt;.001), Aβ40 (r=.439, p=.001; r=.454, p=.001), ACE‐1 activity (r=.363, p=.003; r=.272, p=.041), and VCAM‐1 (r=.511, p&lt;.011; r‐=.401, p=.002) and negatively correlated with Aβ42/40 (r=‐.282, p=.024; r=‐.399, p=.002), controlling for age, sex, race, and education. At both time points, AAs had lower sPDGFRβ, P‐tau, T‐tau, and Aβ40 and higher Aβ42/40 compared to NHWs.ConclusionsPDGFRβ was associated with tau hyperphosphorylation (P‐tau) and neurodegeneration (T‐tau) in a cohort of cognitively unimpaired middle‐aged adults at risk for AD. Pericyte loss may relate to disease pathology early in AD development in at‐risk individuals, providing a potential mechanistic target for early intervention and prevention strategies. sPDGFRβ was associated with ACE‐1 and VCAM‐1, suggesting a potential role for endothelial activation in early BBB breakdown. As we found differences in AD biomarkers by between AA and NHW participants, reference ranges for these biomarkers may vary by race. More research is needed examining pre‐clinical disease pathways in diverse populations.

Abstract 11165: Stimulated Release of Apoptosis- Induced Endothelial Microparticles in Patients with Diabetes and Coronary Artery Disease

Introduction: High endothelial microparticles (EMPs) levels could be used as a marker of vascular dysfunction. Hypothesis: The release of EMPs with apoptotic characteristics in the blood of patients with diabetes is different according to the presence of CAD, and further distinct between chronic CAD and ACS. Methods: A total of 80 participants were recruited and equally classified as: 1) healthy participants without diabetes, 2) healthy diabetics without micro or macro-vascular complications, 3) participants with T2D and chronic CAD, and 4) participants with T2D and ACS. MPs were isolated using ExoQuick-LP TM and analysed using flow cytometry of CD42 and CD31. CD62E was used to determine the apoptotic/activation state of the EMPs. MP content was extracted and profiled using angiogenesis array (R&amp;D systems). Results: Mean age of participants was 56 ±10. Levels of CD42- CD31+ EMPs were significantly increased in diabetics with acute ACS (257.5±35.58) when compared to healthy subjects (105.7±12.96, p&lt;0.01). There was no significant difference when comparing diabetics, with and without chronic CAD. The ratio of CD42-CD62+/ CD42-CD31+ EMPs was reduced in all diabetic groups, with further reduction in ACS when compared to chronic CAD, reflecting a release by apoptotic endothelial cells. The angiogenic content of the full population of MPs was analysed and revealed a significant differential expression of 5 factors in patients with ACS and diabetes: TGF-β1, PD-ECGF, platelet factor 4, serpin E1 and thrombospondin 1 (Figure 1). Ingenuity Pathway Analysis revealed of those 5 differentially expressed molecules, mainly TGF-β1, causes an inhibition of key pathways involved in normal endothelial function. Conclusions: Our data showed that the release of apoptosis-induced EMPs is increased in diabetes, irrespective of the presence of CAD, ACS patients having the highest levels. The protein contents of MPs interact in networks that are indicative of vascular dysfunction.

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&amp;lt;0.0001) compared to placebo. There were significant increases in urine nitrite (p&amp;lt;0.0001) and nitrate (p&amp;lt;0.0001) in addition to salivary nitrite (p&amp;lt;0.0001) and nitrate (p&amp;lt;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&lt;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.