Elevated Endothelin-1 Research Articles

Рівні ендотеліну-1 та тестостерону в крові хворих на цукровий діабет 1-го та 2-го типів

Із цукровим діабетом (ЦД) пов’язана ендотеліальна дисфункція (ЕД) — одна з ключових патологічних подій у розвитку хронічних діабетичних ускладнень. Важливим ефектом ЕД є збільшення продукції та біологічної активності ендотеліну (ЕТ). ET‑1, який виробляється переважно в ендотелії, є основною серцево-судинною ізоформою ендотелінової системи. ЦД — одне із захворювань, пов’язаних із патологічно підвищеним рівнем ЕТ. Отримані докази того, що андрогени можуть грати певну роль у визначенні специфічного для статі артеріального тиску. Чоловіки мають більш високий ризик розвитку ішемічної хвороби серця або гіпертонічної хвороби порівняно з жінками в пременопаузі. Мета — визначення концентрації ЕТ‑1 та тестостерону (Т) в крові хворих на цукровий діабет першого (ЦД1) та другого (ЦД2) типів із різним індексом маси тіла (ІМТ) та різних вікових категорій. Матеріал і методи. Рівень ET‑1 оцінювали методом ІФА в 103 осіб: 17 здорових осіб та 86 пацієнтів із ЦД1 і ЦД2. Для визначення концентрації ET‑1 використовували набір Endotelin (1-21) EIA. Загальний Т визначали за допомогою набору EIA‑1559. Результати. У всіх пацієнтів із діабетом рівень ЕТ‑1 у крові був значно вищим, ніж в осіб контрольної групи. Різниця в кількості ЕТ‑1 у крові пацієнтів із ЦД1 і ЦД2 була невірогідною. Рівень ЕТ‑1 у чоловіків був вищим, ніж у жінок у середньому на 37%. У групі з вищим індексом маси тіла кількість ET‑1 була вищою на 71%, а Т — нижчою на 25%. Рівень ЕТ‑1 у віковій групі до 50 років був нижчим, ніж у старшій групі для обох типів ЦД (123% для ЦД1 і 148% для ЦД2), а кількість Т у хворих на ЦД2 — вища майже на 20%. У групі хворих на ЦД2 з рівнем Т<3 нг/мл концентрація ЕТ‑1 у крові була вищою, ніж у хворих із рівнем Т>3 нг/мл (відповідно 0,550 фмоль/мл і 0,392 фмоль/мл). Висновки. У чоловіків, хворих на ЦД2 з ожирінням спостерігається підвищення концентрації ЕТ‑1 і зниження рівня Т. Ці показники, напевно, безпосередньо не пов’язані з вмістом глікованого гемоглобіну (Нв1Ас). Із віком рівень ЕТ‑1 у крові хворихна ЦД зростає, а рівень Т знижується. Ці процеси можуть бути взаємопов’язаними. Концентрація ЕТ‑1 у крові в чоловіків, хворих на ЦД обох типів вірогідно вища, ніж у жінок.

Abstract 17120: Association of Endotoxemia and Endothelin-1 With Development of Cardiac Allograft Vasculopathy After Heart Transplantation

Introduction: Cardiac allograft vasculopathy (CAV) is a leading cause of death after heart transplant (HT). Inflammation is a known cardiovascular risk factor, with gut derived endotoxemia potentially instigating this process, leading to endothelial damage. Our prior work showed that elevation of biomarkers of inflammation (endothelin-1 (ET-1)) and endotoxemia (lipopolysaccharide (LPS)) persists after HT. We investigated the association of LPS and ET-1 with subsequent development of CAV. Methods: Pts who met the following criteria were included: i) blood sampling ≥6 mo post-HT; ii) no evidence of CAV at the time of sampling. Pts were followed up to 2.3y after sampling. Cox-PH was used to regress freedom from CAV on LPS and ET-1 (≤ vs >median), time from HT to sampling (≤ vs >1y), interaction among variables. Results: 33 HT pts enrolled, mean age 57±11y; 70% male; median time post-HT 1.96(0.5-3.7)y. 17(52%) pts developed CAV at 0.7(0.6-1)y following blood collection. Baseline characteristics of pts who developed CAV vs not were similar, except for longer median time post-HT in pts who developed CAV: 2.4(0.7-5.3) vs 1.05(0.5-2.7)y, p=0.1. Median LPS and ET-1 for the entire cohort were 0.34(0.28-0.45) EU/ml and 1.83(1.26-2.72) pg/ml. Pts with >median LPS or ET-1 values trended towards higher risk of developing CAV: HR 1.79(0.66, 4.85), p=0.3 ( Fig.1A ); HR 2.05(0.71, 5.92), p=0.2 ( Fig.1B ). No association was observed between time post-HT and CAV: HR=0.87 comparing ≤ vs. >1y, p=0.8. Pts with both >median LPS and ET-1 levels (n=7) were at significantly higher risk of CAV: HR 2.96(1.06, 8.27), p=0.039, compared to others ( Fig.1C ). When examining pts sampled within the first year of HT (N=14), pts with >median LPS (N=5) were at particularly increased risk of CAV: HR 9.71(0.97, 96.9), p=0.05, while pts with >median ET-1 were not. Conclusions: Elevated LPS and ET-1 synergistically associate with increased CAV risk post-HT. Further studies are warranted to validate these findings.

Recurrent versus new-onset depressive symptoms: Relationships with biomarkers of cardiovascular health following acute coronary syndrome

ObjectiveNew-onset depressive symptoms commonly arise among persons without a history of major depressive disorder (MDD) in the setting of acute medical illness. Although depressive symptoms in general are associated with alterations in prognostic biomarkers following acute coronary syndrome (ACS), the nature of specifically new-onset depressive symptoms is less well-characterized. It is unclear whether such symptoms neurobiologically resemble recurrent symptoms of MDD or instead represent a distinct condition. In this exploratory analysis, we aimed to examine the effects of prior MDD history on the relationships between post-ACS depressive symptoms and cardiovascular biomarkers. MethodsOne-hundred sixty-four participants attended study visits 2 weeks and 6 months after ACS to complete self-report measures and provide biomarker samples. MDD history was identified by a psychiatrist through systematic electronic medical record review. Generalized estimating equations were performed to examine the moderating effects of MDD history on concurrent relationships between depressive symptoms and several biomarkers (endothelin-1, soluble intercellular adhesion molecule-1, high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha). ResultsTwenty percent (n = 33) of participants had a history of MDD. Depressive symptoms were more strongly associated with levels of endothelin-1 in patients with prior MDD compared to those without (B = 0.024, 95% CI [0.005, 0.043], p = .012), adjusting for age, sex, medical factors, and anxiety. MDD history did not moderate relationships between depressive symptoms and other biomarkers. ConclusionRecurrent post-ACS depressive symptoms are more strongly associated with elevated endothelin-1 levels than new-onset symptoms. Further work is needed to clarify the mechanism and clinical implications of this relationship.

Increasing Vascular Complications Depends on The Duration Disease of Having Been Diabetic Type 2

Angiopathy is a major complication in (T2-DM), Endothelin-1 (ET-1) is considered the main vasoconstrictor (a mitogenic endothelium-derived peptide is mostly, produced by endothelial cells, as well by vascular smooth muscle cells, macrophages, and other cells). Previous studies suggested a link between T2-DM and ET-1. This paper aims to study the association between Endothelin-1 (ET-1) as a marker of endothelial dysfunction and the duration disease among patients with T2-DM, and to identify the effects of obesity and insulin resistance on elevated Endothelin level. The study includes 96 patients with T2-DM, aged between (45-70) years, (56.73 ± 9.14 years) is an average duration of having T2-DM (14.541± 11.462) years, and 96 healthy control subjects, aged (45-70) years, (56.42 ± 8.74 years). We show that the excess of ET-1 level was clearly linked with the duration of T2-DM, where the plasma Endothelin level was significantly changed among the studied groups (according to their duration) (11.607 ±0.783), (13.641± 0.729), (17.736 ± 3.409), (33.816 ± 12.902), (81.165 ± 35.404), and (156.783 ± 12.671) pg/mL respectively. Plasma ET-1 levels significant is positively correlated with T2-DM (R² = 0.9711, p ≤ 0.01), with obesity, insulin resistance, age, HOMO-IR, hypertension, and HDL level (p ≤ 0.05). As a conclusion, the plasma ET-1 level was significantly elevated as long as having been T2-DM.

Breast cancer diagnosis is associated with relative left ventricular hypertrophy and elevated endothelin-1 signaling

BackgroundThe survival rates of women with breast cancer have improved significantly over the last four decades due to advances in breast cancer early diagnosis and therapy. However, breast cancer survivors have an increased risk of cardiovascular complications following chemotherapy. While this increased risk of later occurring structural cardiac remodeling and/or dysfunction has largely been attributed to the cardiotoxic effects of breast cancer therapies, the effect of the breast tumor itself on the heart prior to cancer treatment has been largely overlooked. Thus, the objectives of this study were to assess the cardiac phenotype in breast cancer patients prior to cancer chemotherapy and to determine the effects of human breast cancer cells on cardiomyocytes.MethodsWe investigated left ventricular (LV) function and structure using cardiac magnetic resonance imaging in women with breast cancer prior to systemic therapy and a control cohort of women with comparable baseline factors. In addition, we explored how breast cancer cells communicate with the cardiomyocytes using cultured human cardiac and breast cancer cells.ResultsOur results indicate that even prior to full cancer treatment, breast cancer patients already exhibit relative LV hypertrophy (LVH). We further demonstrate that breast cancer cells likely contribute to cardiomyocyte hypertrophy through the secretion of soluble factors and that at least one of these factors is endothelin-1.ConclusionOverall, the findings of this study suggest that breast cancer cells play a greater role in inducing structural cardiac remodeling than previously appreciated and that tumor-derived endothelin-1 may play a pivotal role in this process.

Plasma big endothelin-1 is an effective predictor for ventricular arrythmias and end-stage events in primary prevention implantable cardioverter- defibrillator indication patients.

ObjectiveTo investigate whether plasma big endothelin-1 (ET-1) predicts ventricular arrythmias (VAs) and end-stage events in primary prevention implantable cardioverter-defibrillator (ICD) indication patigents.MethodsIn total, 207 patients fulfilling the inclusion criteria from Fuwai Hospital between January 2013 and December 2015 were retrospectively analyzed. The cohort was divided into three groups according to baseline plasma big ET-1 tertiles: tertile 1 (< 0.38 pmol/L, n = 68), tertile 2 (0.38–0.7 pmol/L, n = 69), and tertile 3 (> 0.7 pmol/L, n = 70). The primary endpoints were VAs. The secondary endpoints were end-stage events comprising all-cause mortality and heart transplantation.ResultsDuring a mean follow-up period of 25.6 ± 13.9 months, 38 (18.4%) VAs and 78 (37.7%) end-stage events occurred. Big ET-1 was positively correlated with NYHA class (r = 0.165, P = 0.018), serum creatinine concentration (Scr; r = 0.147, P = 0.034), high-sensitivity C-reactive protein (hs-CRP; r = 0.217, P = 0.002), Lg NT-pro BNP (r = 0.463, P < 0.001), left ventricular end diastolic diameter (LVEDD; r = 0.234, P = 0.039) and negatively correlated with left ventricular ejection fraction (LVEF; r = −0.181, P = 0.032). Kaplan-Meier analysis showed that elevated big ET-1 was associated with increased risk of VAs and end-stage events (P < 0.05). In multivariate Cox regression models, big ET-1 was an independent risk factor for VAs (hazard ratio (HR) = 3.477, 95% confidence interval (CI): 1.352–8.940, P = 0.010, tertile 2 vs. tertile 1; HR = 4.112, 95% CI: 1.604–10.540, P = 0.003, tertile 3 vs. tertile 1) and end-stage events (HR = 2.804, 95% CI: 1.354–5.806, P = 0.005, tertile 2 vs. tertile 1; HR = 4.652, 95% CI: 2.288–9.459, P < 0.001, tertile 3 vs. tertile 1).ConclusionsIn primary prevention ICD indication patients, plasma big ET-1 levels can predict VAs and end-stage events and may facilitate ICD-implantation risk stratification.

The Role of Cerebral Hypoperfusion in Multiple Sclerosis (ROCHIMS) Trial in Multiple Sclerosis: Insights From Negative Results.

Background: Accumulating evidence indicates that mitochondrial energy failure is involved in the progressive axonal degeneration in multiple sclerosis (MS). In patients with MS, it has been shown that both levels of N-acetylaspartate (NAA), which is a marker of axonal mitochondrial energy, and cerebral blood flow (CBF) are reduced in cerebral normal appearing white matter (NAWM). The latter is likely due to the vasoconstrictive action of endothelin-1 (ET-1) produced by reactive astrocytes, which is triggered by local proinflammatory cytokines. A preliminary study in patients with MS showed that CBF could be restored to normal values after a single dose of 62.5 mg of the ET-1 antagonist bosentan.Objective: To investigate whether restoring CBF in patients with relapsing remitting MS (RRMS) increases levels of NAA in cerebral NAWM and improves clinical symptoms.Methods: 27 RRMS patients were included in a 4 weeks proof-of-concept, randomized, double-blind placebo-controlled trial (ROCHIMS) to investigate whether bosentan 62.5 mg twice daily could increase the NAA/creatine (NAA/Cr) ratio in NAWM of the centrum semiovale. Magnetic resonance imaging (MRI) assessing CBF and NAA/Cr, and clinical evaluations were performed at baseline and at end of study. Separately from the clinical trial, 10 healthy controls underwent the same baseline multimodal brain MRI protocol as the MS patients.Results: Eleven patients in the bosentan arm and thirteen patients in the placebo arm completed the study. Bosentan did not increase CBF. However, we found that CBF in the patients was not different from that of the healthy controls. There were no effects on NAA levels and clinical symptoms.Conclusions: Our study showed that CBF in RRMS patients is not always decreased and that bosentan has no effect when CBF values are within the normal range. We hypothesize that in our patients there was no significant astrocytic production of ET-1 because they had a mild disease course, with minimal local inflammatory activity. Future studies with bosentan in MS should focus on patients with elevated ET-1 levels in cerebrospinal fluid or blood.

Proximal tubule albumin uptake – potential role for endothelin system in sickle cell disease mice

Elevated plasma endothelin‐1 (ET‐1) reported in sickle cell disease (SCD) patients correlate with microalbuminuria, a major mortality risk factor in SCD. ET‐1 contributes to glomerular and tubular injury in SCD, as evidenced by increased glomerular permeability to albumin and urinary excretion of tubular injury markers. Although selective ETA receptor antagonism reduces albuminuria in humanized sickle cell (HbSS) mice, the mechanism of this action remains unclear. The aim of the study was to determine whether selective ETA receptor antagonism prevents albuminuria by preserving the expression of tubular albumin‐associated transporters in proximal tubule (PT) cells. Male C57BL/6 or HbSS and genetic control (HbAA) mice were used to determine the effect of ET‐1 on the expression of proximal tubule albumin trafficking mediators, such as megalin and NHE‐3. Exposure of primary mouse PT cells to ET‐1 (50nM) for 8h decreased megalin (53% reduction) and doubled NHE‐3 expression. Pre‐treatment with the ETA antagonist, BQ123 (1 μM), preserved megalin expression and had no effect on NHE‐3. Moreover, selective ETB receptor blockade (BQ788, 1 μM) prevented ET‐1‐mediated increase in NHE‐3 expression. Primary PT cells isolated from HbSS mice showed decreased megalin mRNA expression as well as protein abundance relative to HbAA PT controls. Ten‐week treatment with selective ETA receptor antagonist (10mg/kg/day) preserved expression of megalin at control levels. There were no differences in NHE‐3 mRNA expression in HbSS PT cells regardless the treatment. Interestingly, PT cells from HbSS cultured with HbSS plasma and ET‐1 (10nM) had decreased NHE‐3 protein abundance compared to non‐treated cells. These results potentially uncover a novel role for ET‐1 in PT albumin handling and suggest that PT ET‐1 receptor signaling contributes to albuminuria in SCD.Support or Funding InformationSupport provided by an NIH U01 HL117684 to D.M.P, AHA 19CDA34660073 and NIH‐NHLBI K99HL144817 to M.K.

Endothelin Receptor Antagonism Increases Cerebral Perfusion in Humans

Microvascular cerebral perfusion (CP) is critical for adequate oxygenation of neuronal tissue in the brain. However, the mechanisms underlying proper CP regulation in humans have yet to be fully defined. Endothelin is a potent endogenous vasoconstrictor and appears to have a modest role in blood flow regulation in many peripheral vascular beds in healthy individuals. We tested the hypothesis that endothelin receptor antagonism will not influence CP in healthy young adults. Six male subjects (age: 24±4 yrs; BMI: 23±2 kg/m2) participated in the single‐blind study in which endothelin receptor antagonist (Ambrisentan, 10 mg) or placebo was administered orally. Only males participated in the current study due to potential teratogenic effects of Ambrisentan. Resting CP was quantified via 3T MRI using pseudo‐continuous arterial spin labeling (ASL) normalized to gray matter volume approximately 120 minutes following dosing. Blood pressure, heart rate, and end‐tidal CO2 were monitored. Data were analyzed via paired t‐tests and reported as mean±SD. Significance was taken as p≤0.05. Heart rate (57±8 vs. 59±7 bpm), mean arterial pressure (81±7 vs. 79±8 mmHg) and end‐tidal CO2 (34±6 vs. 37±3 mmHg) was not different between placebo and Ambrisentan, respectively (all p&gt;0.05). Compared to placebo, Ambrisentan increased cerebral perfusion (31±3 vs. 34±2 mL/100g/min; p&lt;0.05), representing a 8±5% increase. Regionally, Ambrisentan demonstrated a tendency to increase CP in brain regions supplied by the anterior cerebral circulation (frontal lobe: 36±11 vs. 45±5 mL/100g/min, p=0.05; parietal lobe: 35±10 vs. 43±5 mL/100g/min, p=0.08; temporal lobe: 35±10 vs. 43±6 mL/100g/min, p=0.07; basal ganglia: 35±9 vs. 41±5, p=0.09; cingulate: 39±10 vs. 47±5 mL/100g/min, p=0.08). In contrast, CP in regions supplied by the posterior circulation did not increase to a similar extent (occipital lobe: 37±9 vs. 43±7 mL/100g/min, p=0.13; cerebellum 30±16 vs. 38±6 mL/100g/min, p=0.27). Contrary to our hypothesis, these data suggest endothelin contributes to resting CP by increasing microvascular tone, an effect that may be more pronounced in the anterior brain regions. These preliminary findings contribute to resolving potential mechanisms mediating normal CP in healthy individuals and form the basis of future studies exploring the influence of elevated endothelin signaling in conditions like diabetes or heart failure.Support or Funding InformationADA 1‐16‐ICTS‐099

Zibotentan, an Endothelin A Receptor Antagonist, Prevents Amyloid-β-Induced Hypertension and Maintains Cerebral Perfusion.

Cerebral blood flow is reduced in Alzheimer’s disease (AD), which is associated with mid-life hypertension. In people with increased cerebral vascular resistance due to vertebral artery or posterior communicating artery hypoplasia, there is evidence that hypertension develops as a protective mechanism to maintain cerebral perfusion. In AD, amyloid-β (Aβ) accumulation may similarly raise cerebral vascular resistance by upregulation of the cerebral endothelin system. The level of endothelin-1 in brain tissue correlates positively with Aβ load and negatively with markers of cerebral hypoperfusion such as increased vascular endothelial growth factor. We previously showed that cerebroventricular infusion of Aβ40 exacerbated pre-existing hypertension in Dahl rats. We have investigated the effects of 28-day cerebral infusion of Aβ40 on blood pressure and heart rate and their variability; carotid flow; endothelin-1; and markers of cerebral oxygenation, in the (normotensive) Wistar rat, and the modulatory influence of the endothelin A receptor antagonist Zibotentan (ZD4054). Cerebral infusion of Aβ caused progressive rise in blood pressure (p < 0.0001) (paired t-test: increase of 3 (0.1–5.6) mmHg (p = 0.040)), with evidence of reduced baroreflex responsiveness, and accumulation of Aβ and elevated endothelin-1 in the vicinity of the infusion. Oral Zibotentan (3 mg/kg/d, administered for 31 d) abrogated the effects of Aβ40 infusion on baroreflex responsiveness and blood pressure, which declined, although without reduction in carotid blood flow, and Zibotentan caused uncoupling of the positive linear relationship between endothelin-1 and vascular endothelial growth factor, which as a sensor of tissue oxygenation would be expected to increase if there were hypoperfusion.

Endothelin-1 Level in Patients with Simple Renal Cyst.

Endothelin-1 (ET-1) is potent vasoconstrictive peptide and elevated ET-1 levels are associated with hypertension, endothelial dysfunction and atherosclerosis. Research on (ET-1) has demonstrated that elevated ET-1 levels in autosomal dominant polycystic kidney disease leads to systemic hypertension. The prevalence of simple renal cysts increases with age and the association with simple renal cyst and hypertension is not clear. The aim of this study was to investigate the ET-1 levels in patients with simple renal cyst and compare them with those in healthy adults. The study included patients that underwent laparoscopic renal cyst decortication in the Department of Urology and healthy controls. Serum and urinary ET-1 levels were measured before surgery and one month after it in the patients with simple renal cyst. Serum ET-1 levels were measured in healthy adult patients. Ambulatory blood pressure was measured in all patients. Glomerular filtration rate was measured according to the chronic kidney disease epidemiology collaboration formula. Thirty-two patients were included in the present study. Of these, 16 patients with simple renal cyst were allocated into group 1 and 16 healthy patients - in group 2. There was no significant difference between systolic and diastolic blood pressure between the groups (. The present study demonstrated that serum EL-1 level in patients with simple renal cyst was lower than that in healthy people. Further studies are needed to investigate the EL-1 levels in simple renal cyst patients.

Elevated Endothelin-1 in Intradialytic Hypertension

Objective: To determine the relative change in endothelin-1 (ET-1) during hemodialysis procedure in Stage Five Dialysis-Dependent Chronic Kidney Disease (CKD-5D)patients with and without intradialytic hypertension (IDH). Methods: This was a cross-sectional, observational study involving 40 CKD-5D patients who received two hemodialysis per week for at least three months at the dialysis unit of Dr. Hasan Sadikin Hospital General Bandung, Indonesia during September 2016. Subjects were divided two groups: with IDH (n=20) and without IDH (n=20). Plasma ET-1 level was examined before and after hemodialysis. Results: There was a significant elevation of ET-1 level (mean±SD pg/mL) between pre- and post-dialysis state in patients with IDH (3.33±1.28 vs. 3.84±1.75; relative changes: 15.32%, p=0.013). No change was observed in patients without IDH (3.99±2.30 vs. 4.38±1.81; relative changes: 9.77% p=0.083). The post-dialysis absolute ET-1 level was significantly lower in CKD-5D patients with IDH (3.84±1.75 vs. 4.38±1.81; p=0.024). Conclusion: There was a significant elevation of ET-1 level in CKD-5D patients with IDH during hemodialysis procedure at the dialysis unit of Dr. Hasan Sadikin General Hospital Bandung.

Abstract 071: Endothelin-1 Contributes to Vascular Dysfunction in Peri-Menopausal Women

Declines in vascular function occur early in the menopausal transition, as previously demonstrated by a reduction in endothelial function in perimenopausal women (PERI). However, the mechanisms contributing to this decline remain to be elucidated. We have previously shown that vascular impairments in postmenopausal women (POST) are due in part to endothelin-1 (ET-1). Thus, the purpose of this study is to determine if ET-1 contributes to reductions in vascular function across the stages of the menopausal transition. We hypothesized plasma ET-1 levels would be elevated across menopausal stages, and negatively associated with endothelial function. We further hypothesized that ETB receptors would contribute to impaired vascular function in PERI. Methods: We measured vascular endothelial function (flow-mediated dilation, FMD) and plasma ET-1 in 180 women classified as premenopausal (PRE, n=33, 33±7 years), early PERI (n=20, 50±3 years), late PERI (n=25, 50±4 years), early POST (n=36, 55±3 years), and late POST (n=58, 60±4 years) based on the STRAW criteria. In a separate, secondary study, we measured cutaneous microvascular endothelial function via local heating during microdialysis perfusions of lactated Ringers (control) or ETB receptor antagonist (BQ-788, 300 nM) in 6 PRE (22±2 years) and 8 PERI (50±3 years). Results: Plasma ET-1 concentration increased in a step-wise fashion across menopausal stage (PRE 5.4±1.1, early PERI 5.8±1.0, late PERI 6.1±1.6, early POST 6.4±1.6, late POST 6.4±1.5 pg/mL; P&lt;0.01). Furthermore, there was a significant inverse correlation between plasma ET-1 and brachial artery FMD (r=0.28; P&lt;0.001). In our secondary study, cutaneous microvascular vasodilation was lower in PERI compared to PRE (82±7 vs 92±8 %CVCmax, P &lt;0.05). In PRE, ETB receptor blockade mediated dilation (control: 92±8 vs ETB: 83±9 %CVCmax, P &lt;0.05), however this effect was lost in PERI (82±7 vs 92±4 %CVCmax, P &lt;0.05). Conclusions: These data suggest that elevated ET-1 contributes to impairments in vascular endothelial function across the menopausal transition. Furthermore, the decline in endothelial function is evident in the macro- and micro- circulation during the perimenopausal transition, due in part to a loss of ETB mediated dilation.

Endothelin-1, cardiac morphology, and heart failure: the MESA angiogenesis study

Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis. However, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In this study, we evaluated the relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured. ET1 was measured in 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression, participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 ml smaller per log increase in ET1, 95% confidence interval 17.1-0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%-5.2%, p = 0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p = 0.03 and p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels could not be clearly shown in a model including health behaviors. These results suggest, but do not confirm, that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.

The relationship with clinical course and prognosis of serum endothelin-1, angiopoietin-2, and tie-2 levels in Crimean-Congo hemorrhagic fever

Background/aimCrimean-Congo hemorrhagic fever (CCHF) is a serious illness characterized by fever and hemorrhage. Endothelin-1 (ET-1), angiopoietin-2 (Ang-2), and endothelial cell-specific receptor tyrosine kinase (Tie-2) are believed to be important markers of the pathogenesis, clinical course, and prognosis of the disease. The aim of this study was to determine ET-1, Ang-2, and Tie-2 levels in adults with CCHF and investigate the associations between these markers and pathogenesis and disease course.Materials and methodsSixty CCHF patients were included in the study. The patients were classified according to disease severity criteria and Ang-2, Tie-2, and ET-1 levels were compared.ResultsMean serum ET-1 level was 36.62 ± 27.99 pg/mL in the patient group and 3.70 ± 4.71 pg/mL in the control group (P = 0.001). Mean serum Ang-2 levels were 2511.18 ± 1018.64 pg/mL in the patient group and 3570.76 ± 209.52 pg/mL in the control group (P = 0.001). Mean serum Tie-2 levels were 7.35 ± 7.75 ng/mL in the patient group and 0.67 ± 1.26 ng/mL in the control group (P = 0.001). ConclusionElevated ET-1 and Tie-2 levels were associated with more severe disease course, while Ang-2 level was negatively correlated with severity in adult CCHF patients. ET-1, Tie-2, and Ang-2 levels are important prognostic parameters in CCHF and may contribute significantly to treatment and follow-up.

SUN-079 Loss of Endothelial CEACAM1 Induces Atherogenic Fibrous Plaque Formation

Loss of Endothelial CEACAM1 Induces Atherogenic Fibrous Plaque Formation Carcinoembryonic antigen-related cell adhesion molecule1 (CEACAM1), a substrate of insulin and VEGF receptors, regulates insulin sensitivity by promoting hepatic insulin clearance. Global Ceacam1 gene deletion impaired insulin clearance to cause chronic hyperinsulinemia and peripheral insulin resistance [1]. It also caused spontaneous endothelial dysfunction and hypertension [2] in addition to atherogenic-like plaques in addition to lipid and macrophage deposition, as well as elevated leukocyte rolling and adhesion to the aortic wall in the absence of hypercholesterolemia and hypertriglyceridemia when the mutation was propagated on the C57BL/6 genetic background [3]. Because CEACAM1 promotes endothelial survival, vascular integrity, and pro-angiogenesis, we investigated the cell-autonomous role of endothelial cell CEACAM1 in the pathogenesis of atherosclerosis. To this aim, we generated endothelial cell CEACAM1 knockout mice and backcrossed them with low density lipoprotein receptor deficient mice (ldlr–/– VECad+Cc1fl/fl) prior to feeding them a high cholesterol diet for 3 months and characterizing both of their metabolic and vascular phenotypes. By comparison to ldlr–/– mice, the mutants exhibited insulin sensitivity and moderate hypercholesterolemia. However, they exhibited decreased nitric oxide (NO) bioavailability with a reciprocal increase in plasma endothelin-1 and increased oxidative stress. The mutants also developed fibrotic plaques with elevated macrophage recruitment on the aortic wall without lipid deposition. We postulate that endothelin-1 contributes to fibrosis in these mice. Elevated endothelin-1 levels could stem from increased ras-MAPKinase signaling pathways in response to lower sequestration of Shc and increased coupling of Grb2 to insulin and VEGR in the absence of Ceacam1. Moreover, in the absence of Ceacam1, binding of Shp2 phosphatase to IRS1 increases to reduce IRS-1/Akt/eNOS activity and subsequently, lower NO production. Thus, the ldlr–/– VECad+Cc1fl/fl mouse can provide an in vivo system to delineate the endothelial cell-specific CEACAM1 effect on fibrosis independent of systemic risk factors.

Elevated plasma endothelin-1 is associated with reduced weight loss post vertical sleeve gastrectomy

BackgroundObesity and insulin resistance are positively correlated with plasma endothelin-1 (ET-1) levels; however, the mechanisms leading to increased ET-1 are not understood. Similarly, the full physiological complexity of ET-1 has yet to be described, especially in obesity. To date, one of the best treatments available for morbid obesity is bariatric surgery to quickly reduce body fat and the factors associated with obesity-related disease; however, the effects of vertical sleeve gastrectomy (SG) on plasma ET-1 have not been described. ObjectivesTo determine if SG will reduce plasma ET-1 levels and to determine if plasma ET-1 concentration is associated with weight loss after surgery. SettingThe studies were undertaken at a University Hospital. MethodsThis was tested by measuring plasma ET-1 levels from 12 obese patients before and after SG. All data were collected from clinic visits before SG, 6 weeks after SG, and 6 months after surgery. ResultsAt 6 weeks after SG, plasma ET-1 levels increased by 24%; however, after 6 months, there was a 27% decrease compared with presurgery. Average weight loss in this cohort was 11.3% ± 2.4% body weight after 6 weeks and 21.4% ± 5.7% body weight after 6 months. Interestingly, we observed an inverse relationship between baseline plasma ET-1 and percent body weight loss (R2 = .49, P = .01) and change in body mass index 6 months (R2 = .45, P = .011) post bariatric surgery. ConclusionsOur results indicate that SG reduces plasma ET-1 levels, a possible mechanism for improved metabolic risk in these patients. These data also suggest that ET-1 may serve as a predictor of weight loss after bariatric surgery.

444: 17-Hydroxyprogesterone caproate improves hypertension and endothelin-1 in response to sFlt-1induced hypertension in pregnant rats

Preeclampsia (PE) is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and endothelin-1 (ET-1) levels. We and others have previously demonstrated that infusion of sFlt-1 into pregnant rodents causes hypertension, indicating an important role for sFlt-1 in mediating the pathophysiology of the disease. Currently there is no effective treatment for PE except for delivery of the fetal placental unit, making PE a leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC) is used for prevention of recurrent preterm birth, but not for treatment of PE. This study was designed to test the hypothesis that 17-OHPC improves hypertension and ET-1 in response to sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg−1·day−1 for 6 days, gestation days 13-19) in the presence or absence of 17-OHPC (3.32mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Mean arterial blood pressure (MAP), renal cortex endothelin-1 expression and Nitrate-Nitrite levels were measured on GD 19. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 112+2 (n=11) vs. 98+2 mmHg (n=15, p<0.05). Administration of 17-OHPC attenuated this hypertension reducing MAP to 99+4 mmHg in sFlt-1 treated pregnant rats (n=8). Importantly, renal cortex PPET-1 expression was elevated 3 fold in NP+sFlt-1 rats compare to NP rats, which decreased with 17-OHPC administration. Plasma nitrate-nitrite levels were 26 μM in NP rats (n=6), 17 μM in NP+sFlt-1 (n=4), which increased to 27 μM NP+sFlt-1+17OHPC (n=5). Neither pup nor placental weight was affected by sFlt-1 or 17-OHPC. Administration of 17-OHPC improves hypertension in response to elevated sFlt-1 during pregnancy and should be considered further in the management of PE.

Association of Endothelin-1 With Accelerated Cardiac Allograft Vasculopathy and Late Mortality Following Heart Transplantation

Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans. In 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; P = .007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; P = .01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; P = .003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; P = .44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (P = .047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; P = .02). Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

Risk factors for hypertensive retinopathy in a Chinese population with hypertension: The Beijing Eye study.

Hypertensive retinopathy (HRP) is a clinical feature and systemic manifestation of hypertension. There have been few reports on the risk factors for hypertensive retinopathy in China. The aim of the present study was to describe risk factors associated with HRP in a population-based sample of Chinese patients with hypertension in Beijing. The clinical data of 228 hypertensive patients was retrospectively studied, including 112 patients with retinopathy for the HRP group and 116 patients without retinopathy for the NO-HRP group. Basic clinical data and plasma clinical indicators of the two groups were compared. Logistic regression models were used to assess risk factors associated with HRP. Duration of hypertension, smoking habits, family history of hypertension, plasma level of endothelin-1 (ET-1) and systolic and diastolic blood pressure were significantly increased in the HRP group compared with the NO-HRP group (P<0.05). No significant differences were identified between the two groups for other factors. Logistic regression models indicated that hypertension duration (P<0.001, 95% CI: 0.962-0.988) and ET-1 level (P<0.001, 95% CI: 1.144-1.278) were significantly associated with HRP. The diagnostic threshold of ET-1 to diagnosis HRP was 43.5 ng/l. Of the factors studied, longer hypertension duration and elevated ET-1 level were identified to be risk factors for HRP in patients with hypertension from Beijing. Detecting the plasma level of ET-1 in patients with hypertension may be a useful diagnostic indicator for HRP.