Plasma Endothelin-1 Levels Research Articles

Evaluation of biomarkers related to endothelial dysfunction: proof of vasculopathy in anti-melanoma differentiation-associated gene 5 dermatomyositis.

We aimed to reveal evidence of endothelial dysfunction in the development of anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM). Thirty anti-MDA5 DM patients were enrolled and compared with patients with polymyositis (PM) (n=10) and healthy controls (n=20). The concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelin-1 (ET-1) and von Willebrand factor (vWF) as well as interferon-alpha (IFN-α) and Galcetin-9 in the peripheral blood were tested by enzyme-linked immunosorbent assay (ELISA). Plasma levels of sICAM-1, sVCAM-1, ET-1 and vWF were higher in the anti-MDA5 DM patients than in either the healthy controls or the PM patients. In the anti-MDA5 DM cohort, the ET-1 and vWF levels were significantly lower in the cases without cutaneous ulcers and ILD than the other cases. There was a strong positive relationship between the concentrations of ET-1 and Galectin-9 in the anti-MDA5 DM group. Our data suggest that endothelial dysfunction may be involved in the development of anti-MDA5 DM.

Loss of Hepatic Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Links Nonalcoholic Steatohepatitis to Atherosclerosis.

Patients with nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) commonly develop atherosclerosis through a mechanism that is not well delineated. These diseases are associated with steatosis, inflammation, oxidative stress, and fibrosis. The role of insulin resistance in their pathogenesis remains controversial. Albumin (Alb)Cre+ Cc1flox ( fl ) /fl mice with the liver‐specific null deletion of the carcinoembryonic antigen‐related cell adhesion molecule 1 (Ceacam1; alias Cc1) gene display hyperinsulinemia resulting from impaired insulin clearance followed by hepatic insulin resistance, elevated de novo lipogenesis, and ultimately visceral obesity and systemic insulin resistance. We therefore tested whether this mutation causes NAFLD/NASH and atherosclerosis. To this end, mice were propagated on a low‐density lipoprotein receptor (Ldlr)−/− background and at 4 months of age were fed a high‐cholesterol diet for 2 months. We then assessed the biochemical and histopathologic changes in liver and aortae. Ldlr−/−AlbCre+Cc1fl/fl mice developed chronic hyperinsulinemia with proatherogenic hypercholesterolemia, a robust proinflammatory state associated with visceral obesity, elevated oxidative stress (reduced NO production), and an increase in plasma and tissue endothelin‐1 levels. In parallel, they developed NASH (steatohepatitis, apoptosis, and fibrosis) and atherosclerotic plaque lesions. Mechanistically, hyperinsulinemia caused down‐regulation of the insulin receptor followed by inactivation of the insulin receptor substrate 1–protein kinase B–endothelial NO synthase pathway in aortae, lowering the NO level. This also limited CEACAM1 phosphorylation and its sequestration of Shc‐transforming protein (Shc), activating the Shc–mitogen‐activated protein kinase–nuclear factor kappa B pathway and stimulating endothelin‐1 production. Thus, in the presence of proatherogenic dyslipidemia, hyperinsulinemia and hepatic insulin resistance driven by liver‐specific deletion of Ceacam1 caused metabolic and vascular alterations reminiscent of NASH and atherosclerosis. Conclusion: Altered CEACAM1‐dependent hepatic insulin clearance pathways constitute a molecular link between NASH and atherosclerosis.

Efficacy of Acupuncture Treatment to Prevent Cerebral Vasospasm After Subarachnoid Hemorrhage: A Double-Blind, Randomized Placebo-Controlled Trial.

Objectives: To investigate the efficacy of acupuncture in preventing cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) and explore its underlying mechanism. Design: A randomized, double-blinded, and placebo-controlled trial. Setting/Location: Subjects were recruited from Kyung Hee University Hospital at Gangdong, Seoul, Korea Subjects: A total of 50 patients admitted with acute SAH. Interventions: The study group received acupuncture treatments (n = 25), while the control group underwent mock transcutaneous electrical nerve stimulation and sham acupuncture (n = 25) six times/week for 2 weeks. Outcome measures: The primary outcome was the incidence of delayed ischemic neurologic deficit (DIND), and secondary measurements included angiographic vasospasm, vasospasm-related infarction, modified Rankin Scale score, and plasma nitric oxide (NO) and endothelin-1 (ET-1) levels. Results: The study group treated with acupuncture showed a lower incidence of DIND (9.1%) than the control group (20.8%); however, this difference in the incidence of DIND was not statistically significant. The study group demonstrated better clinical outcomes, especially in functional recovery. Significant alterations in plasma NO and ET-1 levels after the 2-week intervention were observed only in the study group. Conclusions: Their study shows that acupuncture treatment improved functional recovery after SAH and could potentially prevent cerebral vasospasm. These effects could be attributed to the recovery of endothelial dysfunction by acupuncture through modulating the plasma NO and ET-1 levels. The study protocol has been registered on www.clinicaltrials.gov (NCT02275949).

Role of FAK signaling in chagasic cardiac hypertrophy

Cardiac hypertrophy and dysfunction are a significant complication of chronic Chagas disease, with heart failure, stroke, and sudden death related to disease progression. Thus, understanding the signaling pathways involved in the chagasic cardiac hypertrophy may provide potential targets for pharmacological therapy. Herein, we investigated the implication of focal adhesion kinase (FAK) signaling pathway in triggering hypertrophic phenotype during acute and chronic T. cruzi infection. C57BL/6 mice infected with T. cruzi (Brazil strain) were evaluated for electrocardiographic (ECG) changes, plasma levels of endothelin-1 (ET-1) and activation of signaling pathways involved in cardiac hypertrophy, including FAK and ERK1/2, as well as expression of hypertrophy marker and components of the extracellular matrix in the different stages of T. cruzi infection (60–210 dpi). Heart dysfunction, evidenced by prolonged PR interval and decrease in heart rates in ECG tracing, was associated with high plasma ET-1 level, extracellular matrix remodeling and FAK signaling activation. Upregulation of both FAK tyrosine 397 (FAK-Y397) and serine 910 (FAK-S910) residues phosphorylation as well as ERK1/2 activation, lead to an enhancement of atrial natriuretic peptide gene expression in chronic infection. Our findings highlight FAK-ERK1/2 signaling as a regulator of cardiac hypertrophy in Trypanosoma cruzi infection. Both mechanical stress, induced by cardiac extracellular matrix (ECM) augment and cardiac overload, and ET-1 stimuli orchestrated FAK signaling activation with subsequent activation of the fetal cardiac gene program in the chronic phase of infection, highlighting FAK as an attractive target for Chagas disease therapy.

Abstract P180: Effect Of Sunitinib Treatment On Skin Sodium Accumulation In Patients With Metastatic Renal Cancer: A Pilot Study

Angiogenesis is required for invasive tumor growth and metastasis which is controlled mainly by vascular endothelial growth factors (VEGF). Novel strategies for cancer treatment target VEGF signaling. These agents are featured by adverse events including hypertension. New concepts suggest that besides the kidneys, the skin also plays a role in body sodium homeostasis and blood pressure regulation by a VEGF-C–dependent buffering mechanism. Here, we tested the hypothesis that changes in blood pressure correspond to tissue sodium accumulation during sunitinib treatment of metastatic renal cell carcinoma patients (https://clinicaltrials.gov/identifier: NCT04368546; Charité ethical approval EA1/044/15).Male patients (n=4) took sunitinib according to the standard treatment protocol, 50 mg once daily, taken for 4 weeks followed by a 2-weeks off treatment period. Measurements were performed at baseline (before sunitinib treatment), and over a complete on-off-on period. Tissue sodium content was measured using non-invasive 23Na-MRI; skin sodium was measured in a group (n=5) of age-matched healthy subjects, as well. Blood pressure was measured according to AHA guidelines. Blood withdrawal followed after ca. 45 minutes of sitting to measure VEGF-A, VEGF-C, endothelin-1, renin and aldosterone levels.Elevated systolic blood pressure under sunitinib treatment decreased to the baseline level in the off-treatment phase (130.5 mmHg vs 117.5 mmHg, respectively, p<0.05). Plasma endothelin-1 levels mirrored directly and VEGF-A levels inversely the blood pressure changes. Baseline skin sodium content was similar to the skin sodium level of healthy controls. Skin sodium content was elevated after the first on-treatment phase and stayed high in all the following measurements in comparison to control subjects. Patients had high baseline VEGF-C levels that decreased after the first treatment with sunitinib and stayed low independently of further treatment phase.In conclusion, sunitinib treatment suppresses VEGF-C levels permanently which is associated with sustained elevated skin sodium levels. Furthermore, we confirmed the association between plasma endothelin-1 levels and blood pressure changes during sunitinib treatment protocol.

Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model

This study aimed to investigate the role of endothelin-1 (ET-1), originally known as the potent vasoconstrictor, and its receptors in chondrocyte senescence and osteoarthritis (OA) development. Temporal changes of ET-1 and its receptors with OA development were characterized in a posttraumatic OA (PTOA) mouse model at time zero, 1-month and 4-month after surgical induction via destabilization of medial meniscus (DMM). A transgenic ET-1 overexpression (TET-1) mouse model was deployed to assess the impact of upregulated ET-1 on chondrocyte senescence and cartilage degradation. Effects of endothelin receptor blockade on chondrocyte senescence and OA development were further examined both in vitro and in vivo. Local expression of ET-1 in subchondral bone and synovium upregulated after DMM with an increase of plasma ET-1 level from 3.18±0.21pg/ml at time zero to 6.47±0.34pg/ml at 4-month post-surgery. Meanwhile, endothelin type B receptor (ETBR) (53.31±2.42% to 83.8±2.65%) and p16INK4a (10.91±1.07% to 28.2±1.0%) positve chondrocytes accumulated in articular cartilage since 1-month prior to cartilage loss at 4-month post-surgery. Overexpressed ET-1 promoted p16INK4a-positive senescent chondrocytes accumulation and cartilage degradation in TET-1 mice. Selective blockade of ETBR, but not ETAR, lowered the expression of p16INK4a in ET-1 or H2O2-induced chondrocyte senescence model, and mitigated the severity of murine PTOA. Intriguingly, reactive oxygen species (ROS) scavenger, Vitamin C, could rescue ET-1-induced chondrocyte senescence in vitro associated with restoration of mitochondrial dynamics. ET-1 could induce chondrocytes senescence and cartilage damages via ETBR in PTOA.

Hyperglycemia does not Inhibit Insulin's Effects on Microvascular Perfusion in Healthy Humans: A Randomized Crossover Study.

Diabetes mellitus accelerates vascular disease through multiple biochemical pathways driven by hyperglycemia, with insulin resistance and/or hyperinsulinemia also contributing. Persons with diabetes mellitus experience premature large vessel and microvascular disease when compared to normoglycemic controls. Currently there is a paucity of clinical data identifying how acutely the vasculature responds to hyperglycemia and whether other physiologic factors (e.g., vasoactive hormones) contribute. To our knowledge, no prior studies have examined the dynamic effects of acute hyperglycemia on insulin-mediated actions on both micro- and macrovascular function in the same subjects. In this randomized crossover trial, healthy young adults underwent two infusion protocols designed to compare the effects of insulin infusion during euglycemia and hyperglycemia on micro- and macrovascular function. Both euglycemic- and hyperglycemic-hyperinsulinemia increased skeletal (but not cardiac) muscle microvascular blood volume (each p<0.02) and blood flow significantly (each p<0.04), and these increases did not differ between protocols. Hyperglycemic-hyperinsulinemia trended towards increased carotid-femoral pulse wave velocity (indicating increased aortic stiffness; p= 0.065 after Bonferroni adjustment), while euglycemic-hyperinsulinemia did not. There were no changes in post-ischemic flow velocity or brachial artery flow-mediated dilation during either protocol. Plasma endothelin-1 levels significantly decreased during both protocols (each p<0.02). In this study, acute hyperglycemia for 4 hours did not inhibit insulin's ability to increase skeletal muscle microvascular perfusion but did provoke a slight increase in aortic stiffness. Hyperglycemia also did not adversely affect myocardial microvascular perfusion or endothelial function or prevent the decline of endothelin-1 during insulin infusion.

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.

Inhibition of mite-induced dermatitis, pruritus, and nerve sprouting in mice by the endothelin receptor antagonist bosentan.

Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model. We analyzed the mite-induced AD-like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation. Topical application of bosentan significantly attenuated the development of mite-induced AD-like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation-regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13, Il17, and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose- and time-dependent manner, bosentan treatment attenuated this. EDN1 plays a significant role in mite-induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.

Cardiovascular Biomarkers and Calculated Cardiovascular Risk in Orally Treated Type 2 Diabetes Patients: Is There a Link?

The aim of the study was to test the correlation of serum levels of asymmetric dimethylarginine (ADMA), endothelin 1 (ET-1), N-terminal brain natriuretic pro-peptide (NT-proBNP), and placental growth factor (PIGF-1) with estimated cardiovascular (CV) risk. The study group was composed of 102 women and 67 men with type 2 diabetes, having their glycemic and metabolic parameters assessed. All were on oral antidiabetic drugs. Serum levels of NT-proBNP and PIGF-1 were measured by electro-hemi-luminescence on an Elecsys 2010 analyzer. Enzymatic immunoassays were used for ADMA and ET-1. The Framingham Risk Score (FRS), the UKPDS 2.0 and the ADVANCE risk engines were used to calculate cardiovascular risks while statistical analysis was performed on SPSS. Levels of PIGF-1 showed no correlation with the calculated CV risks. The same was true for ADMA, except for a weak correlation with the UKPDS-based 10-year risk for stroke (Pearsons's R=0.167, p=0.039). Plasma levels of ET-1 were correlated with the UKPDS-based 10-year risk for stroke (R=0.184, p=0.032) and fatal stroke (R=0.215, p=0.012) only. NT-proBNP was significantly correlated with all CV risk calculations: ADVANCE-based 4-yr risk (Spearman's Rho=0.521, p<0.001); UKPDS-based 10-year risk for: CHD (Rho=0.209, p=0.01), fatal CHD (Rho=0.282, p<0.001), stroke (Rho=0.482, p<0.001), fatal stroke (Rho=0.505, p<0.001); and 10-year FRS risk (Rho=0.246, p=0.002). In conclusion, ADMA and PIGF-1 did not seem useful in stratifying CV risk while ET-1 is linked to the risk of stroke, and NT-proBNP to all CV risk estimations.

Insights into Endothelin-3 and Multiple Sclerosis.

Endothelins are powerful vasoconstrictor peptides that play numerous other roles. Endothelin-1 (ET1) is the principal isoform produced by the endothelium in the human cardiovascular system. Endothelin-3 (ET3) and its rPptor affinity have been demonstrated to support neuronal repair mechanisms throughout life. In multiple sclerosis (MS), the role of vasoactive peptides are not well defined. Here we focus on ET3, specifically the plasma levels between MS patients and healthy subjects. Furthermore, we evaluated the changes in ET1 and ET3 plasma levels during different disease phases, the correlation between ET3 and cerebral circulation time, and the relationship between ET1 and ET3. In MS patients, the ET3 plasma levels were altered in a time-dependent manner. These results could support a putative role of ET3 in neuroprotection and/or neuroimmune modulation over time.

Effect of positive end-expiratory pressure ventilation on plasma nitric oxide, endothelin-1 and vascular celladhesion molecule-1 levels in patients undergoing uvulopalatopharyngoplasty.

During uvulopalatopharyngoplasty (UPPP), cardiovascular adverse events may occur which can be harmful to patients. To evaluate the effect of the protective ventilation strategy on the function of vascular endothelial cells. Forty obstructive apnea syndrome (OSA) patients who underwent uvulopalatopharyngoplasty (UPPP) were enrolled. Patients were randomly divided into the control group (group C, PEEP = 0 cm H2O) and PEEP group (group P, PEEP = 5 cm H2O). Each group (n= 20) received intermittent volume controlled ventilation (VCV) with tidal volume 6 ml/kg of the predicted body weight, I:E 1:2, rate titrated for ETCO2 35-45, FiO2 0.7. Blood from the radial artery was sampled for blood gas analysis at four time points: the fifth minute of inhaling pure oxygen (T0), after tracheal intubation (T1), at the end of the operation (T2), and 20 minutes after extubation (T3). Three ml of arterial blood was retained, preserved at -20∘C after serum isolation, and plasma nitric oxide (NO), endothelin-1 (ET-1) and vascular celladhesion molecule-1 (VCAM-1) levels were determined by enzyme linked immunosorbent assay (ELISA). Compared with group C, plasma ET-1 at T3 decreased in group P, and plasma NO levels at T2 and T3 increased (P< 0.05). Compared with samples collected at T0, plasma VCAM-1 levels at T1, T2 and T3 increased in group C, while plasma VCAM-1 levels at T2 and T3 decreased in group P (P< 0.05). Compared with group C, plasma VCAM-1 levels T2 and T3 decreased in group P (P< 0.05). Positive end-expiratory pressure (PEEP) ventilation has a protective effect on vascular endothelial cell function in patients during UPPP.

Down-regulation of EDN1 gene expression by circulating miR-206 is associated with risk of preeclampsia.

To study the correlation between circulating microRNA-206 (miR-206) levels and endothelin-1 (ET-1) levels, and to explore its association with preeclampsia (PE) risk.Reverse transcription-PCR (RT-PCT) was used to compare the plasma miR-206 levels in 200 PE patients and 200 healthy controls. The correlation between miR-206 and ET-1 levels in plasma of PE patients was analyzed by Pearson analysis. MiR-206 was transfected into human umbilical vein endothelial cells cells and ET-1 expression was analyzed by enzyme-linked immunosorbent assay.RT-PCR results showed that plasma miR-206 levels in PE patients were significantly higher than those in the control group (P < .01). The results of receiver operating characteristic curve analysis showed that the area under the curve of plasma miR-206 level in the diagnosis of PE was 0.94 (95% confidence interval: 0.92-0.96). Plasma ET-1 levels in PE patients were significantly lower than those in the control group by enzyme-linked immunosorbent assay (P < .01). The area under the curve of plasma ET-1 level in the diagnosis of PE was 0.92 (95% confidence interval: 0.90-0.95). The level of miR-206 in plasma was negative correlated with ET-1 level (r = -0.37, P < .01). The expression level of ET-1 was significantly decreased in human umbilical vein endothelial cells cells transfected with miR-206.miR-206 can down-regulate the expression of EDN1 gene, which may be related to the increased risk of preeclampsia.

Radix Puerariae rebalances vasomotor factors and improves left ventricular diastolic dysfunction in patients with essential hypertension.

The aim of the present study was to validate the beneficial role of Radix Puerariae in rebalancing the plasma levels of endothelin, angiotensin II (AngII) and calcitonin gene-related peptide (CGRP) in patients with essential hypertension (EHT). A total of 150 patients with EHT were enrolled consecutively and randomized to receive antihypertensive drugs according to guideline-directed medical therapy (GDMT group) and GDMT plus Radix Puerariae (GDMT + RP group). The blood pressure was recorded biweekly. At baseline and at the end of the follow-up (12 weeks), the plasma levels of endothelin, AngII and CGRP were detected, whilst the left ventricular (LV) diastolic function was evaluated by echocardiography. At baseline, the two groups did not differ in terms of demographic characteristics and LV diastolic dysfunction. At the end of the follow-up, lower blood pressure was observed in the GDMT + RP compared with that in the GDMT group. The plasma levels of AngII and endothelin were also significantly lower in the GDMT + RP group. The plasma levels of CGRP increased significantly in the GDMT + RP compared with those in the GDMT group. The addition of Radix Puerariae improved LV diastolic function, with the percentage of dysfunction decreasing to only 9%, while this percentage remained significantly elevated (21%) in the GDMT group. The results of the present study demonstrated that Radix Puerariae is able to regulate blood pressure and the plasma levels of endothelin, AngII and CGRP in patients with EHT. LV diastolic dysfunction was also improved, as detected by echocardiography.

Plasma Endothelin-1 and Risk of Death and Hospitalization in Patients Undergoing Maintenance Hemodialysis.

Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide implicated in the pathogenesis of hypertension, congestive heart failure, and inflammation, all of which are critical pathophysiologic features of CKD. To test the hypothesis that plasma endothelin-1 levels are associated with increased risks of mortality and hospitalization in patients with chronic kidney failure, we measured plasma endothelin-1 levels in a prospective cohort of 794 individuals receiving maintenance hemodialysis. The primary outcomes were time to death and time to hospitalization. The median plasma endothelin-1 level was 2.02 (interquartile range, 1.57-2.71) pg/ml. During a median follow-up period of 28 (interquartile range, 21-29) months, 253 individuals (32%) died and 643 individuals (81%) were hospitalized at least once. In multivariable models adjusted for demographic, clinical, and laboratory variables, individuals in the highest quartile of plasma endothelin-1 had a 2.44-fold higher risk of death (hazard ratio, 2.44; 95% confidence interval, 1.61 to 3.70) and a 1.54-fold higher risk of hospitalization (hazard ratio, 1.54; 95% confidence interval, 1.19 to 1.99) compared with individuals in the lowest quartile. The Harrell C-statistic of the fully adjusted model increased from 0.73 to 0.74 after addition of natural log-transformed plasma endothelin-1 (P<0.001) for all-cause mortality, and increased from 0.608 to 0.614 after addition of natural log-transformed plasma endothelin-1 (P=0.002) for hospitalization. Higher plasma endothelin-1 is associated with adverse clinical events in patients receiving hemodialysis independent of previously described risk factors. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020_05_15_CJN11130919.mp3.

Clinical research of Xiaoqinglong Decoction and Tingli-Dazao-Xiefei Decoction on treating chronic heart failure with syndrome of cold phlegm obstructing lung

Objective To observe the effects of Xiaoqinglong Decoction and Tingli-Dazao-Xiefei Decoction in treating chronic heart failure with syndrome of cold phlegm obstructing lung. Methods Eighty-six chronic heart failure patients from January of 2017 to December of 2018 in our hospital who met the inclusion criteria were selected and divided into 2 groups according to the random number table method with 43 patients in each group. The control group was treated with conventional therapy, and the observation group was orally treated with Xiaoqinglong Decoction and Tingli-Dazao-Xiefei Decoction. Both groups were treated for 3 months. Then scored the symptoms of cold phlegm obstructing lung from four aspects: palpitations, cough and asthma, uria and edema, and sputum. The ultrasonic cardiogram was used to detect the left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular ejection fraction (LVEF). The ELISA method was used to measure levels of vascular pseudohemophilia factor (vWF),endothelin-1 (ET-1) and serum levels of total antioxidant capacity (TAC), lipid peroxide (LPO), SOD, MDA. The efficacy was evaluated. Results The total effective rate of the observation group was 90.7% (39/43), significantly higher than that of the control group as 69.8% (30/43), and the difference between the two groups was statistically significant (χ2=4.692, P=0.030). After the treatment, scores of palpitation, cough and asthma, urine and sputum in the observation group were obviously lower than those of the control group (t value were 7.621, 7.033, 6.831, 6.635, respectively, all Ps<0.01); the LVEDD (51.41 ± 5.69 mm vs. 58.49 ± 6.77 mm, t=9.809), LVESD (40.04 ± 4.48 mm vs. 43.25 ± 5.21 mm, t=6.776) of the observation group were significantly lower than that of the control group, and while LVEF (50.16% ± 5.89% vs. 45.87% ± 5.16%, t=7.761) was significantly higher than that of the control group (P<0.01). Plasma levels of vWF (103.55% ± 11.98% vs. 138.11% ±15.71%, t=41.453) and ET-1 (67.05 ± 7.18 pg/ml vs. 81.72 ± 10.03 pg/ml, t=18.990) in the observation group were significantly lower than that of the control group (P<0.01). The serum levels of TAC and SOD levels in the observation group were significantly higher (t value were 4.662, 13.331, respectively, all Ps<0.01), while LPO and MDA levels were significantly lower than the control group (t value were 4.982, 4.031, all Ps<0.01). Conclusions The Xiaoqinglong Decoction and Tingli-Dazao-Xiefei Decoction in treating chronic heart failure can improve the heart function and symptoms with syndrome of cold phlegm obstructing lung, and increaseclinical efficacy. Key words: Heart failure; Cold phlegm obstructing lung; Xiao Qing Long Tang; Tingli-Dazao-Xiefei Decoction; Therapies, investigational

Mandibular Advancement Devices Prevent the Adverse Cardiac Effects of Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS)

Although considerable research highlights the interactions between obstructive sleep apnea-hypopnea syndrome (OSAHS) and cardiovascular diseases, the effect of mandibular advancement device (MAD) treatment on cardiovascular complications in OSAHS patients remains unclear. We evaluated the effect of OSAHS treatment with MADs on the myocardium. All methods in this study were in accordance with relevant guidelines and regulations of the medical ethics committee in Hospital of Stomatology, Hebei Medical University approved the work. Thirty New Zealand rabbits were randomized into three groups: the control group, Group OSAHS, and Group MAD. Hydrophilic polyacrylamide gel was injected into the soft palate of the rabbits to induce OSAHS. In Group MAD, a MAD was positioned after OSAHS induction. All animals were induced to sleep in a supine position for 4–6 h/day for 8 weeks. Echocardiography was used to determine the structure and function of the heart. The histological changes were detected by optical microscopy and transmission electron microscopy (TEM). The levels of ET-1(endothelin-1) and Ang II (Angiotensin II) in the plasma were measured by an enzyme-linked immunosorbent assay (ELISA). The expression of ET-1 mRNA in heart tissue was detected by RT-PCR. Histological abnormalities, left ventricular hypertrophy, and left ventricular dysfunctions were demonstrated in Group OSAHS, and the abnormities were rescued with MAD treatment. Higher levels of plasma ET-1 and Ang II and elevated expression of ET-1 mRNA in cardiac tissue were detected in Group OSAHS compared with Group MAD and the control group. The blood oxygen saturation was negatively correlated with the levels of ET-1 and Ang II. OSAHS-induced elevated levels of ET-1 and Ang II may be attributed to myocardial structural abnormalities and dysfunction. Early treatment of MADs may play an important role in preventing myocardial damage in OSAHS rabbit model.

Intravenous Endothelin-1 Infusion Does Not Induce Aura or Headache in Migraine Patients With Aura.

To investigate whether intravenously infused provokes migraine aura and migraine headache in migraine patients with aura. Migraine with aura has been associated with endothelial dysfunction and increased stroke risk. The initiating mechanism of migraine aura symptoms is not known. Experimental provocation of migraine headache using vasoactive peptides has provided tremendous advances in the understanding of migraine pathophysiology but substances that can induce migraine aura have not been identified. Endothelin-1 (ET-1), an endogenous, potent vasoconstrictor peptide released from the vascular endothelium, has been proposed to trigger migraine aura. This hypothesis is based on reports of increased plasma ET-1 levels early during the migraine attacks and the observation that ET-1 applied to the cortical surface potently induces the cortical spreading depolarization, the underlying electrophysiological phenomenon of migraine aura, in animals. Further, endothelial damage due to, for example, carotid puncture and vascular pathology is known to trigger aura episodes. We investigated whether intravascular ET-1 would provoke migraine aura in patients. Using a two-way crossover, randomized, placebo-controlled, double-blind design, we infused high-dose (8ng/kg/minutes for 20minutes) intravenous ET-1 in patients with migraine with typical aura. The primary end-point was the difference in incidence of migraine aura between ET-1 and placebo. Experiments were carried out at a public tertiary headache center (Danish Headache Center, Rigshospitalet Glostrup, Denmark). Fourteen patients received intravenous ET-1. No patients reported migraine aura symptoms or migraine headache during or up to 24hours following the ET-1 infusion. Four patients reported mild to moderate headache only on the ET-1 day, 3 patients reported moderate headache on the placebo day, and 1 patient reported mild headache on both days. No serious adverse events occurred during or after infusion. Provocation of migraine aura by procedures or conditions involving vascular irritation is unlikely to be mediated by ET-1.

Profile of Endothelin-1, Nitric Oxide, and Prostacyclin Levels in Pulmonary Arterial Hypertension Related to Uncorrected Atrial Septal Defect: Results from a Single Center Study in Indonesia.

Methods The study design was cross-sectional. The subjects were adult uncorrected secundum ASD with PAH. Pulmonary artery pressure was measured with right heart catheterization. Pulmonary venous blood was obtained during catheterization for measuring endothelin-1, prostacyclin, and nitric oxide. Correlation tests were performed to determine any association between biomarkers and mean pulmonary artery pressure (mPAP). The levels of biomarkers were compared based on the severity of PAH. Statistical significance was determined at p < 0.05. Results Forty-four subjects were enrolled in this study. Endothelin-1 level and mPAP had significant moderate positive correlation (r = 0.423 and p value = 0.004). However, no significant correlation was observed between prostacyclin, nitric oxide levels, and mPAP. The pattern of endothelin-1, prostacyclin, and nitric oxide was distinctive. Levels of endothelin-1 were incrementally increased from mild, moderate, to severe PAH. The levels of prostacyclin and nitric oxide had similar pattern in association with the severity of PAH, which was increased in mild-to-moderate PAH but decreased in severe PAH. Conclusions There was a distinctive pattern of endothelin-1, prostacyclin, and nitric oxide based on severity of PAH in adult uncorrected ASD. Significant correlations existed between endothelin-1 and the severity of PAH and mPAP.

Nesiritide protects endothelial function after balloon-induced trauma in the iliac artery in rabbits

To assess the effect of nesiritide on the endothelial function of iliac arteries following endothelia trauma. Right iliac artery trauma was created with a balloon catheter. Ten rabbits were treated with a 4-week subcutaneous injection of nesiritide at a fixed daily dose of 0.1mg/kg. Ten rabbits received daily normal saline injection. Plasma endothelin 1 (ET-1), nitric oxide (NO), and Von Willebrand Factor (vWF) were measured before and after the therapies. Tissue proliferating cell nuclear antigen (PCNA) was measured after the treatment. After the treatment, in the therapeutic group, the area under internal elastic membrane and the residual lumen area were higher than in the normal saline group (P <0.05). The plasma levels of ET-1 (91.6±6.8 vs 114.9±6.3 ng/L, P =0.001), vWF (134.6±10.8% vs 188.8±10.4%, P =0.001) and the ratio of PCNA positive expression (11.7±4.2% vs 36.2±11.4%, P =0.005) in the therapeutic group was lower than in the normal saline group, while the plasma levels of NO was higher (89.7±9.3 vs 43.5±5.3 µmol/L, P =0.001). Nesiritide inhibited remodeling of rabbit iliac artery following endothelial trauma. The inhibition of vascular remodeling may be related to the alleviated endothelial dysfunction and reduced expression of tissue proliferating cell nuclear antigen.