Plasma Endothelin-1 Levels Research Articles

Transition from post-capillary pulmonary hypertension to combined pre- and post-capillary pulmonary hypertension in swine: a key role for endothelin.

Key points Passive, isolated post‐capillary pulmonary hypertension (PH) secondary to left heart disease may progress to combined pre‐ and post‐capillary or ‘active’ PHThis ‘activation’ of post‐capillary PH significantly increases morbidity and mortality, and is still incompletely understood.In this study, pulmonary vein banding gradually produced post‐capillary PH with structural and functional microvascular remodelling in swine.Ten weeks after banding, the pulmonary endothelin pathway was upregulated, likely contributing to pre‐capillary aspects in the initially isolated post‐capillary PH.Inhibition of the endothelin pathway could potentially stop the progression of early stage post‐capillary PH. Passive, isolated post‐capillary pulmonary hypertension (IpcPH) secondary to left heart disease may progress to combined pre‐ and post‐capillary or ‘active’ PH (CpcPH) characterized by chronic pulmonary vascular constriction and remodelling. The mechanisms underlying this ‘activation’ of passive pulmonary hypertension (PH) remain incompletely understood. Here we investigated the role of the vasoconstrictor endothelin‐1 (ET) in the progression from IpcPH to CpcPH in a swine model for post‐capillary PH. Swine underwent pulmonary vein banding (PVB; n = 7) or sham‐surgery (Sham; n = 6) and were chronically instrumented 4 weeks later. Haemodynamics were assessed for 8 weeks, at rest and during exercise, before and after administration of the ET receptor antagonist tezosentan. After sacrifice, the pulmonary vasculature was investigated by histology, RT‐qPCR and myograph experiments. Pulmonary arterial pressure and resistance increased significantly over time. mRNA expression of prepro‐endothelin‐1 and endothelin converting enzyme‐1 in the lung was increased, while ETA expression was unchanged and ETB expression was downregulated. This was associated with increased plasma ET levels from week 10 onward and a more pronounced vasodilatation to in vivo administration of tezosentan at rest and during exercise. Myograph experiments showed decreased endothelium‐dependent vasodilatation to Substance P and increased vasoconstriction to KCl in PVB swine consistent with increased muscularization observed with histology. Moreover, maximal vasoconstriction to ET was increased whereas ET sensitivity was decreased. In conclusion, PVB swine gradually developed PH with structural and functional vascular remodelling. From week 10 onward, the pulmonary ET pathway was upregulated, likely contributing to pre‐capillary activation of the initially isolated post‐capillary PH. Inhibition of the ET pathway could thus potentially provide a pharmacotherapeutic target for early stage post‐capillary PH.

The Value of Combining Plasma D-Dimer and Endothelin-1 Levels to Predict No-Reflow After Percutaneous Coronary Intervention of ST-Segment Elevation in Acute Myocardial Infarction Patients with a Type 2 Diabetes Mellitus History.

BackgroundNo-reflow phenomenon is a well-known problem, often accompanying percutaneous coronary intervention (PCI) for ST-segment elevation acute myocardial infarction (STEAMI). This study investigated the value of plasma D-dimer and Endothelin-1 (ET-1) levels on admission in predicting no-reflow after primary PCI and long-term prognosis in STEAMI patients with type 2 diabetes mellitus (T2DM).Material/MethodsThere were 822 patients with STEAMI and T2DM undergoing successful primary PCI included in this study: 418 patients showed normal re-flow after PCI, while 404 patients showed no-reflow phenomenon after PCI. The predictive value of plasma ET-1 and D-dimer level, and other clinical parameters for the no-reflow phenomenon were analyzed.ResultsThe high plasma ET-1 and D-dimer levels showed predictive value for the no-reflow phenomenon in STEAMI patients with T2DM. Patients with high D-dimer and ET-1 levels showed higher risk (4.212, with 95%CI of 2.973–5.967 and 2.447 with 95%CI of 1.723–3.476, respectively) of no-reflow phenomenon compared with patients with low plasma D-dimer and ET-1 levels. Sensitivity of high plasma ET-1 and D-dimer levels in predicting no-reflow was 0.766. Both plasma D-dimer and ET-1 were adverse prognosticators for STEAMI patients with a T2DM post PCI (P<0.001).ConclusionsIn conclusion, plasma D-dimer and ET-1 levels on admission independently predict no-reflow after PCI in STEAMI patients with T2DM. When combined, the D-dimer and ET-1 levels as predictive and prognostic values are clinically promising. The plasma D-dimer and ET-1 levels provided a novel marker for treatment selection for the STEAIM patients with a T2DM history.

Effects of Virgin Olive Oils Differing in Their Bioactive Compound Contents on Metabolic Syndrome and Endothelial Functional Risk Biomarkers in Healthy Adults: A Randomized Double-Blind Controlled Trial.

The aim of this study was to evaluate the effect of virgin olive oils (VOOs) enriched with phenolic compounds and triterpenes on metabolic syndrome and endothelial function biomarkers in healthy adults. The trial was a three-week randomized, crossover, controlled, double-blind, intervention study involving 58 subjects supplemented with a daily dose (30 mL) of three oils: (1) a VOO (124 ppm of phenolic compounds and 86 ppm of triterpenes); (2) an optimized VOO (OVOO) (490 ppm of phenolic compounds and 86 ppm of triterpenes); and (3) a functional olive oil (FOO) high in phenolic compounds (487 ppm) and enriched with triterpenes (389 ppm). Metabolic syndrome and endothelial function biomarkers were determined in vivo and ex vivo. Plasma high density lipoprotein cholesterol (HDLc) increased after the OVOO intake. Plasma endothelin-1 levels decreased after the intake of the three olive oils, and in blood cell cultures challenged. Daily intake of VOO enriched in phenolic compounds improved plasma HDLc, although no differences were found at the end of the three interventions, while VOO with at least 124 ppm of phenolic compounds, regardless of the triterpenes content improved the systemic endothelin-1 levels in vivo and ex vivo. No effect of triterpenes was observed after three weeks of interventions. Results need to be confirmed in subjects with metabolic syndrome and impaired endothelial function (Clinical Trials number NCT02520739).

Effects of resistance training on arterial compliance and plasma endothelin-1 levels in healthy men.

Arterial compliance (AC) is an index of the elasticity of large arteries. Endothelial dysfunction has been reported to result in reduced arterial compliance, which represents increased arterial stiffness. A reduction in AC is elicited by high-intensity resistance training, however the mechanisms are obscure. Because a single bout of resistance exercise causes a transient increase in circulating plasma endothelin-1 in humans, some vasoconstrictors may play a role in the mechanisms. The present study aimed to investigate whether resistance training-induced decrease in AC is associated with changes in circulating vasoconstrictors levels in young men. Young sedentary men were assigned to control (n=5) or training (n=9) groups. The training group performed four-week high-intensity resistance training (weight training exercise; three sessions/week). We measured AC and plasma levels of endothelin-1, angiotensin II, and norepinephrine before and after intervention. Resistance training significantly decreased AC, whereas the changes in plasma levels of neither endothelin-1, nor angiotensin II, nor norepinephrine were significantly different between the control and the training groups. Moreover, we found no significant correlations between changes in circulating plasma levels (endothelin-1, angiotensin II, and norepinephrine) and in the AC. Despite of no alteration of the resting circulating plasma levels (endothelin-1, etc.), we cannot exclude a possibility that the tissue/local concentrations of vasoconstrictors (endothelin-1, etc.) around the vessels might be increased and also involved in a reduction of AC in the training group. Taken together, the present results suggest that circulating vasoconstrictors (endothelin-1, etc.) in plasma are not involved in a reduction in AC by the resistance training.

Evaluation of Circulating Plasma VEGF-A, ET-1 and Magnesium Levels as the Predictive Markers for Proliferative Diabetic Retinopathy.

Diabetic retinopathy (DR) is the most common cause for preventable blindness in India. The onset of micro and macrovascular complications in T2DM is multifactorial and difficult to predict. The status of micronutrients, several inflammatory cytokines, elevated triacylglycerols, oxidative stress etc., are being studied extensively. Hypomagnesemia plays a pivotal role in worsening of insulin resistance. Although, Vascular Endothelial Growth Factor-A (VEGF-A) and Endothelin-1 (ET-1) are known to be elevated in DR, yet few reports cite their role, especially in Indian population. In this study, we included thirty subjects with T2DM in each of the three groupsnamely, T2DM cases without retinopathy, Non Proliferative DR (NPDR) and Proliferative DR (PDR) retinopathy. The glycemic status, circulating plasma VEGF-A, ET-1 levels, serum magnesium and lipids were estimated and compared among the groups. An ROC was drawn to evaluate VEGF-A, ET-1 and serum magnesium levels as the predictive markers for PDR. On comparison VEGF-A, ET-1 and serum magnesium levels showed a significant difference among the three groups. PDR cases had higher circulating levels of VEGF-A, ET-1 and low serum magnesium levels when compared to others. ROC for VEGF-A and ET-1 showed an optimum cut-off of 1521ng/ml (AUC 0.975) and 16pg/ml (AUC 0.96) respectively. A negative ROC was drawn to check the lower cut-off limit for serum magnesium; we documented an optimum cut off of 1.7mg/dl (AUC 0.837). ET-1, VEGF-A and serum Magnesium levels are significantlyaltered in PDR and can be used as the predictive markers of PDR.

Clinical research of the Tanreqing injection combined with Danshen-Chuanxiongqin injection for the patients with acute exacerbation of chronic obstructive pulmonary disease

Objective To study the clinical effects of the Tanreqing injection combined with Danshen-Chuanxiongqin injection for the patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and its effects on plasma NO and endothelin-1 (ET-1) levels. Methods A total of 79 patients with AECOPD in our hospital from May 2014 to January 2017 were enrolled in this study. The subjects were randomly divided into the control group (n=39) and the combined therapy group (n=40). The control group were treated with Tanreqing injection, the combined therapy group were treated with Tanreqing injection combined with Danshen-Chuanxiongqin injection. The two groups were treated for 10 days. The clinical effects of the two groups after treatment were compared. The MPAP, PASP, PADP, PaO2, PaCO2, SaO2, NO and ET-1 of the two groups before and after treatment were compared. Results The total efficacy rate of the combined therapy group was 97.5% (39/40), which was significantly higher than 82.1% (32/39) of the control group (χ2=5.178, P=0.023). After treatment, the MPAP (25.19 ± 8.71 mmHg vs. 35.28 ± 9.52 mmHg, t=4.917), PASP (44.35 ± 12.26 mmHg vs. 57.24 ± 11.17 mmHg, t=4.881), PADP (17.16 ± 4.05 mmHg vs. 26.40 ± 3.85 mmHg, t=10.38), PaCO2 (42.70 ± 6.31 mmHg vs. 51.44 ± 6.83 mmHg, t=5.910) of the combined therapy group were significantly lower than those of the control group (P<0.05). After treatment, the PaO2 (73.95 ± 7.82 mmHg vs. 67.21 ± 7.16 mmHg, t=3.993), SaO2 (94.86% ± 5.11% vs. 83.63% ± 4.27%, t=10.586) of the combined therapy group were significantly higher than those of the control group (P<0.05). After treatment, the plasma NO (55.82 ± 10.08 μmol/L vs. 46.34 ± 8.50 μmol/L, t=4.513) of the combined therapy groupwas significantly higher than the control group (P<0.05) and the plasma ET-1 (80.41 ± 8.95 ng/L vs. 87.68 ± 9.24 ng/L, t=3.552) of the combined therapy groupwere significantly lower than the control group (P<0.05). Conclusions The Tanreqing injection combined with Danshen-Chuanxiongqin injection showed good efficacy for the patients with AECOPD, and the therapy can reduce the pulmonary arterial hypertension and ET-1, improve the lung tissue oxygen supply and NO release, and improve the cardiopulmonary function. Key words: Pulmonary disease, chronic obstructive; Tanreqing injection; Danshen-Chuanxiongqin injection; Nitric oxide; Endothelin-1

A Metabolism-Based Synergy for Total Coumarin Extract of Radix Angelicae Dahuricae and Ligustrazine on Migraine Treatment in Rats

Radix Angelicae dahuricae, containing coumarins, which might affect cytochrome P450 enzyme (CYP450) activity, has been co-administered with ligustrazine, a substrate of CYP450s, for the clinical treatment of migraine. However, whether a pharmacokinetic-based synergy exists between Radix Angelicae dahuricae and ligustrazine is still unknown. In this study, the total coumarin extract (TCE) of Radix Angelicae dahuricae (50 mg/kg, orally) reinforced the anti-migraine activity of ligustrazine by declining head scratching, plasma calcitonin gene-related peptide, and serum nitric oxide, as well as increasing plasma endothelin levels in rats (p < 0.05). Moreover, the pharmacokinetic study reflected that TCE potentiated the area under the concentration–time curve of ligustrazine and prolonged its mean retention time in rats (p < 0.05). Besides, the IC50 for TCE, imperatorin and isoimperatorin inhibiting ligustrazine metabolism were 5.0 ± 1.02, 1.35 ± 0.46, 4.81 ± 1.14 µg/mL in human liver microsomes, and 13.69 ± 1.11, 1.19 ± 1.09, 1.69 ± 1.17 µg/mL in rat liver microsomes, respectively. Moreover, imperatorin and isoimperatorin were CYP450s inhibitors with IC50 < 10 µM for CYP1A2, 2C9, 2D6, and 3A4. Therefore, this study concluded that Radix Angelicae dahuricae could increase ligustrazine plasma concentration and then reinforce its pharmacological effect by inhibiting its metabolism through interference with CYP450s. This could be one mechanism for the synergy between Radix Angelicae dahuricae and ligustrazine on migraine treatment.

POLYMORPHISM -786T&gt;C ENDOTHELIAL NO-SYNTHASE AS A RISK FACTOR OF ARTERIAL HYPERTENSION

A variety of studies demonstrates the association between the -786T&gt;C polymorphism of eNOS, nitric oxide (NO) level and different parameters of cardiovascular system (CVS). The majority of these studies includes middle-aged and elderly individuals with cardiovascular disorders (CVD), so it is difficult to evaluate the role of genotypes of -786T&gt;C polymorphism of eNOS in arterial hypertension (AH). The aim of this study is to determine the association between -786T&gt;C polymorphism of eNOS and hemodynamic and vascular risk factors of AH in young healthy adults from European North. Metods. 286 healthy young men and women constantly living in Arctic region were examined in this cross-sectional study. Genotyping of -786T&gt;C polymorphism of eNOS, hemodynamic parameters before and after physical probe (peripheral resistance, arterial pressure, heart rate, pulse pressure etc.), NO and endothelin-1 (ET-1) plasma level, index NO/ET-1 were determined in this study. Statistical methods include Pearson x2 test. Results. The imbalance of vasoactive endothelial factors (which lead to vasoconstriction) and higher incidence of hemodynamic risk factors were revealed in young men with CC genotype. There is no association between CC genotype and NO, ET-1 level and hemodynamics in the group of young women. Conclusion. Genotype CC of -786T&gt;C polymorphism of eNOS can be genetic predictor of AH for young men from European North but not for young women from European North.

Effect of renal sympathetic denervation on ventricular and neural remodeling.

BackgroundThis study assessed the therapeutic effects of renal sympathetic denervation (RDN) on post-myocardial infarction (MI) ventricular remodeling and sympathetic neural remodeling in dogs. The possible mechanisms and optimal time for treatment are discussed.MethodsWe randomly assigned 30 dogs to five groups: RDN 1 week before MI (RDN1w + MI; n = 6), RDN 1 week after MI (MI1w + RDN; n = 6), RDN 2 weeks after MI (MI2w + RDN; n = 6), control (N; n = 6), and MI (n = 6). A canine model of myocardial infarction was established by interventional occlusion with a gelatin sponge via the femoral artery. Brain natriuretic peptide (BNP) and endothelin-1 (ET-1) levels were measured and echocardiography was performed to assess cardiac function and heart size. All dogs were killed at the end of the experiment and samples of cardiac and renal arteries were obtained. The expression of matrix metalloproteinase (MMP)-2 and MMP-9 in cardiac and of tyrosine hydroxylase (TH) in renal arteries was assessed by immunohistochemistry. Sympathetic innervations in the infarction border zone were investigated via Western blotting and real-time PCR.ResultsLeft ventricular function in the MI group decreased significantly, while plasma BNP and ET-1 levels as well as MMP-2 and MMP-9 expression increased. Compared with the MI group, the RD groups showed significantly reduced MMP‑2, MMP‑9, TH, and growth-associated protein (GAP) 43 expression in the RDN1w + MI, MI1w + RDN, and MI2w + RDN groups was significantly improved. Additionally, the expression of TH in renal arteries decreased after RDN.ConclusionRDN has preventive and therapeutic effects on post-MI ventricular remodeling and sympathetic neural remodeling. The mechanism of RDN is likely mediated through restraint of renal sympathetic nerve activity.

Expression Profiles of eNOS, iNOS, endothelin receptors and microRNAs‐27b, 155 and 199 in the corpus cavernosum of rats submitted to chronic alcoholism and diabetes mellitus.

IntroductionEthanol consumption has been described to increase the levels of plasma endothelin‐1 (ET‐1) suggesting that chronic consumption activates endothelinergic pathway and also to affect nitric oxide synthase (NOS) derived nitric oxide (NO) and NOS expression in different tissues. Recent evidence showed that chronic ethanol consumption increases ET‐1‐induced sustained contraction of trabecular smooth muscles cells of the corpora cavernosal in corpus cavernosum of rat by mechanism that involves increased expression of ETA eee and ETB receptors.ObjectivesTo evaluate the effects of chronic ethanol consumption associated with diabetes affected the endothelin system in the cavernosal smooth muscle (CSM) of rats, as well as the effects of chronic ethanol consumption and diabetes on nitric oxide (NO)‐mediated relaxation of cavernosal smooth muscle (CSM).Materials and MethodsCorpus cavernosum were divided into four groups: control, ethanol, diabetic and ethanol‐diabetic of Male Wistar rats. We analyzed protein and gene expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS) and endothelin receptors (ETA eeeand ETB) by immunohistochemistry and real time‐PCR. The expression of miRNAs‐27a, 199 and 155 by real time‐PCR in corpus cavernosum. It was also evaluated the effect of ethanol consumption associated with diabetes on the relaxation induced by acetylcholine (ACh; 0.01–1000 micromol/L) and in the contraction induced by Endothelin‐1 (ET‐1 0.1 nmol‐ 1μmol L‐1) in organ chambers for measurement of isometric tension.ResultsThe endothelium‐dependent relaxation induced by ACh was decreased in CSM from ethanol, diabetic, ethanol‐diabetic groups when compared with the control group. Immunohistochemistry for eNOS, iNOS, ETA eeeand ETB showed an increase in cavernosal smooth muscle cells in the ethanol, diabetic and ethanol‐diabetic groups when compared with the control group. Similarly, the mRNA levels for eNOs, ETA eeeand ETB were increased in CSM of groups ethanol, diabetic and ethanol‐diabetic and miRNAs‐27a, 155 and 199 were decreased in cavernosal smooth muscle from the ethanol, diabetic and ethanol‐diabetic groups.ConclusionsOur results showed that chronic ethanol consumption associated with diabetes was an impairment of relaxation of CSM from ethanol, diabetic, and ethanol‐diabetic rats that involved a decrease in the NO pathway by endothelium‐dependent mechanisms accompanied by a change in the corpus cavernosum contractile sensitivity. We can also suggest that chronic ethanol consumption associated with diabetes changed the endothelinergic system in the CSM played a role in the pathogenesis of erectile dysfunction, suggesting that these changes of endothelin receptors were regulated by miRNAs‐155, 199.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Role of Endothelin in the Pathophysiology of Migraine-a Systematic Review.

Vasoactive peptides play a key role in the attack-initiating cascade of migraine. Recent studies have highlighted a potentially important role for endothelin-1, a potent vasoconstrictor peptide, in migraine pathophysiology. Here, we review the current data on endothelin's involvement in migraine. We identified 23 articles. Nine studies reported on endothelin-1 plasma concentrations in patients with migraine, eight studies investigated relevant genetic associations, five studies investigated endothelin-1 and spreading depression in animals, and one randomized controlled clinical trial tested the efficacy of an endothelin antagonist in the acute treatment of migraine in patients both with and without aura. Elevated endothelin-1 plasma levels have been reported in the early phase of migraine attacks. Genetic abnormalities related to the endothelin type A receptor have been reported in migraineurs. Endothelin-1 potently induces spreading depression in animals, which may explain the connection between endothelial irritation and migraine aura. Endothelin-1 could be a primary factor in the attack-triggering cascade of migraine attacks with and without aura. Additional studies in humans and animal models are needed to further elucidate the role of endothelin-1 in migraine.

Adult Sickle Cell Anaemia Patients in Bone Pain Crisis have Elevated Pro-Inflammatory Cytokines.

Background and ObjectivesInflammatory markers that influence bone pain crisis (BPC) and other complications of sickle cell anaemia (SCA) are numerous and play various roles. This study determined the plasma levels of tumour necrosis factor (TNF) - α, interleukin - 8 (IL-8), and endothelin - 1 (ET-1) in adult SCA patients during BPC and in steady state. In addition, the plasma levels of these cytokines were correlated with the severity of BPC of the patients.Methods and MaterialsSixty adult SCA patients (30 during BPC and 30 during steady state) and 30 haemoglobin A controls were enrolled for this cross-sectional study. The severity of BPC was assessed clinically, and questionnaires were filled. Plasma levels of TNF- α, IL-8 and ET-1 were quantified by ELISA, and haematological parameters were determined using a 5-part auto-analyzer. Plasma levels were correlated with the severity of bone pain crisis. Results were considered statistically significant if p<0.05.ResultsPlasma TNF-α, IL-8, and ET-1 were significantly elevated in the BPC group than in the steady state group and the controls. Plasma TNF-α, IL-8 and ET-1 were markedly higher in the severe BPC groups than the steady state and control groups, There was a positive correlation between TNF-α and ET-1 in the bone pain crisis group.ConclusionElevated levels of plasma TNF-α, IL-8, and ET-1 further establish the chronic inflammatory state in SCA and equally affirm their significant contribution, not only to pathogenesis but also to the severity of pain in SCA.

Çocukluk çağı primer hipertansiyonuna etki eden faktörlerin araştırılması

Aim: Primary hypertension is the most important risk factor for chronic kidney disease in adulthood. The genesis of essential hypertension is likely to be multifactorial. The aim of this study is to investigate the causing factors of primary hypertension detected by ambulatory blood pressure monitoring in children.Materials and Methods: Fifty-six patients who had blood pressure higher than 90 percentile during the healthy children follow-up and 27 healthy children with the normal blood pressure were included in the study. Twenty-four hour blood pressure measurements with the blood pressure monitor were recorded as the day-night mean blood pressure, the blood pressure loads and the dipper-non-dipper characteristics. Plasma renin levels, serum aldosterone, nitric oxide and endothelin levels and amounts of sodium and potassium excretion in the 24 hour urine and were investigated in all patients and the control group.Results: Laboratory evaluations of the patients showed that the patient group has higher mean levels of plasma renin, lower mean levels of blood endothelin and mean levels of urinary sodium excretion than the control group.Conclusion: In the pathogenesis of childhood primary hypertension and white coat hypertension, which were seen in the half of the children diagnosed as primary hypertension, plasma renin and urinary sodium excretion had important roles.

A pilot study with flow mediated skin fluorescence: A novel device to assess microvascular endothelial function in coronary artery disease.

Endothelial dysfunction is one of the earliest vascular manifestations in the pathogen-esis of cardiovascular disease. Noninvasive, simple, and inexpensive methods of endothelial function assessment are therefore needed. Microvascular endothelial function was assessed in coronary artery disease (CAD) patients by flow mediated skin fluorescence (FMSF), based on measurements of reduced form of nicotinamide adenine dinucleotide (NADH) fluorescence intensity during brachial artery occlusion (ischemic re-sponse [IRmax]) and immediately after occlusion (hyperemic response [HRmax]). Additionally, plasma levels of asymmetric dimethylarginine (ADMA) and endothelin-1 (ET-1) were measured to assess the association between biochemical markers and microvascular function evaluated in vivo by FMSF. A significant inverse correlation was found between ADMA levels and hyperemic response (r = -0.534, p = 0.003), while ET-1 levels were inversely related to the ischemic response (r= -0.575, p = 0.001). Both IR and HR were found lowest in patients with advanced CAD and diabetes. When the repeatability of the method was tested, the intraclass correlation coefficient for IRmax and HRmax were 0.985 (p < 0.001) and 0.914 (p < 0.001), respectively. Moreover, in Bland and Altman analysis, both variables IRmax and HRmax showed good agreement in repeated measurements. In this pilot study, it was demonstrated that NADH fluorescence measured by FMSF device in CAD patients was associated with established plasma endothelial markers, and that both ischemic and hyperemic response were blunted in patients with advanced disease and diabetes. Fur-thermore, FMSF device showed excellent repeatability and good agreement for repeated measurements. However, further study is warranted to confirm these results in a larger patient cohort. (Cardiol J 2018; 25, 1: 120-127).

Cardiac effects of fish oil in a rat model of streptozotocin-induced diabetes

Background and aimsFish oil (FO) is rich in omega-3 polyunsaturated fatty acids, which have cardio-protective effects. This study aims to evaluate effects of FO in a rat model of streptozotocin (STZ) induced diabetes. Methods and resultsAdults male Wistar rats were assigned to control (4 μl corn oil/g corn oil given by oral gavage), FO (4 μl Menhaden FO/g body weight given by oral gavage), diabetes (DM, 35 mg/kg STZ single intraperitoneal injection, corn oil), and DM + FO groups for 8 weeks. Plasma and cardiac biomarkers of oxidative stress, inflammation, and fibrosis were evaluated. STZ-induced diabetes as indicated by the significant increase in serum levels of glucose and percentage of glycated hemoglobins. FO reduced plasma arachidonic acid (AA) percentage and ratio of AA: docosahexaenoic acid (DHA). Plasma and cardiac levels of total nitrite, endothelin -1 (ET-1), and myeloperoxidase (MPO) increased in the DM group, whereas cardiac activities of catalase and superoxide dismutase (SOD) decreased. FO reduced cardiac nitrite and MPO, and plasma ET-1 levels. FO increased cardiac glutathione, catalase and SOD activities. Levels of thiobarbituric acid substances increased in the FO and DM groups with significant synergism in the DM + FO group. FO prevented cardiac fibrosis associated with DM and decreased cardiac transforming growth factor beta-1and p38 MAP kinases. Cardiac levels of matrix metalloproteinase -2 were significantly elevated in FO and DM + FO groups. ConclusionsFO decreased plasma and cardiac oxidative stress, inflammation and myocardial fibrosis. FO could be used in diabetes to reduce risk and burden of CVDs.

Neprilysin inhibition and endothelin-1 elevation: Focus on the kidney

Increasing the degree of renin-angiotensin system (RAS) blockade by combining ≥2 RAS blockers marginally increases efficacy, but results in more side effects. Hence, interference with other systems is currently being investigated, like potentiation of natriuretic peptides with neprilysin inhibitors. However, the neprilysin inhibitor thiorphan was recently found to increase endothelin-1 when administered to TGR(mREN2)27 (Ren2) rats on top of RAS blockade. Here we investigated whether this effect is thiorphan-specific, by comparing the neprilysin inhibitors thiorphan and sacubitril, administered by osmotic minipumps at a low or high dose for 7 days, in Ren2 rats. Plasma and urinary levels of endothelin-1, atrial and brain natriuretic peptide (ANP, BNP) and their second messenger cyclic guanosine 3′5′ monophosphate (cGMP) were monitored. No significant differences were found in the plasma concentrations of endothelin-1, cGMP, ANP and BNP after treatment, although plasma ANP tended to be higher in the high-dose thiorphan treatment group and the low- and high-dose sacubitril treatment groups, compared with vehicle. Urinary endothelin-1 increased in the low-dose thiorphan and high-dose sacubitril groups, compared with baseline, although significance was reached for the former only. Urinary cGMP rose significantly in the high-dose sacubitril treatment group compared with baseline. Both urinary endothelin-1 and cGMP were significantly higher in the high-dose sacubitril group compared with the low-dose sacubitril group. In conclusion, endothelin-1 upregulation occurs with both thiorphan and sacubitril, and is particularly apparent in neprilysin-rich organs like the kidney. High renal neprilysin levels most likely also explain why sacubitril increased cGMP in urine only.

Atorvastatin Reduces Plasma Inflammatory and Oxidant Biomarkers in Patients With Risk of Atherosclerotic Cardiovascular Disease.

Oxidative stress and inflammation are associated with endothelial injury and coronary artery disease. Inflammatory factors that promote oxidative damage include endothelin-1 (ET-1), myeloperoxidase (MPO), and C-reactive protein (CRP). Current guidelines recommend the use of statins in patients with risk of atherosclerotic cardiovascular disease (ASCVD). To assess the impact of atorvastatin on plasma inflammatory and oxidant biomarkers in patients with moderate to very high risk of ASCVD. Two hundred ten patients presented to the cardiology clinic were included and stratified into low, moderate, high, and very high risk of ASCVD. Moderate- (20 mg/d) to high-intensity (40 mg/d) atorvastatin was prescribed. Plasma levels of lipids, ET-1, CRP, MPO, total nitrite, lipid peroxides (thiobarbituric acid reactive substances [TBARS]), and superoxide dismutase (SOD) activities were measured at baseline and 12 weeks after treatment. Relative to low-risk patients, baseline plasma inflammatory markers of CRP, MPO, ET-1, and nitrite were higher in patients with very high risk of ASCVD, whereas plasma SOD was lower (all P < .05). Use of high and moderate atorvastatin therapy significantly reduced low-density lipoprotein and total cholesterol levels, as well as plasma levels of CRP, MPO, nitrite, and TBARS, and increased plasma SOD activity in patients with moderate to very high risk of ASCVD, independent of lipid-lowering effects. Key markers of oxidative stress/inflammation such as CRP, ET-1, total nitrite, and MPO are associated with an increased risk of ASCVD. Moderate- and high-intensity atorvastatin use reduces plasma oxidative stress and inflammation regardless of ASCVD risk and independent of its lipid-lowering effect.

Effects of Short-term High Dose Atorvastatin on Left Ventricular Remodeling in Patients with First Time Attack of Anterior Acute Myocardial Infarction.

Objects The aim of this trial was to evaluate the effect of short-term high-dose atorvastatin therapy on levels of high-sensitivity C-reactive protein (hs-CRP), malonaldehyde (MDA), endothelin-1(ET-1), matrix metalloproteinases (MMPs), and left ventricular (LV) remodeling in patients with first time attack of acute anterior myocardial infarction (AAMI) .Methods A hundred and three patients with first time attack of AAMI who underwent successful primary percutaneous coronary intervention were randomized to receive atorvastatin 40 mg once daily for 1 week followed by 20 mg once daily (intensive treatment group, IT group, n=49), or atorvastatin 20 mg once daily (standard treatment group, ST group, n=54). Plasma levels of hs-CRP, MDA, ET-1, MMP-2 and MMP-9 were measured on admission, at 1 week, 2 weeks and 6 months follow up and compared between the IT group and ST group. Echocardiography was performed on admission, at 2 week, and 1 year follow up. The left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and left ventricular ejection fraction (LVEF) were measured at each echocardiographic examination and compared between the IT group and ST group.Results Plasma levels of hs-CRP (F=7.718, P=0.009), ET-1 (F=7.882, P=0.006), MMP-9 (F=4.834, P=0.028) and pro-BNP (F=4.603, P=0.032) were significantly lower at 1 week after initial onset of AAMI in the IT group compared with the ST group. The changes of LVEDV, LVESV, and LVEF at the 1 year follow-up from the admission did not differ between the IT group and the ST group (t=0.722, P=0.444; t=1.228, P=0.221; t=1.354, P=0.187, repectively).Conclusions Short-term high-dose atorvastatin treatment for AAMI was associated with lower hs-CRP, ET-1 and MMP-9 levels compared to the standard dose treatment. However, this beneficial effect is not likely to related to the left ventricular remodeling.

Effect of Tongxinluo Capsule on Patients with Syndrome X and Affective Disorder

Background: To explore the therapeutic effect of Tongxinluo capsule (Tongxinluo) on patients with Syndrome X and Affective Disorder. Methods: Fifty-six patients with Syndrome X and Affective Disorder were randomly divided into a Tongxinluo capsule group and a placebo control group. The duration of treatment was 12 weeks. A 6-minute walking test, exercise load electrocardiogram and clinical symptom assessment were performed before and after treatment. After 12 weeks of treatment, the scores of the Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) were repeated. The levels of serum endothelin-1 (ET-1) and nitric oxide (NO) were measured before and after treatment. Results: Compared with the placebo control group, the Tongxinluo group SAS and SDS scores were lower than those before treatment (all P 0.05) when compared to before treatment. In the Tongxinluo treatment group, the levels of plasma endothelin-1 decreased significantly (P < 0.01) and nitric oxide levels were significantly increased (P < 0.01), with a significant difference when compared to the control group (P < 0.01). Conclusions: The Tongxinluo capsule can improve the Affective Disorder of Syndrome X, reduce the degree of anxiety and depression, increase exercise tolerance, reduce clinical symptoms, and improve vascular endothelial function.

Endothelin-1 activation in pediatric patients undergoing surgical coarctation of the aorta repair.

AIMTo determine endothelin-1 (ET-1) concentration before and after surgical coarctectomy and evaluate its association with left ventricular geometric change.METHODSA prospective, cohort study of 24 patients aged 2 d to 10 years with coarctation of the aorta undergoing surgical repair. A sub-cohort of patients with age < 1 mo was classified as “neonates”. Echocardiograms were performed just prior to surgery and in the immediate post-op period to assess left ventricle mass index and relative wall thickness (RWT). Plasma ET-1 levels were assessed at both time points. Association between ET-1 levels and ventricular remodeling was assessed.RESULTSPatients < 1 year demonstrated higher pre-op ET-1 than post-op (2.8 pg/mL vs 1.9 pg/mL, P = 0.02). Conversely, patients > 1 year had no change in ET-1 concentration before and after surgery (1.1 vs 1.4, NS). Pre-op, patients < 1 year demonstrated significantly higher ET-1 than older children (2.8 vs 1.1, P = 0.001). Post-op there was no difference between the age groups (1.9 vs 1.4, NS). Neither RWT nor left ventricle mass index (LVMI) varied from pre-op to post-op. The subset of neonates showed a strong positive correlation between pre-op ET-1 and RWT (r = 0.92, P = 0.001). Patients with ET-1 > 2 pg/mL pre-op demonstrated higher LVMI (65.7 g/m2.7 vs 38.5 g/m2.7, P = 0.004) and a trend towards higher RWT (45% vs 39%, P = 0.07) prior to repair than those with lower ET-1 concentration.CONCLUSIONET-1 concentration is significantly variable in the peri-operative period surrounding coarctectomy. Older children and infants have different responses to surgical repair suggesting different mechanisms of activation.