Vasodilator Function Research Articles

The Peroxisome Proliferator-Activated Receptor γ Agonist Pioglitazone Protects Vascular Endothelial Function in Hypercholesterolemic Rats by Inhibiting Myeloperoxidase.

Objective Hypercholesterolemia- (HC-) induced endothelial dysfunction is the first step of atherogenesis, and the peroxisome proliferator-activated receptor γ (PPARγ (PPARγ (PPARγ) has been reported to attenuate atherosclerosis formation; however, the underlying mechanisms are not fully understood. The present study was designed to determine whether myeloperoxidase (MPO) mediates HC-induced endothelial dysfunction and the role of the PPARγ agonist pioglitazone (PIO) in attenuating endothelial dysfunction. Methods Male Wistar rats were fed with normal or high cholesterol diets for 8 weeks. HC rats were randomized to receive dapsone (DDS, the MPO inhibitor) during the last 6 days or PIO for the remaining 4 weeks. Vascular endothelial function was determined by comparing vasorelaxation to ACh, an endothelium-dependent vasodilator, and SNP, an endothelium-independent vasodilator in vascular rings in vitro. The vascular MPO activity, NOx content, and cGMP level were measured by the MPO activity assay kit, NO assay kit, and cGMP RIA kit. Results Compared with rats fed with normal diet, endothelium-dependent vasodilation, NOx content, and cGMP level were decreased, and MPO activity was increased in thoracic aortas of rats fed with HC diet. There was a negative correlation between vascular endothelial function, NOx content or cGMP level, and MPO activity. PIO obviously reduced the MPO activity, increased NOx content and cGMP level, and improved endothelium-dependent vasodilation function in HC rats, which was essentially the same as that seen with DDS. And, there was a negative correlation between vascular endothelial function, NOx content or cGMP level, and MPO activity in the HC group and the PIO intervention group. Conclusion MPO might provoke vascular endothelial dysfunction in hypercholesterolemic rats by reducing the NO biological activity and impairing the NO/cGMP/cGK signaling pathway. PIO might inhibit vascular MPO activity and increase NO bioavailability with the net result of reversing endothelial dysfunction.

ENDOTHELIAL DYSFUNCTION AND CAROTID ARTERY ATHEROSCLEROTIC PHENOTYPES

Endothelial dysfunction plays a key role in the initial development of atherosclerosis. The presence of atherosclerosis by ultrasound examination of the carotid arteries is associated with an increased risk of development of coronary heart disease (CHD) by 1.2% –3.3% per year. The study of the relationship between morphological and functional vascular alterations is an important step toward an improvement of prognostic assessment of the risk of cardiovascular diseases (CVD) and the development of new tools for their prevention. We aimed to perform a systematic review of published studies evaluating the relationship between flow-mediated vasodilation (FMD) during reactive hyperemia test and carotid artery intima-media thickness (IMT). Material and methods. Publications on selected topic were analyzed from 2000 to 2019. We used various Internet resources such as PubMed (https://www.ncbi.nlm.nih.gov/pubmed), Google Scholar (https://scholar.google.ru), the scientific electronic library eLIBRARY.ru (https://elibrary.ru) and major Russian cardiology journals. Results. The analysis of the literature showed that a relationship between a decrease of FMD and an increase of IMT is consistently found in patients with type 2 diabetes mellitus, with verified atherosclerosis of different locations (including CHD and peripheral arterial atherosclerosis), and arterial hypertension. However, these studies were conducted predominantly on small clinical groups (from 10 to 136 people). Few large studies (more than 1000 people) among subjects with arterial hypertension and type 2 diabetes mellitus did not show any convincing relationship between IMT and FMD. In the current literature there is a lack of large studies on the problem, and the data of existing studies are contradictory. New larger studies on this issue are required in various populations and in a wide age range. Conclusion. The studying of association between phenotypes of vasodilation function and structural changes of the vascular wall (for example, between FMD and IMT) remains topical for prognostic assessments of the risk of developing of cardiovascular diseases.

Дисфункция эндотелия как главный фактор кардиоваскулярного риска, лимитирующий работоспособность юных спортсменов: методы оценки и коррекция с помощью специализированных продуктов питания на основе апифитокомпонентов

Objective: to assess with exercise tests the endothelial dysfunction (ED) and performance before and after the treatment with specialized athlete’s nutrition product (SANP) with apian and herbal components. Materials and methods: 88 athletes aged 16-18 we tested. The main group included 58 athletes, who took SANP (candy bar «Gold F25 ApiSpeis Light») for 2 months. The control group-1 included 32 schoolchildren and students, non-athletes, with normal endothelium-dependent vasodilatation function of the brachial artery (EDVD BA) at the peak of the reactive hyperemia test (RHT). Control group-2, 30 athletes who did not take SANP, was formed for the comparison with the main group after taking SANP. For all individuals, we evaluated the level of EDVD, endothelium-dependent vasoconstriction (EDVC BA) at the peak of the hyperventilation test (HVT), the coefficients (C) of the endothelial sensitivity to shear stress and the blood flow velocity (Vps) of the BA at the peak of the RHT and HVT, the endothelial sensitivity index (ESI), and the maximum load (Wmax), the anaerobic threshold time (ATT). We also did general and biochemical blood tests. Results: the earliest manifestation of endothelial dysfunction is a decrease in sensitivity to shear stress during RHT and HVT resulting from endotheliocyte overstrain which can be assessed with ESI (sensitivity 80.9%, specificity 99.4 The EDVD diagnostic significance was 5.6 times lower than that of EIS, while 10.5% of athletes with over 10% EDVD actually had ED, with a predominant vasospasm and high cardiovascular risk. After the course of SANP in the main group, EDVD increased by 70%, EDVC decreased by 2.2 times, and the ESI increased by 2.3 times, against the background of improved performance. Total cholesterol decreased by 13%, triglycerides by 17%, cortisol by 14%, lactate by 25%. Red blood cell and mineral levels increased. A correlation was found between an increase in ATT a decrease in cortisol (r=-0.53; p<0.0001), an increase in red blood cells (r=0.62; p<0.0001), and an increase in Vps in BA during of hyperventilation with an increase in Wmax (r=0.52; p<0.0001). Conclusions: ED is the main factor of cardiovascular risk, limiting working capacity and forming a spastic type of regional hemodynamics of young athletes. The ESI criterion enables the detection of a decrease in the endothelial sensitivity to shear stress during a hyperventilation test, which causes the predominant vasospasm. Th e tested SANP can be used in the system of biomedical support for young athletes.

Impact of High-Intensity Interval Training, Moderate-Intensity Continuous Training, and Resistance Training on Endothelial Function in Older Adults.

It is unclear if high-intensity interval training (HIIT) elicits superior improvements in brachial artery (BA) flow-mediated dilation (FMD) responses (i.e., endothelial-dependent vasodilation) than moderate-intensity continuous training (MICT) or resistance training (RT) in otherwise healthy older adults. Whether HIIT enhances lower-limb FMD responses and/or augments low flow-mediated constriction (L-FMC) (endothelial-dependent vasoconstriction) responses more than MICT or RT is also unknown. We tested the hypothesis that HIIT would improve BA and popliteal artery (POP) FMD and L-FMC responses more than MICT or RT in healthy older adults. Thirty-eight older adults (age, 67 ± 6 yr) performed 6 wk of either HIIT (2 × 20 min bouts alternating between 15-s intervals at 100% of peak power output [PPO] and passive recovery [0% PPO]; n = 12), MICT (34 min at 60% PPO; n = 12), or whole-body RT (8 exercises, 2 × 10 repetitions; n = 14). The L-FMC and FMD were measured before and after training using high-resolution ultrasound and quantified as the percent change in baseline diameter during distal cuff occlusion and after cuff release, respectively. Resting BA blood flow and vascular conductance (both, P < 0.003) were greater after HIIT only. The HIIT and MICT similarly increased BA-FMD (pre-post: both, P < 0.001), but only HIIT improved BA L-FMC (P < 0.001). Both HIIT and MICT similarly enhanced POP FMD and L-FMC responses (both, P < 0.045). Resistance training did not impact FMD or L-FMC responses in either artery (all, P > 0.20). HIIT and MICT, but not RT, similarly improved lower-limb vasodilator and vasoconstrictor endothelial function in older adults. Although HIIT and MICT groups enhanced BA vasodilator function, only HIIT improved resting conductance and endothelial sensitivity to low-flow in the BA. In the short-term, HIIT may be most effective at improving peripheral vascular endothelial function in older adults.

Disruption of Pressure-Induced Ca2+ Spark Vasoregulation of Resistance Arteries, Rather Than Endothelial Dysfunction, Underlies Obesity-Related Hypertension.

Obesity-related hypertension is one of the world's leading causes of death and yet little is understood as to how it develops. As a result, effective targeted therapies are lacking and pharmacological treatment is unfocused. To investigate underlying microvascular mechanisms, we studied small artery dysfunction in a high fat-fed mouse model of obesity. Pressure-induced constriction and responses to endothelial and vascular smooth muscle agonists were studied using myography; the corresponding intracellular Ca2+ signaling pathways were examined using confocal microscopy. Principally, we observed that the enhanced basal tone of mesenteric resistance arteries was due to failure of intraluminal pressure-induced Ca2+ spark activation of the large conductance Ca2+ activated K+ potassium channel (BK) within vascular smooth muscle cells. Specifically, the uncoupling site of this mechanotransduction pathway was at the sarcoplasmic reticulum, distal to intraluminal pressure-induced oxidation of Protein Kinase G. In contrast, the vasodilatory function of the endothelium and the underlying endothelial IP-3 and TRPV4 (vanilloid 4 transient receptor potential ion channel) Ca2+ signaling pathways were not affected by the high-fat diet or the elevated blood pressure. There were no structural alterations of the arterial wall. Our work emphasizes the importance of the intricate cellular pathway by which intraluminal pressure maintains Ca2+ spark vasoregulation in the origin of obesity-related hypertension and suggests previously unsuspected avenues for pharmacological intervention.

Acute lower leg hot water immersion protects macrovascular dilator function following ischaemia-reperfusion injury in humans.

• What is the central question of this study? What is the effect of lower leg hot water immersion on vascular ischaemia-reperfusion injury induced in the arm of young healthy humans? • What is the main finding and its importance? Lower leg hot water immersion successfully protects against vascular ischaemia-reperfusion injury in humans. This raises the possibility that targeted heating of the lower legs may be an alternative therapeutic approach to whole-body heating that is equally efficacious at protecting against vascular ischaemia-reperfusion injury. Reperfusion that follows a period of ischaemia paradoxically reduces vasodilator function in humans and contributes to the tissue damage associated with an ischaemic event. Acute whole-body hot water immersion protects against vascular ischaemia-reperfusion (I-R) injury in young healthy humans. However, the effect of acute lower leg heating on I-R injury is unclear. Therefore, the purpose of this study was to test the hypothesis that, compared with thermoneutral control immersion, acute lower leg hot water immersion would prevent the decrease in macro- and microvascular dilator functions following I-R injury in young healthy humans. Ten young healthy subjects (5 female) immersed their lower legs into a circulated water bath for 60min under two randomized conditions: (1) thermoneutral control immersion (∼33°C) and (2) hot water immersion (∼42°C). Macrovascular (brachial artery flow-mediated dilatation) and microvascular (forearm reactive hyperaemia) dilator functions were assessed using Doppler ultrasound at three time points: (1) pre-immersion, (2) 60min post-immersion, and (3) post-I/R (20min of arm ischaemia followed by 20min of reperfusion). Ischaemia-reperfusion injury reduced macrovascular dilator function following control immersion (pre-immersion 6.0±2.1% vs. post-I/R 3.6±2.1%; P<0.05), but was well-maintained with prior hot water immersion (pre-immersion 5.8±2.1% vs. post-I/R 5.3±2.1%; P=0.8). Microvascular dilator function did not differ between conditions or across time. Taken together, acute lower leg hot water immersion prevents the decrease in macrovascular dilator function that occurs following I-R injury in young healthy humans.

Tetramethoxystilbene-Loaded Liposomes Restore Reactive-Oxygen-Species-Mediated Attenuation of Dilator Responses in Rat Aortic Vessels Ex vivo.

The methylated analogue of the polyphenol resveratrol (RV), 2,3′,4,5′-tetramethoxystilbene (TMS) displays potent antioxidant properties and is an effective cytochrome P450 (CYP) 1B1 inhibitor. The bioavailability of TMS is low. Therefore, the use of liposomes for the encapsulation of TMS is a promising delivery modality for enhanced uptake into tissues. We examined the effect of delivery of TMS in liposomes on the restoration of vasodilator responses of isolated aortic vessels after acute tension elevation ex vivo. Aortic vessels from young male Wistar rats were isolated, and endothelial-dependent (acetylcholine, ACh) and -independent (sodium nitroprusside, SNP) responses assessed. Acute tension elevation (1 h) significantly reduced ACh dilator responses, which were restored following incubation with superoxide dismutase or apocynin (an NADPH oxidase inhibitor). Incubation with TMS-loaded liposomes (mean diameter 157 ± 6 nm; PDI 0.097) significantly improved the attenuated dilator responses following tension elevation, which was sustained over a longer period (4 h) when compared to TMS solution. Endothelial denudation or co-incubation with L-NNA (Nω-nitro-l-arginine; nitric oxide synthase inhibitor) resulted in loss of dilator function. Our findings suggest that TMS-loaded liposomes can restore attenuated endothelial-dependent dilator responses induced by an oxidative environment by reducing NADPH-oxidase-derived ROS and potentiating the release of the vasodilator nitric oxide. TMS-loaded liposomes may be a promising therapeutic strategy to restore vasodilator function in vascular disease.

Improved endothelial-dependent and endothelial-independent skin vasodilator responses following remote ischemic preconditioning

One week of daily remote ischemic preconditioning (RIPC) improves cutaneous vasodilatory (VD) function. However, the underlying mechanisms and the number of sessions needed to optimize this adaptive response remain unclear. We hypothesized that the responses to localized heating of the skin will be greater after 2 wk as opposed to 1 wk of RIPC. Furthermore, 2 wk of repeated RIPC will augment cutaneous VD responses to thermal and pharmacological stimuli. In methods, twenty-four participants (24 ± 2 yr; 13 men, 11 women) performed repeated RIPC (7 daily sessions over 1 wk, n = 11; 12 sessions over 2 wk, n = 13), consisting of four repetitions of 5 min of arm blood flow occlusion separated by 5 min reperfusion. Laser speckle contrast imaging was used to measure skin blood flow responses, in perfusion units (PU), to local heating (Tloc = 42°C), acetylcholine (ACh), and sodium nitroprusside (SNP) before and after repeated RIPC. Data were expressed as cutaneous vascular conductance (CVC, in PU/mmHg). In results, the VD response to local heating increased after RIPC (∆CVC from baseline; 1 wk: 0.94 ± 0.11 to 1.19 ± 0.15, 2 wk: 1.18 ± 0.07 to 1.33 ± 0.10 PU/mmHg; P < 0.05) but the ∆CVC did not differ between weeks. SNP-induced VD increased after 2 wk of RIPC (∆CVC; 0.34 ± 0.07 to 0.63 ± 0.11 PU/mmHg; P < 0.05), but ACh-induced VD did not. In conclusion, repeated RIPC improves local heating- and SNP-mediated cutaneous VD. When compared with 1 wk of RIPC, 2 wk of RIPC does not induce further improvements in cutaneous VD function.NEW & NOTEWORTHY Repeated RIPC increases the cutaneous vasodilatory response to local heating and to sodium nitroprusside but not to acetylcholine. Thus, endothelial-independent and local heating-mediated cutaneous vasodilation are improved following RIPC. However, 2 wk of RIPC sessions are not more effective than 1 wk of RIPC sessions in enhancing local heating-mediated cutaneous vasodilation.

ENDOTHELIAL PROTECTIVE ACTIVITY OF 2,6-DIISOBORNYL-4-METHYLPHENOL IN A MODEL OF MYOCARDIAL ISCHEMIA/REPERFUSION IN RATS

Objective: Our research focuses on the endothelial protective effects of 2,6-diisobornyl-4-methylphenol. Its effect was revealed while studying rats experiencing myocardial ischemia/reperfusion. The research results demonstrated that there are significant disturbances in the vascular endothelium manifested by a decrease in the vasodilating activity and antiplatelet properties of 2,6-diisobornyl-4-methylphenol.&#x0D; Methods: We designed our own model of myocardial ischemia/reperfusion and applied it to 52 adult outbred Wistar males. We employed some methods of hemostasiological research such as thromboelastography to determine the antiplatelet activity of the vascular wall, G. Born nephelometric method to study platelet aggregation, phase contrast microscopy to count platelet counts in blood plasma, measurement of intra-arterial pressure to study the endothelial vasodilating function, and calculated the endothelial dysfunction coefficient in rats.&#x0D; Results: Preventive intragastric injection of 2,6-diisobornyl-4-methylphenol (100 mg/kg, 3 days before and 5 days after reproducing the myocardial ischemia/reperfusion model) increased the antiplatelet activity of the vascular endothelium in rats by 37% compared to the endothelium of the abdominal aorta segment of untreated animals. Moreover, 2,6-diisobornyl-4-methylphenol decreased the endothelial dysfunction coefficient by 43% in comparison with the value in the control group.&#x0D; Conclusion: 2,6-diisobornyl-4-methylphenol has an endothelial protective effect proved by its ability to increase antiplatelet properties of the endothelium and decrease the endothelial dysfunction coefficient. The revealed endothelial protective properties of 2,6-diisobornyl-4-methylphenol can be regarded as one of the potential mechanisms of cardioprotective activity of the drug.

Effects of ghrelin supplementation on the acute phase of Chagas disease in rats

BackgroundTrypanosoma cruzi is the causative agent of Chagas disease, which is endemic to subtropical and tropical Americas. The disease treatment remains partially ineffective, involving therapies directed to the parasite as well as palliative strategies for the clinical manifestations. Therefore, novel candidates for disease control are necessary. Additionally, strategies based on parasite inhibition via specific targets and application of compounds which improve the immune response against the disease is welcomed. Ghrelin is a peptide hormone pointed as a substance with important cardioprotective, vasodilatory, anti-apoptotic, anti-oxidative and immune modulatory functions. The aims of this study were to evaluate the immunomodulatory effects of ghrelin in male Wistar rats infected with the Y strain of T. cruzi.MethodsIn order to delineate an immune response against T. cruzi mediated by ghrelin, we evaluated the following parameters: quantification of blood and cardiac parasites; analysis of cell markers (CD3+, CD8+, NK, NKT, CD45RA+, macrophage and RT1B+); nitric oxide (NO) production; lymphoproliferation assays; splenocyte apoptosis; and INF-γ, IL-12 and IL-6 quantification in sera.ResultsThe animals infected with T. cruzi and supplemented with ghrelin demonstrated an upregulated pattern in macrophage and NO production, whereas an anti-inflammatory response was observed in T cells and cytokines. The low response against T. cruzi mediated by T cells probably contributed to a higher colonization of the cardiac tissue, when compared to infected groups. On the other side, the peptide decreased the inflammatory infiltration in cardiac tissue infected with T. cruzi.ConclusionsGhrelin demonstrated a dual function in animals infected with T. cruzi. Further studies, especially related to the decrease of cardiac tissue inflammation, are needed in order to determine the advantages of ghrelin supplementation in Chagas disease, mostly for populations from endemic areas.

Local angiotensin-(1-7) administration improves microvascular endothelial function in women who have had preeclampsia.

Despite remission of clinical symptoms postpartum, women who have had preeclampsia demonstrate microvascular endothelial dysfunction, mediated in part by increased sensitivity to angiotensin II (ANG II). Angiotensin-(1-7) [Ang-(1-7)] is an endogenous inhibitor of the actions of ANG II and plausible druggable target in women who had preeclampsia. We therefore examined the therapeutic potential of Ang-(1-7) in the microvasculature of women with a history of preeclampsia (PrEC; n = 13) and parity-matched healthy control women (HC; n = 13) hypothesizing that administration of Ang-(1-7) would increase endothelium-dependent dilation and nitric oxide (NO)-dependent dilation and decrease ANG II-mediated constriction in PrEC. Using the cutaneous microcirculation, we assessed endothelium-dependent vasodilator function in response to graded infusion of acetylcholine (ACh; 10-7 to 102 mmol/L) in control sites and sites treated with 15 mmol/L NG-nitro-l-arginine methyl ester (l-NAME; NO-synthase inhibitor), 100 µmol/L Ang-(1-7), or 15 mmol/L l-NAME + 100 µmol/L Ang-(1-7). Vasoconstrictor function was measured in response to ANG II (10-20-10-4 mol/L) in control sites and sites treated with 100 µmol/L Ang-(1-7). PrEC had reduced endothelium-dependent dilation (P < 0.001) and NO-dependent dilation (P = 0.04 vs. HC). Ang-(1-7) coinfusion augmented endothelium-dependent dilation (P < 0.01) and NO-dependent dilation (P = 0.03) in PrEC but had no effect in HC. PrEC demonstrated augmented vasoconstrictor responses to ANG II (P < 0.01 vs. HC), which was attenuated by coinfusion of Ang-(1-7) (P < 0.001). Ang-(1-7) increased endothelium-dependent vasodilation via NO synthase-mediated pathways and attenuated ANG II-mediated constriction in women who have had preeclampsia, suggesting that Ang-(1-7) may be a viable therapeutic target for improved microvascular function in women who have had a preeclamptic pregnancy.

P875Myocardial perfusion reserve assessment in patients with angina pectoris and suspected coronary spasm

Abstract Background Patients with signs and symptoms of myocardial ischemia yet unobstructed coronary arteries represent a diagnostic and therapeutic challenge. Coronary vasomotor disorders such as coronary epicardial or microvascular spasm are frequently found among these patients. They can be diagnosed using intracoronary acetylcholine testing (ACH-test). It has been shown that patients with epicardial spasm have a worse prognosis compared to patients with microvascular spasm. The reasons for this finding are however not apparent. We speculated in this study that patients with epicardial spasm have a worse vasomotor dysfunction compared to patients with microvascular spasm or normal ACH-test. To assess this hypothesis all patients in this study not only underwent ACH-testing but in addition also adenosine stress perfusion cardiac MRI (CMR) with calculation of the myocardial perfusion reserve index (MPRI). The latter method allows for assessment of vasodilatory function compared to the vasoconstrictor assessment using acetylcholine. Methods Between 2012 and 2016, 129 consecutive patients (mean age 64±13 years, 46% female) with signs and symptoms of myocardial ischemia yet unobstructed coronary arteries were enrolled in this study. All patients underwent ACH-testing as well as adenosine stress perfusion CMR. According to the results of the acetylcholine test, patients were allocated to 3 groups: a) epicardial spasm (angina, ischemic ECG changes and &gt;75% coronary diameter reduction), b) microvascular spasm (angina, ischemic ECG changes and &lt;75% coronary diameter reduction) and c) no evidence of coronary artery spasm. CMR-derived MPRI was calculated semiquantitatively from myocardial signal intensity-over-time curves of adenosine stress and rest perfusion. Results Epicardial and microvascular spasm was found in 31 (24%) and 69 (53%) patients, respectively, while 29 (22%) patients had no evidence of coronary spasm on ACH-testing. Women were more likely to have microvascular spasm than men (68% vs. 36%, p&lt;0.001). The prevalence of epicardial spasm did not significantly differ between female and male patients (18% vs. 31%, p=0.08). MPRI was similar in patients with microvascular spasm compared to patients without spasm (1.30 vs. 1.27, p=0.43). However, patients with epicardial spasm had significantly lower MPRI than patients without spasm (1.16 vs. 1.30, p&lt;0.05) or those with microvascular spasm (1.16 vs. 1.27, p&lt;0.05). Conclusion MPRI determined by stress perfusion CMR was significantly reduced in patients with epicardial spasm compared to those with microvascular spasm or normal ACH-test. This could indicate that patients with epicardial spasm have a more generalized coronary vasomotor disorder compared to other patients. This may be the reason for the worse outcome observed and could lead to more aggressive medical therapy and closer follow-up. Acknowledgement/Funding This work was funded by the Robert-Bosch-Stiftung, Stuttgart, Germany and the Berthold-Leibinger-Stiftung, Ditzingen, Germany.

P4625On women with ST-elevation myocardial infarction: raised concentrations of pro-C-type natriuretic peptide predict increased one-year mortality

Abstract Introduction Endothelial C-type natriuretic peptide (CNP) contributes to the local regulation of vascular homeostasis including a vasodilatory function in the microcirculation when studied in animal models. Clinical investigations have shown that high concentrations of C-type natriuretic peptides in plasma are associated with adverse clinical outcome in subgroups of patients with cardiac disease. Purpose To determine the prognostic potential of pro-C-type natriuretic peptide (proCNP) measurement in plasma sampled on admission of patients with ST-elevation myocardial infarction (STEMI). Methods In 1760 patients (470 women, 1290 men) with confirmed STEMI, we measured proCNP concentration in plasma obtained on hospital admission before coronary angiography. We divided patients into groups of low, normal or raised proCNP concentrations based on lower and upper cut-off values of sex- and age-specific 95% reference intervals from a reference population (688 individuals). We estimated differences in baseline characteristics including medical history and determined the prognostic value of proCNP measurement by Kaplan-Meier plots including log-rank tests and Cox regression survival analyses (expressed as hazard ratio (HR) and 95% confidence interval). Results Raised proCNP concentrations in plasma were associated with a higher prevalence of hypertension (P&lt;0.001), diabetes mellitus (P=0.009), and peripheral artery disease (P=0.023), and a higher one-year all-cause mortality rate compared with normal proCNP concentrations (Plog-rank = 0.009, HR: 1.6 (1.1–2.4)). However, when adjusted for sex, an interaction between sex and groups of normal vs. raised proCNP was found (P=0.030). In sex-stratified analyses only women with raised proCNP concentrations showed an increased one-year all-cause mortality rate (women: Plog-rank &lt;0.001, HR: 2.6 (1.5–4.6), men: Plog-rank= 0.66, HR: 1.1 (0.6–1.9)). Furthermore, in women, stepwise increases of proCNP concentration in the upper range (proCNP concentration &gt; median) were independently associated with increased risk of death within one year after adjusting for age, plasma concentrations of creatinine and proANP, and quartiles of plasma troponins (HR: 1.02 (1.00–1.05) per 1 pmol/L increase of proCNP, P=0.047). One-year all-cause mortality rates Conclusion In patients with STEMI, a raised concentration of proCNP from plasma sampled on admission was associated with a higher risk of death within one year. However, only women displayed this difference of mortality rate in sex-specific estimates. Moreover, stepwise increases of proCNP concentration in the upper range independently predicted a higher risk of one-year death in women following STEMI after adjusting for potential confounders.

Correlations of carotid intima-media thickness with endothelial function and atherosclerosis degree in patients with type 2 diabetes mellitus.

To investigate the correlation of carotid intima-media thickness (IMT) with endothelial function and atherosclerosis degree in patients with type 2 diabetes mellitus. A total of 80 patients with type 2 diabetes mellitus admitted and treated in our hospital from January 2017 to January 2018 were selected and randomly divided into two groups (n = 40). Patients who were definitely diagnosed with type 2 diabetes mellitus were selected as observation group, and individuals who received health examination and were excluded from type 2 diabetes mellitus were enrolled as control group. The diagnosed proportions of carotid plaque, Crouse scores, endothelial-dependent flow-mediated vasodilation (FMD) function and nitroglycerin-mediated dilation (NMD) function of the brachial arteries in the two groups were compared. The indexes related to vascular endothelial functions [vascular endothelial growth factor (VEGF), endothelin-1 (ET-1) and nitric oxide (NO) levels] in the two groups were detected. The correlations of Crouse score with brachial arterial FMD value, VEGF level, ET-1 level and NO level in observation group were analyzed. The diagnosed proportion of carotid plaque in observation group was significantly higher than that in control group (P < 0.05), and the Crouse score in observation group was higher than that in control group (P < 0.05). The brachial arterial FMD value in observation group was remarkably lower than that in control group (P < 0.05). Compared with control group, VEGF and ET-1 levels were significantly reduced in observation group (P < 0.05), with the statistical increase of NO level (P < 0.05). In observation group, the Crouse score was negatively correlated with the brachial arterial FMD value, VEGF level and ET-1 level, whereas positively correlated with the NO level (P < 0.05). Our data show that the carotid IMT is increased significantly among patients with type 2 diabetes mellitus, and the vascular endothelial function is impaired. Moreover, after the occurrence of atherosclerosis, we found the carotid IMT is negatively correlated with endothelial-dependent FMD, as well as levels of VEGF and ET-1, whereas shows positive correlation with the vasodilative factor NO.

Angiotensin II Type 1 Receptor Antagonist Azilsartan Restores Vascular Reactivity Through a Perivascular Adipose Tissue-Independent Mechanism in Rats with Metabolic Syndrome.

Perivascular adipose tissues (PVAT) are involved in the regulation of vascular tone. In mesenteric arteries, the compensatory vasodilatory effects of PVAT appear when vascular relaxation is impaired and disappear at around 23weeks of age in SHRSP.Z-Leprfa/IzmDmcr (SHRSP.ZF) rats with metabolic syndrome (MetS). The renin-angiotensin system is involved in the development of endothelium and vascular dysfunction. Therefore, we investigated whether azilsartan, a potent angiotensin II type 1 (AT1) receptor antagonist, can protect against the deterioration of the PVAT compensatory vasodilator function that occurs with aging in MetS. Two age groups of SHRSP.ZF rats (13 and 20weeks of age) were administered azilsartan or vehicle through oral gavage once daily for 10weeks. The vasodilation response of the isolated superior-mesenteric arteries upon addition of endothelium-dependent and -independent agonists was determined in the presence or absence of PVAT using organ bath methods. In vivo treatment with azilsartan improved the acetylcholine-induced vasodilation in mesenteric arteries with and without PVAT at both time-points. The mRNA levels of AT1 receptor and AT1 receptor-associated protein were unchanged in PVAT upon azilsartan treatment. Furthermore, in vitro treatment with azilsartan (0.1 and 0.3μM for 30min) did not affect the compensatory effect of PVAT on vasodilation in response to acetylcholine in SHRSP.ZF rat mesenteric arteries. Our results provide evidence supporting the use of azilsartan for the long-term protection against vascular dysfunctions in MetS. Azilsartan did not improve the dysfunction of PVAT-mediated modulation of vascular tone during MetS. The protective effect of azilsartan is mediated by restoring the endothelium- and vascular smooth muscle-mediated mechanisms.

Calcification biomarkers and vascular dysfunction in obesity and type 2 diabetes: influence of oral hypoglycemic agents.

Vascular aging in obesity and type 2 diabetes (T2D) is associated with progressive vascular calcification, an independent predictor of morbidity and mortality. Pathways for vascular calcification modulate bone matrix deposition, thus regulating calcium deposits. We investigated the association between biomarkers of vascular calcification and vasodilator function in obesity or T2D, and whether antidiabetic therapies favorably impact those markers. Circulating levels of proteins involved in vascular calcification, such as osteopontin (OPN), osteoprotegerin (OPG), regulated on activation, normal T cell expressed and secreted (RANTES), and fetuin-A were measured in lean subjects, individuals with metabolically healthy obesity (MHO), and patients with metabolically unhealthy obesity (MUO) or T2D. Vasodilator function was assessed by infusion of ACh and sodium nitroprusside (SNP). Circulating levels of OPN were higher in the MUO/T2D group than in lean subjects (P < 0.05); OPG and RANTES were higher in MUO/T2D group than in the other groups (both P < 0.001); fetuin-A was not different between groups (P > 0.05); vasodilator responses to either ACh or SNP were impaired in both MUO/T2D and MHO compared with lean subjects (all P < 0.001). In patients with T2D who were enrolled in the intervention trial, antidiabetic treatment with glyburide, metformin, or pioglitazone resulted in a significant reduction of circulating OPG (P = 0.001), without changes in the other biomarkers and vasodilator responses (all P > 0.05). In conclusion, obese patients with MUO/T2D have elevated circulating OPN, OPG, and RANTES; in these patients, antidiabetic treatment reduces only circulating OPG. Further study is needed to better understand the mechanisms of vascular calcifications in obesity and diabetes.

Heterogeneity in the vasodilatory function of individual extremities.

Objectives Heterogeneity and homogeneity in the flow-mediated dilation of the human body's individual extremities are not fully understood, and the relationship between flow-mediated dilation and local muscle activity is unclear. We assessed the flow-mediated dilation of four individual extremities and sought to determine the contribution of local muscle activity (evaluated as muscle strength) to the flow-mediated dilation in each extremity. Methods Thirteen healthy young right-handed nonactive males participated. The flow-mediated dilation in the brachial and popliteal arteries at both arms and legs was assessed by ultrasound Doppler. Muscle strength was evaluated as the grip strength and knee extension. Results There was a significant difference in the brachial artery (BA)-FMD values between the subjects' dominant and non-dominant sides (8.0 ± 2.8 vs. 5.5 ± 2.2%, p &lt; 0.05), whereas the two sides showed similar popliteal artery (PA)-FMD values. There was no significant correlation in flow-mediated dilation between the dominant brachial artery and popliteal artery. The BA-FMD was significantly correlated with the grip strength in both upper extremities (dominant: r = 0.562, non-dominant: r = 0.548; p &lt; 0.05, respectively). Conclusion These results demonstrated heterogeneity in the flow-mediated dilation of individual extremities. We observed that local muscle activity can affect the local vascular function. Measurements of vasodilatory function in individual extremities should thus be carefully considered.

The Impact of Different Exercise Intensities on Vasodilation and Shear Rate Patterns in Children.

The effect of exercise intensity on vasodilator function is poorly understood in children. The authors compared the acute effect of high-intensity interval exercise (HIIE) with moderate-intensity steady-state exercise (MISS) on postexercise vasodilation and shear patterns in 7- to 12- year-old children. Superficial femoral artery diameter, shear rates, and flow-mediated dilation were measured pre, immediately following (post), and 1 hour after (post60) HIIE (six 1-min sprints at 90% peak power [Wmax], with 1-min recovery) and MISS (15min at 44% Wmax). Baseline superficial femoral artery diameter increased similarly following both HIIE (pre 4.23 [0.41]mm, post 4.73 [0.56]mm) and MISS (pre 4.28 [0.56]mm, post 4.59 [0.64]mm), returning to preexercise values post60. Blood flow and antegrade shear rate were increased post HIIE and MISS, but to a greater extent, post HIIE (P < .05). Retrograde shear rate was attenuated post both exercise conditions and remained post60 (P < .001). There was a decline in flow-mediated dilation postexercise (HIIE Δ -2.9%; MISS Δ -2.4%), which was no longer apparent when corrected for baseline diameter. Acute bouts of external work-matched HIIE or MISS exert a similar impact on shear-mediated conduit artery vasodilation and flow-mediated dilation in children, and this is reversed 1 hour after exercise.

Significant impact of left ventricular assist device models on the value of flow-mediated dilation: effects of LVAD on endothelial function.

The precise physiological changes associated with the use of left ventricular assist device (LVAD) are not well characterized. We examined the impact of changes in hemodynamic state using LVAD on endothelial function. We measured flow-mediated vasodilation (FMD) to evaluate endothelial vasodilator function of the brachial artery in 53 patients (dilated cardiomyopathy: 39, ischemic cardiomyopathy: 4, and others: 10) with an implanted LVAD (DuraHeart, EVAHEART, or HeartMate II). We found that FMD value in the HeartMateII LVAD group (9.3% ± 2.9%) was significantly higher than those in the other two groups (EVAHEART: 6.7% ± 2.8% and DuraHeart: 6.2% ± 4.0%). Other factors that affected the FMD value were age (r = - 0.31, p = 0.026), Brinkman index (r = - 0.30, p = 0.029); however, aortic opening, aortic regurgitation, and other hemodynamic parameters such as cardiac index or pulmonary capillary wedge pressure did not correlate with FMD. Multivariate analyses revealed that the difference among the LVAD models most significantly affected the FMD values after adjusting for age and smoking status (t = 2.6, p = 0.014). Event free survival rate of death and cerebral infarction was not significantly different according to the value of FMD. The difference among the LVAD groups most significantly affected the state of endothelial function and it had more impact than other clinical factors.

Attenuation of Retinal Endothelial Vasodilator Function in a Rat Model of Retinopathy of Prematurity

ABSTRACTPurpose: Retinopathy of prematurity (ROP) is characterized by morphological abnormalities in retinal blood vessels, but how an episode of ROP affects vascular function remains to be fully elucidated. The purpose of the present study was to assess the distribution of pericyte/smooth muscle in retinal blood vessels and retinal vasodilator responses in a rat model of ROP.Methods: ROP was induced in rats by the subcutaneous injection of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor KRN633 (10 mg/kg) on postnatal day (P) 7 and P8. The distribution of pericyte/smooth muscle in retinal blood vessels was examined on P14 and P35 by immunohistochemistry. Retinal vasodilator responses were assessed on P35 by measuring the diameter of retinal arterioles in fundus images.Results: In retinas of KRN633-treated (ROP) rats, progressive angiogenesis, tortuous arteries, enlarged veins, and enhanced expression of α-smooth muscle actin in pericytes on capillaries and veins were observed on P14. These abnormalities in retinal vasculature showed a tendency to normalize by P35. Vasodilation of retinal arterioles induced by acetylcholine, an endothelium-dependent vasodilator, was smaller in P35 ROP rats than age-matched controls, whereas retinal vasodilator responses to the nitric oxide (NO) donor NOR3 were unaltered.Conclusions: Phenotypic changes in pericytes occur in the ROP model rats and endothelium-dependent vasodilatory mechanisms in retinal blood vessels are impaired. The impaired vasodilator function may contribute to the progression and pathogenesis of ROP.