Impaired Endothelial Function Research Articles

Lipoprotein(a) Is Elevated and Inversely Related to Coronary Endothelial Function in People With HIV.

HIV-associated cardiovascular disease (CVD) is increasing in prevalence. The mechanisms underlying the heightened cardiovascular risk faced by people with HIV (PWH), however, remain poorly defined. Recent studies indicate an important role of lipoprotein(a) (Lp[a]) in predicting CVD risk in the general population, but little is known regarding its role in HIV-associated CVD. Thus, we sought to evaluate whether Lp(a) is elevated in PWH and if it is associated with impaired coronary endothelial function (CEF), a known mediator of CVD in PWH. In this cross-sectional study, cardiac magnetic resonance imaging with isometric handgrip exercise, an endothelial dependent stressor, was performed to assess CEF in 65 PWH and 52 controls without HIV. Percent changes in coronary cross-sectional area and coronary blood flow from rest to stress were used to quantify CEF. Lp(a) levels were assessed by immunoturbidimetric assay at the time of magnetic resonance imaging. Lp(a) levels were higher in PWH compared with controls (78 nmol/L [39-137 nmol/L] versus 45.5 nmol/L [18-102.5 nmol/L], P<0.01). Both percent change in coronary cross-sectional area (0.38% [-6.1% to 5.4%] versus 7.43% [2.4%-11.2%], P<0.0005) and coronary blood flow (9.1% [-1.3% to 23.1%] versus 24.1% [3.3%-39.8%], P<0.05) were lower in PWH compared with controls. In PWH, Lp(a) was inversely associated with percent change in coronary cross-sectional area (β=-6.18±1.01%/nmol/L, P<0.001) but not with percent change in coronary blood flow even after adjustment for confounding risk factors. No association between Lp(a) and measures of CEF was observed in individuals without HIV. Lp(a) concentrations are elevated in PWH and inversely related to CEF in PWH.

The Role of Sex in the Effects of Smoking and Nicotine in Cardiovascular Function, Atherosclerosis, and Inflammation.

Cigarette smoke (CS) invokes an inflammatory response associated with vascular dysfunction and atherosclerosis. The role of sex and nicotine in CS effects on cardiovascular function and atherosclerosis is unexplored. Male and female C57Bl/6 WT (wild type) and ApoE-/- mice were exposed to CS and nicotine with access to chow and water ad libitum for 16 weeks to fill this gap. Heart rate and endothelial function were measured in the aorta of WT mice, while the lipid profile, cytokines, chemokines, and plaque area and composition were assessed in ApoE-/- mice. CS increased heart rate similarly in both sexes and induced a more substantial impairment in endothelial function in males and more plaque in females than nicotine. Necrotic core areas were similar for both treatments in both sexes, while females had higher collagen deposition across treatments. Both treatments elevated senescence-associated GLB1/-galactosidase (SA-GLB1) and interleukin 17A (IL17A) similarly in both sexes. CS upregulated cholesterol in both sexes, triglycerides, VLDL, HDL, and C-X-C motif chemokine ligand-5 (CXCL5/LIX) only in males, and LDL and IL1A only in females. Additionally, nicotine metabolism showed sex-specific responses to nicotine but not smoking. Findings suggest sex influences cardiovascular function and atherosclerosis following exposure to nicotine and CS. The purpose of this study was to fill the existing literature gap through assessment of the differential sex effects of CS and nicotine on vascular function and atherosclerosis to identify sex-specific risk factors. We show sex-specific differences in endothelial function, plaque, inflammation, and extracellular matrix (ECM) regulators with exposure to CS and nicotine, which underscore the importance of assessing sex in tobacco and nicotine exposure studies. This study also shows the negative effect of oral nicotine administration as many oral dissolvable nicotine products, like pouches and gum, are becoming increasingly popular among adolescents and young adults.

PCSK-9-inhibitor therapy improves endothelial function in high-risk patients with cardiovascular disease.

Impaired endothelial function predicts cardiovascular events. The aim of this study was to analyze the effect of evolocumab on endothelial function in patients with cardiovascular disease. This was a prospective, double-blinded, randomized, controlled, single center study including patients with cardiovascular disease and treated with statins. Patients were consecutively randomized (1:1) to either evolocumab treatment or placebo. All patients underwent examination of endothelial function at baseline, and after 1, 4 and 8weeks of treatment by a semi-automatic high-resolution ultrasound system (UNEX EF 18G). Parameters of endothelial function were flow-mediated vasodilation (FMD), low flow-mediated vasoconstriction (L-FMC) and vasoactive range (VAR). Hundred three patients with a mean age of 66.2 ± 7.7years and a mean LDL-cholesterol of 98 ± 19.1mg/dl completed the study. The change in VAR from baseline to week 8 was significantly different with evolocumab compared to placebo (p = 0.045). Moreover, VAR increased after 8weeks of treatment with evolocumab compared to baseline (p = 0.034). No change has been noticed in FMD and L-FMC after 8weeks of treatment with evolocumab. In subgroup analyses, VAR improved in patients with age ≤ 67years, lower systolic blood pressure (≤ 125mmHg) and higher baseline LDL-cholesterol (> 95mg/dl), (p = 0.006, p = 0.049 and p = 0.042, respectively) after 8weeks of evolocumab treatment. No serious adverse event related to study medication occurred during the study. Our data indicate that endothelial function improved with evolocumab treatment in high-risk patients on statin therapy with preexisting cardiovascular disease. Our results contribute to the mechanistic explanation why lower incidence of the cardiovascular composite endpoint has been demonstrated in the FOURIER study.

Mechanistic insights into the regression of atherosclerotic plaques.

Atherosclerosis is a major contributor to cardiovascular diseases and mortality globally. The progression of atherosclerotic disease results in the expansion of plaques and the development of necrotic cores. Subsequent plaque rupture can lead to thrombosis, occluding blood vessels, and end-organ ischemia with consequential ischemic injury. Atherosclerotic plaques are formed by the accumulation of lipid particles overloaded in the subendothelial layer of blood vessels. Abnormally elevated blood lipid levels and impaired endothelial function are the initial factors leading to atherosclerosis. The atherosclerosis research has never been interrupted, and the previous view was that the pathogenesis of atherosclerosis is an irreversible and chronic process. However, recent studies have found that the progression of atherosclerosis can be halted when patients' blood lipid levels are reversed to normal or lower. A large number of studies indicates that it can inhibit the progression of atherosclerosis lesions and promote the regression of atherosclerotic plaques and necrotic cores by lowering blood lipid levels, improving the repair ability of vascular endothelial cells, promoting the reverse cholesterol transport in plaque foam cells and enhancing the ability of macrophages to phagocytize and clear the necrotic core of plaque. This article reviews the progress of research on the mechanism of atherosclerotic plaque regression. Our goal is to provide guidance for developing better therapeutic approaches to atherosclerosis by reviewing and analyzing the latest scientific findings.

Abstract 4134277: Impairment of Vascular Endothelial Function by Inhalation of Smoke or Aerosol from Tobacco and Marijuana Products is Dependent on Vagus Nerve Input from the Airway

Background: Smoke or vaporizer aerosol from different tobacco or marijuana products can cause vascular endothelial dysfunction in humans and rodents. Mechanisms of acute smoke-induced endothelial dysfunction are complex and remain ambiguous. We reported that endothelial functional impairment by tobacco smoke is dependent on intact vagus nerves, leading us to hypothesize that endothelial function impaired by smoke/aerosol from tobacco or marijuana relies on vagal input from the airway. Methods: We used Sprague-Dawley rats at 10-12 weeks of age (n=8/group; 4M+4F). Rats were anesthetized by ketamine/xylazine and exposed to one session of exposure to smoke/aerosol of tobacco (Marlboro Red) or marijuana (~10% THC) cigarettes, e-cigarettes (JUUL), or IQOS (American HeatSticks). Exposure was pulsatile (10 cycles of 5s 2x/min for 5 min via nosecone). Endothelial function was assessed as flow-mediated dilation (FMD) in the femoral artery pre- (baseline) and post-exposure. Surgical bilateral cervical vagotomy was performed in the anesthetized rats post-baseline FMD (before exposure). Sham surgical procedures were carried out without severing vagus nerves. We used paired Student t tests to compare FMD values in each group pre- and post-exposure. Significance was P &lt;.05. Results: FMD was decreased from pre- to post-exposure in all exposed sham groups as expected, whereas the impairment of FMD by smoke/aerosol exposure was completely abrogated in all vagotomized groups (Figure), with no apparent effect of sex. The pre- vs. post-exposure FMD values (mean±SD) in exposed sham groups were 16.0±3.0% vs. 6.7±3.1% for tobacco cigarettes, 13.1±2.3% vs. 5.0±2.3% for JUUL, 14.3±3.0% vs. 6.0±2.2% for IQOS, and 16.2±4.9% vs. 7.1±3.6% for marijuana. For exposed vagotomized groups, pre- vs. post-exposure FMD values were 13.3±3.7% vs. 12.6±3.7% for tobacco cigarettes, 12.8±2.6% vs. 13.0±3.2% for JUUL, 13.9±2.2% vs. 13.3±2.7% for IQOS, and 14.4±4.2% vs. 15.1±5.0% for marijuana. Heart rate was increased and respiratory rate was decreased in vagotomized groups as expected. Conclusions: Inhaling smoke or aerosol causes vascular endothelial impairment via a common mechanism involving vagal stimulation from the airway.

Mid-late gestation leptin infusion induces placental mitochondrial and endoplasmic reticulum unfolded protein responses in a mouse model of preeclampsia

IntroductionPreeclamptic patients, both lean and obese, present with elevated leptin levels which are associated with the development of maternal endothelial dysfunction and adverse fetal outcomes, such as growth restriction, leading to low birth weight. Recent studies in pregnant mice demonstrate that mid-late gestation leptin infusion induces clinical characteristics of preeclampsia, including elevated maternal blood pressure, maternal endothelial dysfunction and fetal growth restriction. However, whether leptin triggers placental stress responses that contribute to adverse fetal outcomes as in preeclampsia is unknown. MethodsIn the current study we measured the expression of proteins involved in the endoplasmic reticulum (UPRer) and mitochondrial (UPRmt) unfolded protein responses in placentas of wild-type sham normal pregnant and leptin-infused preeclamptic mice. ResultsThe data show that mid-late gestation leptin infusion induced activation of indices of placental UPRer and UPRmt, while reducing placental repair mechanisms to UPRmt in preeclamptic mice. Mid-late gestation infusion with leptin upregulated markers of placental oxidative stress, reduced the placental expression levels of mitochondrial electron transport chain complexes I and II and increased the expression of placental endothelin-1 (ET-1) in preeclamptic mice. The leptin-induced activation of several placental UPRmt markers as well as ET-1 levels correlated with fetal growth restriction and impaired maternal endothelial function in preeclamptic mice. DiscussionCollectively, these data indicate that elevated levels of leptin in mid-late pregnancy in mice promote placental stress responses, akin to those in pregnant women with preeclampsia.

Polyphenol-rich Ocimum gratissimum leaf extract attenuates angiotensin-converting enzyme activity and impaired endothelial vascular function in diabetic rats

Endothelial vascular dysfunctions are prevalent among diabetic patients, significantly impacting their quality of life and prognosis. This study examined the effects of polyphenol-rich extracts from Ocimum gratissimum leaves on oxidative stress markers, serum lipid profiles, and angiotensin-converting enzyme activity in diabetic cardiac tissue. Forty Wistar rats (150–220 g) were divided into five groups: normal control, diabetic control, low-dose Ocimum gratissimum (122.46 mg/kg), medium-dose Ocimum gratissimum (244.98 mg/kg), and a positive control (standard diabetic drug). All rats except the normal control group were made diabetic via an intraperitoneal injection of 50 mg/kg streptozotocin, followed by 28 days of extract administration. Diabetes induction led to a significant (p&lt;0.05) disruptions in lipid profiles, oxidative stress markers, and ACE activity. Treatment with Ocimum gratissimum extracts at both doses significantly (p&lt;0.05) decreased triglyceride, low-density lipoprotein cholesterol, and very-low-density lipoprotein cholesterol levels while increasing high-density lipoprotein cholesterol. Lipid peroxidation marker, malondialdehyde, was significantly (p&lt;0.05) decreased, and antioxidant enzyme activities significantly (p&lt;0.005) improved. ACE activity was significantly (p&lt;0.05) reduced, approaching control levels. These results suggest that the polyphenol-rich extract of Ocimum gratissimum exerts antioxidant and cardio-protective effects, improving vascular functions in diabetic rats by improving lipid profiles, reducing oxidative stress, and suppressing ACE activity.

Early impairment of endothelial and myocardial function in patients with hidradenitis suppurativa

Abstract Background/Introduction Hidradenitis suppurativa (HS) is a chronic, recurrent, debilitating, inflammatory skin disease manifested by painful, deep-seated, inflamed lesions of the apocrine gland-bearing areas of the body (axillae, submammary folds, inguinal and anogenital region). HS has been associated, among others, with an increased cardiovascular risk. Purpose We aimed to investigate the endothelial, arterial and left ventricular (LV) myocardial function in patients with severe HS. Methods Twenty-eight, not previously treated patients (mean age: 36 ± 13 years) with Hurley stage III disease and a mean score of 19±8 on the International Hidradenitis Suppurativa Severity Score System (IHS4) scale, were studied. Twenty healthy sex-, age- and body mass index -matched individuals, who were also weighted for common cardiovascular risk factors, served as the control group. Both patients and controls were evaluated for: a) perfused boundary region (PBR) of the sublingual microvessels with a diameter of 5-25 μm (an increased PBR value is considered as an indicator of a decrease in thickness of the endothelial glycocalyx), using a dedicated camera (Microscan, GlycoCheck), b) carotid-femoral pulse wave velocity (PWV-Complior), c) flow-mediated dilation (FMD) of the brachial artery and d) LV global longitudinal strain (GLS) using the speckle-tracking echocardiography. Results Compared to healthy controls, HS patients had increased PBR value (2.32 ± 0.19 vs. 1.99 ± 0.14 μm, p &amp;lt; 0.001) and decreased FMD (5.7 ± 2.9 vs. 10.3 ± 1.9 %, p &amp;lt; 0.001) and GLS values (-18.6 ± 2.8 vs. -22.5 ± 2.3 %, p &amp;lt; 0.001). In contrast, similar PWV values (9.2 ± 2 vs. 9.1 ± 1.9 m/s, p = 0.937) were recorded between patients and controls (Table). Increased IHS4 score (more severe disease) was associated with increased PBR values (r = 0.42, p = 0.026) and decreased FMD values (r = -0.37, p = 0.045). Conclusion Patients with HS show early impairment of endothelial and LV myocardial function, which correlates with the severity of the underlying systemic inflammation.Table

Increased endothelial cell uptake of erythrocyte-derived extracellular vesicles carrying arginase-1 induces endothelial dysfunction in type 2 diabetes

Abstract Background Recently, we have demonstrated that red blood cells (RBCs) from individuals with type 2 diabetes (T2D-RBCs) induce endothelial dysfunction. However, the mechanism by which RBCs communicate with the vessel is unknown. Extracellular vesicles (EVs) are actively secreted by practically all cell types, including RBCs, and represent a novel mechanism of intercellular communication. However, the involvement of EVs from RBC in the development of endothelial dysfunction remains to be elucidated. Purpose This study was designed to test the hypothesis that EVs are key players in the communication and the transfer of signalling between RBCs and the vascular endothelium to induce endothelial dysfunction in T2D. Methods RBCs from T2D patients and age-matched healthy controls (H-RBCs) were incubated for 18h with Krebs-Henseleit buffer (20% haematocrit) for EV release. RBC-derived EVs in the conditioned medium were isolated using a membrane affinity column. The EVs were co-incubated with mouse aortae to evaluate endothelium-dependent relaxation and with endothelial cells for expression analysis. The uptake of the EVs by endothelial cells and their content of arginase-1 were determined. The functional involvement of arginase was investigated using pharmacological interventions and expression analyses. All animal experiments were performed according to the principles of laboratory animal care (NIH Publication no. 85-23 revised 1985) and human procedures according to the declaration of Helsinki with approval by the Swedish Ethical Review Authority. Results The uptake of EVs derived from T2D-RBCs by endothelial cells was 2-fold greater than that of EVs from H-RBCs (Fig. 1A-B). Inhibiting the uptake of EVs derived from T2D-RBCs by the addition of heparin during the co-incubation rescued the endothelial function (Fig. 1C). Arginase-1 was detected in RBC-derived EVs (Fig. 2A). Arginase-1 mRNA and protein levels were increased in endothelial cells following co-incubation with EVs derived from T2D-RBCs (Fig. 2B-D). Additionally, the increase in arginase-1 protein induced by EVs derived from T2D-RBCs in endothelial cells was observed also following mRNA silencing for arginase-1 (Fig. 2E-F). Finally, mouse aortae co-incubated with EVs derived from T2D-RBCs in the presence or absence of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid significantly attenuated the impairment in endothelial function induced by EVs derived from T2D-RBCs (Fig. 2G). Conclusion Increased uptake of RBC-derived EVs by the endothelial cells is an important feature of the endothelial dysfunction induced by these EVs in T2D. In addition, these EVs carry arginase-1 protein to induce endothelial dysfunction. The mechanism underlying the increased uptake of EVs in target cells is of importance to identify in future studies, as it could lead to new treatment strategies.

HIV and cardiovascular risk: should we use other targets for cholesterol control? Brazilian data compared to major studies

Abstract In daily clinical practice, cardiologists are confronted with patients with HIV/AIDS and this population needs special attention due to their higher cardiovascular risk. Studies show an increase in cardiovascular disease (CVD) among people with HIV/AIDS and one of the main causes of death in this group. HIV is associated with dyslipidaemia and endothelial damage, which have been proposed as a cause of the increased risk of events, and HIV replication is a determining factor in endothelial dysfunction. With antiretroviral therapy (ART) there has been a reduction in morbidity and mortality from HIV/AIDS, however, several studies have shown an increase risk factors for CVD in this population, both in individuals on ART and those not on it. Two high-impact studies related to cardiovascular risk in the HIV population are Start and Smart. Studies are important for understanding this occurrence and its relationship with the presence of the virus and the use of antiretroviral therapy in this population. In view of the higher cardiovascular risk of these patients and the question of whether they deserve a different cholesterol target from other populations. Methods A retrospective, observational study was carried out on a sample of HIV patients from the Brazilian STD/AIDS Reference Centre (CRT), selected by lottery using their registration number, from 1 January 2011 to February 2023, aged over 18. 148 medical records were assessed and the following were collected population characteristics. Discussion: the CRT data were compared with the Start and Smart studies. The Reprieve study showed benefits earlier than expected with patients receiving a statin. An interim analysis revealed a 35 per cent reduction in serious adverse cardiovascular events in the statin group, leading to the placebo group stopping earlier. The viral load varied between the studies, with CRT having an average of 500,000 copies/ml, Start 12,759 copies/ml and Smart less than 400 copies/ml. Studies have associated HIV infection and higher viral loads with impaired endothelial function and vasodilation. Despite the data in the literature, all the patients with heart disease had undetected viral loads and CD4+ cell counts above 500 cells/mm³. Those with a high viral load in the study were not the ones with CVD. Conclusions In CRT, the percentage of primary events attributable to serious conditions unrelated to AIDS was 1.3 per cent. Analysing biomarkers could elucidate the effects of antiretroviral therapy on arterial disease. Another fact that probably justifies the low occurrence of cardiovascular and cerebral events in CRT is the multidisciplinary care given to patients, providing intensive primary and secondary prevention through counselling and follow-up. We suggest better control of cardiovascular risk factors with multi-professional intervention and more aggressive targets for the control of comorbidities.Characteristics and Cardiovascular risk

Association of type-D personality and left-ventricular remodelling in patients treated with primary percutaneous intervention after ST-segment elevation myocardial infarction

BackgroundType-D personality is an established predisposing factor for various diseases. Type-D traits have been shown to pose a 26% increased risk of coronary artery disease after controlling for other confounding factors. Significant associations have been reported between type-D personality traits and dyslipidaemia, impaired endothelial function, coronary heart disease (CAD), acute myocardial infarction, and other adverse cardiovascular events.ObjectiveTo assess the association between type-D personality and left-ventricular adverse remodelling in patients treated with percutaneous coronary intervention following index ST-segment elevation myocardial infarction.MethodsAll patients hospitalized and treated with percutaneous coronary intervention (PCI) after their index ST-segment elevation myocardial infarction (STEMI) between 1 January 2022 to 31 December 2023 were prospectively enrolled. Type-D personality traits in the study population were determined at baseline using type-D Scale-14 (DS14) instrument, whereas any positive change in left ventricular end diastolic volume (LVEDV) ≥ 20% at follow up period of 12-months from baseline was defined as left-ventricular adverse remodelling (LVAR). Univariate and multivariate analysis was done to establish the independent predictors of LVAR. The area under receiver-operating characteristic curve (AUROC) was employed to assess the sensitivity and specificity of the identified independent predictors.ResultsA total of 124 patients were enrolled in the study. The mean age of the study population was 67 ± 10 years and the overall incidence of LVAR was found to be 25%. Multivariate regression analysis revealed that type-D personality is a significant independent predictor of LVAR \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:(OR:2.51;95\\%CI:1.16-5.77;p=0.03)$$\\end{document} apart from the already established independent predictors Killip Class\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:\\:(OR:7.30;95\\%CI:3.03-17.55;p<0.0001)$$\\end{document}, baseline Global Longitudinal strain (GLS)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:\\:(OR:2.69;95\\%CI:1.19-6.61;p=0.01)$$\\end{document}, and 3-vessel CAD\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\:\\:(OR:2.27;95CI:1.10-5.33;p=0.04)$$\\end{document}. In ROC curve analysis type-D personality as an independent predictor of LVAR achieved a sensitivity of 41.4% and a specificity of 87.1%, p < 0.02.ConclusionType-D personality trait is a significant independent predictor of LVAR in patients treated with PCI after their index-STEMI.

Effect of antiretroviral treatment on myocardial work and arterial function of treatment-naive patients with HIV

Abstract Background/Aim HIV infection is related with cardiovascular adverse events. We investigated the effects of antiretroviral treatment in myocardial and vascular function of newly diagnosed patients with HIV. Patients and methods A total of 70 newly diagnosed HIV patients (41.2±8.7 years old, 87 % male) were enrolled. Patients were randomized to the newer integrase inhibitor Dolutegravir or to the older protease inhibitor Darunavir/Cobicistat. We measured at baseline and 12 months posttreatment: (a) Left Ventricular (LV) Global Longitudinal Strain (GLS), (b) LV Global Work Index (GWI), Global Constructive Work (GCW), Global Wasted Work (GWW), Global Work Efficiency (GWE), (c) Coronary Flow Reserve (CFR) of Left Anterior Descending Artery. At baseline, we compared the HIV patients with 35 healthy matched controls. Results At baseline patients with HIV had impaired myocardial function, endothelial function and endothelial glycocalyx compared with healthy controls. Twelve months after intervention HIV patients improved myocardial function, as assessed by GLS, GWI, GCW, GWW and GWE (p&amp;lt;0.05). Moreover, twelve months after intervention HIV patients improved endothelial function, as evaluated by an increase in CFR and a decrease in PBR5-25 (p&amp;lt;0.05). Response to therapy was similar between the two groups of treatment. Nevertheless, in HIV patients 12 months post treatment myocardial, endothelial function and endothelial glycocaylyx was impaired in comparison with healthy controls. Conclusions Treatment with antiretroviral therapy partially improves myocardial and arterial function 12 months post treatment.

Inhibition of ketohexokinase prevents fructose-induced insulin resistance and endothelial dysfunction in high fat and sucrose-fed mice via enhancing energy expenditure

Abstract Introduction Cardiovascular disease linked to fatty liver poses a significant threat to health. Consumption of high-fat diets (HFD) is known to trigger a cascade of health issues including obesity, diabetes and non-alcoholic fatty liver disease (NAFLD). These conditions are exacerbated, with the addition of dietary sugar to high-fat diets (HFSD), resulting in non-alcoholic steatohepatitis (NASH). Studies have shown that fructokinase (ketohexokinase or KHK) knockdown protects mice from HFSD-induced NASH. Purpose This study focused on examining the temporal changes of metabolic perturbations, triggered by sugar consumption, particularly in the transition from fatty liver to cardiovascular disease. Methods C57/BL6 wild type (WT) and KHK-knockout mice were fed with HFD or HFSD for different durations between 6 to 20 weeks, to induce NAFLD and NASH. Western blotting and quantitative-PCR were carried out on tissues and isolated endothelial cells for protein and mRNA expressions, respectively. Glucose and insulin tolerance tests and whole-body energy measurements were performed at different time-points. Combined Laboratory Animal Monitoring System was used to monitor various parameters of energy expenditure. Functional interactions between endothelial cells and adipose tissues were carried out using an in-house Organ-On-a-chip technology. Endothelial function was studied by measuring isometric tensions in organ bath. Results KHK-deficient mice had significantly lower weight compared to WT littermates. Wild-type mice fed HFD and HFSD exhibited significant glucose intolerance, insulin resistance, and endothelial dysfunction compared to KHK-knockout mice. However, HFSD led to more severe outcomes compared to HFD, demonstrating differing temporal effects on glucose intolerance and insulin resistance. Interestingly, KHK-knockout mice were significantly protected from the effects induced by HFSD, as well as, such as increased body weight, fasting hyperglycemia, hyperinsulinemia and endothelial function. KHK-knockout mice exhibited significant increase in oxygen consumption and energy expenditure, both in HFD and HFSD-fed conditions. These data suggest that high energy-expenditure is one of the primary mechanisms, in reducing adiposity and body weight in HFSD-fed knockout mice. Notably, KHK-deficient mice were protected against sugar-induced fat accumulation, random hyperinsulinemia and significant impairment of endothelial function. Conclusions A novel finding in this study is that KHK ablation protects not only against HFSD-induced, but also HFD-induced pathologies via significantly enhancing energy expenditure. The results suggest that targeting KHK could potentially mitigate the development of fatty liver and cardiovascular diseases, induced by high calorie diets.

STING-mediated DNA damage response in diabetes-induced vascular complications

Abstract Background Hyperglycemia drives endothelial dysfunction, a key factor in the development of diabetes vascular complications. The stimulator of interferon genes (STING) signal, plays a crucial role in the immune system and is implicated in the pathogenesis of inflammatory diseases. Therefore we investigated the role of STING in endothelial dysfunction in streptozotocin (STZ)-induced diabetic mice. Methods and Results Diabetes was induced by single-dose administration of STZ in 8-week-old C57BL/6 and Sting-/- mice. STZ injection promoted the expression of STING and DNA damage markers in the aorta of C57BL/6 mice. Genetic deletion of STING ameliorated endothelial dysfunction as determined by vascular reactivity assay (P &amp;lt; 0.001) and increased aortic eNOS phosphorylation (P &amp;lt; 0.05) in STZ-injected mice. Stimulation of STING agonist (cGAMP), or mtDNA increased inflammatory molecules expression (e.g., VCAM1 and IFNB) and decreased eNOS phosphorylation in HUVECs. In ex-vivo experiments, cGAMP significantly impaired endothelial function which was ameliorated in the presence of an STING inhibitor or a neutralizing IFN-β antibody. Furthermore, the administration of STING inhibitor ameliorated endothelial dysfunction in STZ-induced diabetic mice (P &amp;lt; 0.01). Conclusion The DNA damage response regulated by STING aggravated diabetes-induced endothelial dysfunction. STING signaling may be a potential therapeutic target for diabetic vascular complications.

Leukotrienes E4 and B4 and vascular endothelium – New insight into the link between vascular inflammation and peripheral arterial

Leukotrienes are proinflammatory mediators that participate in the process of atherogenesis and contribute to the development of symptomatic peripheral arterial disease. The aim was to evaluate the relationship between leukotriene E4 (LTE4) and B4 (LTB4) with parameters reflecting endothelial vascular function in patients with chronic lower limb ischemia. This prospective observational study enrolled 50 consecutive patients undergoing endovascular treatment due to chronic lower limb ischemia (Rutherford 3). All participants were followed-up for one year (after 1, 3, 6 and 12 months), with a sequential assessment of urinary LTE4 and LTB4, as well as measures of endothelial and vascular function: Flow-Mediated Dilatation (FMD), Intima-Media Thickness (IMT), corrected Augmentation Index (AI75), Shear Rate (SR), Ankle-Brachial Index (ABI), Toe-Brachial Index (TBI). There was a significant relationship between LTE4 and measures of vascular function: FMD (R2 = 0.69, P < 0.001), IMT (R2 = 0.12, P < 0.01), AI75 (R2 = 0.43, P < 0.001), SR (R2 = 0.48, P < 0.001). Similar findings were noted for LTB4: FMD (R2 = 0.47, p < 0.001), IMT (R2 = 0.23, P < 0.001), AI75 (R2 = 0.61, P < 0.001) and SR (R2 = 0.33, P < 0.001). Alterations in parameters were significantly related: ΔLTE4 vs ΔFMD(R2 = 0.63, P < 0.001), ΔSR (R2 = 0.42, P < 0.001) and ΔLTB4 vs AI75(R2 = 0.40, P < 0.001), SR(R2 = 0. 29, P < 0.001). We conclude, that increasing concentrations of LTE4 and LTB4 are associated with impairment of vascular and endothelial function, which may lead to worse endovascular treatment clinical outcomes.

Effects of inhaled nitric oxide on endothelial function in patients with ischemic stroke

BACKGROUND: A crucial pathogenetic link in the development of stroke is the deterioration of endothelial function, which is a pathological condition characterized by an imbalance between endothelium-dependent relaxing and constricting factors. An example of an endothelium-dependent relaxing factor is nitric oxide, a substance synthesized by the body’s cells that has a vasodilating, antithrombogenic, anti-inflammatory, and antiproliferative effect. Studies have shown the neuroprotective function of inhaled nitric oxide after ischemia; however, determining the minimum effective dose of inhaled nitric oxide in patients who have suffered an acute cerebrovascular accident remains challenging. AIM: To analyze the protective effect of exogenous nitric oxide using the TIANOX device on the vascular endothelium in patients who have had an ischemic stroke in the early and late recovery period during medical rehabilitation. MATERIALS AND METHODS: The study involved 21 patients (10 people in the main group, 56.9±8.9 years old, 11 people in the control group, 57.2±8.8 years old) in the early or late recovery period after an ischemic stroke. Patients in the main group underwent an individual medical rehabilitation program and a course of 8–10 inhalations of a gas mixture with nitric oxide at 20 ppm for 20 minutes. Those in the control group underwent an individual rehabilitation course without nitric oxide therapy. Flow-dependent vasodilation of the brachial artery was evaluated to assess endothelial function. RESULTS: In the main group, a statistically insignificant (p 0.05) increase was found in the diameter of the brachial artery (3.68±0.64 mm), whereas in the control group, this indicator at rest during repeated diagnostics was less than the initial one (3.09±0.87 mm). During repeated diagnostics, the average endothelial shear velocity in patients of the control group increased from 141.53±52.62 to 159.3±82 versus from 143.17±43.53 to 143.48±46.37 in the main group; however, the results were not statistically significant (p=0.753). CONCLUSION: The increase in the diameter of the brachial artery during flow-dependent vasodilation in patients in the main group may indicate a prosthetic effect of the exogenous form of nitric oxide when using the Tianox device on the vascular endothelium, owing to the possibility of depositing nitric oxide in the body. To confirm the obtained data, a larger sample size of patients is critical in order to further divide the groups of patients into early and late recovery periods after ischemic stroke.

Dietary Protein in a Challenge Meal Does Not Alleviate Postprandial Impairments in Vascular Endothelial Function in Healthy Older Adults with Cardiometabolic Risk: A Randomized Crossover-Controlled Trial

BackgroundPostprandial vascular endothelial dysfunction is an early marker of atherosclerosis. Meal protein has been reported to reduce endothelial dysfunction in adults, and the effect could be mediated by the amino acid content. ObjectivesThis trial aims to assess the effect of a specifically designed plant-protein blend that contains high leucine, arginine, and cysteine on postprandial endothelial function in the elderly. MethodsIn a randomized, double-blind, 3-period crossover (2-wk washout), controlled trial, we compared the vascular effects of 3 high-saturated-fat high-sucrose (HFHS) meals based on either our specific plant-protein blend, milk protein, or without added protein. The trial was conducted on 29 healthy adults aged >65 y presenting ≥2 cardiometabolic risk factors. Postprandial vascular function was evaluated at fasting, 3 h, and 5 h postprandially, using brachial flow-mediated dilation (FMD), hand microvascular reactivity (using Flowmetry Laser Doppler, FLD), and finger reactive hyperemia index (using Peripheral Arterial Tonometry, RHI). Immune cell count and gene expression in peripheral blood mononuclear cells (PBMCs) were also assessed postprandially. Data were analyzed using mixed linear models with repeated measurements on participants for meal composition and time of sampling. This trial was registered at clinicaltrials.gov as NCT04923555. ResultsFMD incremental AUC value decreased after meals (time effect P < 0.01), with no significant differences between meals. RHI also decreased with time (P < 0.01). PBMC count and monocyte chemoattractant protein-1, IL-1b, and IL-6 expression increased after meals showing postprandial endothelial activation (P < 0.05). Overall, meal composition had no effect on any of the postprandial changes (Ps>0.10). ConclusionsIn healthy adults aged >65 y presenting cardiometabolic risk, adding protein to an HFHS challenge meal does not mitigate postprandial impairments in vascular endothelial function and inflammatory activation. Further studies are needed to explore the potential differences with younger adults.

Impairment of microvascular endothelial Kir2.1 channels contributes to endothelial dysfunction in human hypertension.

Hypertension is associated with decreased endothelial function through reduced contributions of nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K+ (Kir2.1) channels. The goal of this study was to establish whether these channels contribute to the impairment of endothelial function, measured by flow-induced vasodilation (FIV) in peripheral resistance arteries of humans with hypertension. We measured FIV in vessels isolated from subcutaneous fat biopsies from 32 subjects: normotensive [n = 19; 30.6 ± 9.8 yr old; systolic blood pressure (SBP): 115.2 ± 7 mmHg; diastolic blood pressure (DBP): 75.3 ± 5.7 mmHg] and hypertensive (n = 13; 45.3 ± 15.3 yr old; SBP: 146.1 ± 15.2 mmHg; DBP: 94.4 ± 6.9 mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive adults as demonstrated by a significant reduction in FIV when compared with the normotensive adults. Furthermore, our data suggest that the impairment of FIV in hypertensive adults is partially attributed to a reduction in Kir2.1-dependent vasodilation. Specifically, we show that blocking Kir2.1 with ML133 or functionally downregulating Kir2.1 with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (dnKir2.1) result in a significant reduction in FIV in normotensive subjects but with a smaller effect in hypertensive adults. The Kir2.1-dependent vasodilation was negatively correlated to both SBP and DBP, indicating that the Kir2.1 contribution to FIV decreases as blood pressure increases. In addition, we show that exposing vessels from normotensive adults to acute high-pressure results in loss of Kir2.1 contribution, as high pressure impairs vasodilation. No effect is seen when these vessels were incubated with dnKir2.1. Overexpressing wtKir2.1 in the endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive adults. Our data suggest that hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.NEW & NOTEWORTHY Impairment of endothelial function under high blood pressure is linked to the loss of inwardly rectifying K+ (Kir2.1) channels activity in human resistance arteries, leading to a reduction in flow-induced vasodilation and possibly leading to a vicious cycle between elevation of blood pressure, and further impairment of Kir2.1 function and flow-induced vasodilation.

Individuals With Post-Acute Sequelae Of COVID-19 Have Impaired Endothelial Function, But Combined Exercise Training Restores Endothelial Function

Individuals With Post-Acute Sequelae Of COVID-19 Have Impaired Endothelial Function, But Combined Exercise Training Restores Endothelial Function

Impaired Endothelial And Microvascular Functions In Obese Patients: Analysis Of Blood Flow In The Femoral Artery During Passive Leg Movements

Impaired Endothelial And Microvascular Functions In Obese Patients: Analysis Of Blood Flow In The Femoral Artery During Passive Leg Movements