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1.
Acute Exenatide Therapy Attenuates Postprandial Vasodilation in Humans with Prediabetes: A Randomized Controlled Trial.
Hamidi, V, Riggs, K, Zhu, L, Bermudez Saint Andre, K, Westby, C, Coverdale, S, Dursteler, A, Wang, H, Miller Iii, C, Taegtmeyer, H, et al
Metabolic syndrome and related disorders. 2020;(5):225-233
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Abstract
Background: The state of prediabetes comprises atherosclerotic changes leading to decreased vascular function in humans. This study examined the effects on incretin mimetics on vascular physiology in the prediabetic postprandial state. Methods: Fifteen obese adults with prediabetes participated in a randomized, crossover, double-blinded trial comparing the postprandial effects of exenatide, saxagliptin, and placebo on peripheral vasodilation. All studies utilized a standardized high-fat meal. Resting and peak forearm blood flow (FBF) were measured via strain gauge venous occlusion plethysmography, and makers of vascular dysfunction were measured in plasma. Results: Exenatide attenuated resting FBF at 3 hr (P = 0.003) and 6 hr (P = 0.056) postmeal, compared to placebo. Nonsignificant reductions in resting FBF were observed between saxagliptin and placebo at the same time points. No group differences were observed for peak FBF, plasma nitrotyrosine, and plasma 8-iso-prostaglandin F2alpha. A transient increase in plasma triglyceride was abated in the exenatide group, when compared to saxagliptin and placebo groups. Only exenatide group showed no significant upsurge in plasma insulin. Plasma-free fatty acids significantly declined in all three groups, although less markedly for exenatide. Postmeal glucose increased at 2 hr with placebo and saxagliptin, but simultaneously decreased with exenatide. Conclusions: Acute treatment with exenatide blunted the postprandial vasodilatory effect of a high-fat meal in prediabetes. Exenatide's acute effects derived primarily from multiple endothelium-independent processes. Trial Registration Number: NCT02104739.
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The Effects of Resveratrol Supplementation on Endothelial Function and Blood Pressures Among Patients with Metabolic Syndrome and Related Disorders: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Akbari, M, Tamtaji, OR, Lankarani, KB, Tabrizi, R, Dadgostar, E, Kolahdooz, F, Jamilian, M, Mirzaei, H, Asemi, Z
High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension. 2019;(4):305-319
Abstract
INTRODUCTION There are current trials investigating the effect of resveratrol supplementation on endothelial function and blood pressures among patients with metabolic syndrome (MetS); however, the findings are controversial. AIM: This systematic review and meta-analysis of randomized controlled trials (RCTs) were carried out to summarize the effects of resveratrol supplementation on endothelial activation and blood pressures among patients with MetS and related disorders. METHODS We searched systematically online databases including: PubMed-Medline, Embase, ISI Web of Science and Cochrane Central Register of Controlled Trials until October, 2018. Two independent authors extracted data and assessed the quality of included articles. Data were pooled using the fixed- or random-effects model and considered as standardized mean difference (SMD) with 95% confidence intervals (95% CI). RESULTS Out of 831 electronic citations, 28 RCTs (with 33 findings reported) were included in the meta-analyses. The findings showed that resveratrol intervention significantly increased flow-mediated dilatation (FMD) levels (SMD 1.77; 95% CI 0.25, 3.29; P = 0.02; I2: 96.5). However, resveratrol supplements did not affect systolic blood pressure (SBP) (SMD - 0.27; 95% CI - 0.57, 0.03; P = 0.07; I2: 88.9) and diastolic blood pressure (DBP) (SMD - 0.21; 95% CI - 0.52, 0.11; P = 0.19; I2: 89.8). CONCLUSIONS Resveratrol supplementation significantly increased FMD among patients with MetS and related disorders, but did not affect SBP and DBP. Additional prospective studies are needed to investigate the effect of resveratrol supplementation on endothelial function and blood pressures, using higher-dose of resveratrol with longer durations.
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Brachial Artery Flow-mediated Dilatation and Carotid Intima-Media Thickness in Children With Idiopathic Nephrotic Syndrome.
Youssef, DM, Gomaa, MA, El-Akhras, A, Tolba, SAR, Abd Allah, GM, Daoud, O, Saber, S
Iranian journal of kidney diseases. 2018;(6):331-340
Abstract
INTRODUCTION Disturbances of lipid metabolism has been reported in nephrotic syndrome (NS) and may predispose to atherosclerosis. This study aimed to investigate the correlation between cardiovascular risk factors and carotid intima-media thickness (CIMT) and brachial artery flow-mediated dilatation in patients with idiopathic NS. MATERIALS AND METHODS This case-control study included 31 patients with NS and 31 healthy individuals as the control group. All patients were subjected to full clinical examination; laboratory investigations in the form of lipid profile, kidney function tests, serum protein, serum albumin, C-reactive protein, and ferritin; carotid ultrasonography, and brachial artery flow-mediated dilatation. RESULTS Serum cholesterol, low-density lipoprotein cholesterol, and triglyceride levels was significantly higher in the case group than the control group. High-density lipoprotein cholesterol and albumin levels were significantly lower in the case group. The absolute change in brachial artery diameter was significantly lower in the case group than that of the control group. Proportionate change in brachial artery diameter was significantly lower in the case group than that of the control group. Common carotid artery CIMT in the case group was significantly higher than that of the controls. Lastly, there were significant increases in weight and body mass index in the relapse group than the remission group. CONCLUSIONS Patients with NS are more prone to atherosclerosis and vascular changes; CIMT was thicker in nephrotic children compared to the controls. The significantly abnormal values of flow-mediated dilatation in children with NS suggests an ongoing process of endothelial dysfunction.
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Regional myocardial function abnormalities are associated with macro- and microcirculation dysfunction in the metabolic syndrome: the RESOLVE study.
Obert, P, Walther, G, Dutheil, F, Lesourd, B, Chapier, R, Courteix, D, Vinet, A
Heart and vessels. 2018;(6):688-694
Abstract
Abnormalities in myocardial and vascular function have been reported in the metabolic syndrome (MetS), but whether these alterations are related remains poorly documented. Our aim was accordingly to investigate interrelationships between macro- and microcirculatory vasoreactivity and left ventricular (LV) myocardial function in MetS patients. Eighty-eight MetS individuals and 44 age- and gender-matched healthy controls were enrolled. LV global longitudinal strain (GLS) was measured using Vector Velocity Imaging. Endothelial-dependent and independent reactivity in macro- and microcirculatory territories was established using flow-mediated dilation and nitrate-mediated dilation of the brachial artery and cutaneous blood flow measured with laser Doppler flowmetry in response to iontophoresis of acetylcholine and sodium nitroprusside, respectively. Carotid intima-media thickness (cIMT) was measured according to the Mannheim consensus. Compared to controls, MetS patients presented with reduced GLS (p < 0.001) increased cIMT and impaired (p < 0.001) endothelial and smooth muscle function of the brachial artery and the forearm skin microcirculation. Highly significant relationships (p < 0.01) were noticed between GLS and vascular outcomes. In addition, cIMT (β = 0.21, p = 0.024) and microcirculatory endothelium-dependent reactivity (β = - 0.20, p = 0.035) were identified as independent predictors of GLS. In MetS, abnormalities in myocardial function and endothelial as well as smooth muscle function of small and large arteries co-exist and are closely associated. This study supports a role for microvascular dysfunction in the pathogenesis of LV myocardial dysfunction.
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Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators.
Fiorucci, S, Zampella, A, Cirino, G, Bucci, M, Distrutti, E
American journal of physiology. Heart and circulatory physiology. 2017;(1):H21-H32
Abstract
Bile acids are end products of cholesterol metabolism generated in the liver and released in the intestine. Primary and secondary bile acids are the result of the symbiotic relation between the host and intestinal microbiota. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals that exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid-activated receptors, GPBAR1 (also known as TGR5) and the farnesosid-X-receptor (FXR), have also been detected in the vascular system and their activation mediates the vasodilatory effects of bile acids in the systemic and splanchnic circulation. GPBAR1, is a G protein-coupled receptor, that is preferentially activated by lithocholic acid (LCA) a secondary bile acid. GPBAR1 is expressed in endothelial cells and liver sinusoidal cells (LSECs) and responds to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-γ-lyase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSECs is due to genomic and nongenomic effects, involves protein phosphorylation, and leads to release of H2S. Despite that species-specific effects have been described, vasodilation caused by GPBAR1 ligands in the liver microcirculation and aortic rings is abrogated by inhibition of CSE but not by eNOS inhibitor. Vasodilation caused by GPBAR1 (and FXR) ligands also involves large conductance calcium-activated potassium channels likely acting downstream to H2S. The identification of GPBAR1 as a vasodilatory receptor is of relevance in the treatment of complex disorders including metabolic syndrome-associated diseases, liver steatohepatitis, and portal hypertension.
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Exercise-mediated vasodilation in human obesity and metabolic syndrome: effect of acute ascorbic acid infusion.
Limberg, JK, Kellawan, JM, Harrell, JW, Johansson, RE, Eldridge, MW, Proctor, LT, Sebranek, JJ, Schrage, WG
American journal of physiology. Heart and circulatory physiology. 2014;(6):H840-7
Abstract
We tested the hypothesis that infusion of ascorbic acid (AA), a potent antioxidant, would alter vasodilator responses to exercise in human obesity and metabolic syndrome (MetSyn). Forearm blood flow (FBF, Doppler ultrasound) was measured in lean, obese, and MetSyn adults (n = 39, 32 ± 2 yr). A brachial artery catheter was inserted for blood pressure monitoring and local infusion of AA. FBF was measured during dynamic handgrip exercise (15% maximal effort) with and without AA infusion. To account for group differences in blood pressure and forearm size, and to assess vasodilation, forearm vascular conductance (FVC = FBF/mean arterial blood pressure/lean forearm mass) was calculated. We examined the time to achieve steady-state FVC (mean response time, MRT) and the rise in FVC from rest to steady-state exercise (Δ, exercise - rest) before and during acute AA infusion. The MRT (P = 0.26) and steady-state vasodilator responses to exercise (ΔFVC, P = 0.31) were not different between groups. Intra-arterial infusion of AA resulted in a significant increase in plasma total antioxidant capacity (174 ± 37%). AA infusion did not alter MRT or steady-state FVC in any group (P = 0.90 and P = 0.85, respectively). Interestingly, higher levels of C-reactive protein predicted longer MRT (r = 0.52, P < 0.01) and a greater reduction in MRT with AA infusion (r = -0.43, P = 0.02). We concluded that AA infusion during moderate-intensity, rhythmic forearm exercise does not alter the time course or magnitude of exercise-mediated vasodilation in groups of young lean, obese, or MetSyn adults. However, systemic inflammation may limit the MRT to exercise, which can be improved with AA.
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Amylin in vasodilation, energy expenditure and inflammation.
Yang, F
Frontiers in bioscience (Landmark edition). 2014;(6):936-44
Abstract
Metabolic syndrome significantly increases the incidence of atherosclerosis-related diseases including coronary artery disease, stroke, and type 2 diabetes. Recent progress has demonstrated that amylin, or islet amyloid polypeptide, is circulating multifunctional hormone and neuropeptide, which is co-secreted with insulin into the bloodstream by pancreatic beta cells and plays a very important role in regulating feeding, energy homeostasis and inflammation. Recent FDA approval of amylin analog pramlintide as a new drug for treating type 1 and 2 diabetes positions amylin in the spotlight. In this analytical review, I summarize the recent progress on amylin studies in the following sections: 1) introduction to the molecular features of amylin; 2) amylin's amyloidogenic and proinflammatory effects; 3) a satiety hormone and new drug in increasing energy expenditure; and 4) a vasodilator inducing hypotension and tachycardia; and 5) a neuropeptide in depolarizing cholinergic neurons via closure of potassium channels. Continued improvement of our understanding on this multifunctional hormone would lead to future development of pramlintide as novel therapies for other inflammatory, hematological, metabolic, neurological and vascular diseases.
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Effects of GLP-1 on forearm vasodilator function and glucose disposal during hyperinsulinemia in the metabolic syndrome.
Tesauro, M, Schinzari, F, Adamo, A, Rovella, V, Martini, F, Mores, N, Barini, A, Pitocco, D, Ghirlanda, G, Lauro, D, et al
Diabetes care. 2013;(3):683-9
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Abstract
OBJECTIVE Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS. RESEARCH DESIGN AND METHODS Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5). RESULTS In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P < 0.001 for both), but not during saline (P > 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both). CONCLUSIONS In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.
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Different galenic formulations of fluvastatin have equal lipid-lowering potential but differ in reducing lipemia-induced endothelial dysfunction.
Westphal, S, Abletshauser, C, Luley, C
Coronary artery disease. 2009;(1):81-5
Abstract
BACKGROUND Postprandial lipemia is known to exert a reversible detrimental effect on endothelium-dependent flow-mediated vasodilation (FMD). Fasting FMD has shown to be improved by fluvastatin. In this study, we investigated whether lipemia-induced endothelial dysfunction can be mitigated by fluvastatin in two (immediate-release and extended-release) formulations. METHODS In 27 patients with the metabolic syndrome, randomized in a three-period crossover design for 5 weeks each to 80 mg extended-release fluvastatin daily, 40 mg immediate-release fluvastatin twice daily (b.i.d.) or placebo, the fasting and postprandial lipids and FMD of the brachial artery were measured at baseline and after 5 weeks of each treatment period. Postprandial lipemia was induced by administration of whipping cream containing 33% fat (1 g fat/kg body weight). FMD was determined by two-dimensional ultrasonography of the brachial artery in the fasting state and 4 h after the fatty meal. Lipids were determined using routine methods. RESULTS Fasting triglycerides were reduced after immediate-release and extended-release fluvastatin by 16 and 23%, respectively, and postprandial triglycerides by 20 and 29%, respectively. The fasting FMD was also improved by each treatment. The postprandial FMD impairment, however, was mitigated only after 40 mg b.i.d. After 80 mg fluvastatin, the last dose of which had been administered the previous evening, the lipemic FMD impairment was the same as after the placebo. CONCLUSION Fluvastatin improves fasting FMD regardless of whether it is administered as 40 mg b.i.d. or 80 mg daily given in the evening. The lipemic FMD impairment, in contrast, is improved only by 40 mg b.i.d. when the tablet is taken in the morning of the test day. As the half-life of fluvastatin is about 2 h, we surmise that an improvement occurs only when sufficient amounts of fluvastatin are present in the bloodstream.
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Effects of dietary carbohydrate restriction versus low-fat diet on flow-mediated dilation.
Volek, JS, Ballard, KD, Silvestre, R, Judelson, DA, Quann, EE, Forsythe, CE, Fernandez, ML, Kraemer, WJ
Metabolism: clinical and experimental. 2009;(12):1769-77
Abstract
We previously reported that a carbohydrate-restricted diet (CRD) ameliorated many of the traditional markers associated with metabolic syndrome and cardiovascular risk compared with a low-fat diet (LFD). There remains concern how CRD affects vascular function because acute meals high in fat have been shown to impair endothelial function. Here, we extend our work and address these concerns by measuring fasting and postprandial vascular function in 40 overweight men and women with moderate hypertriacylglycerolemia who were randomly assigned to consume hypocaloric diets (approximately 1500 kcal) restricted in carbohydrate (percentage of carbohydrate-fat-protein = 12:59:28) or LFD (56:24:20). Flow-mediated dilation of the brachial artery was assessed before and after ingestion of a high-fat meal (908 kcal, 84% fat) at baseline and after 12 weeks. Compared with the LFD, the CRD resulted in a greater decrease in postprandial triacylglycerol (-47% vs -15%, P = .007), insulin (-51% vs -6%, P = .009), and lymphocyte (-12% vs -1%, P = .050) responses. Postprandial fatty acids were significantly increased by the CRD compared with the LFD (P = .033). Serum interleukin-6 increased significantly over the postprandial period; and the response was augmented in the CRD (46%) compared with the LFD (-13%) group (P = .038). After 12 weeks, peak flow-mediated dilation at 3 hours increased from 5.1% to 6.5% in the CRD group and decreased from 7.9% to 5.2% in the LFD group (P = .004). These findings show that a 12-week low-carbohydrate diet improves postprandial vascular function more than a LFD in individuals with atherogenic dyslipidemia.