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Levcromakalim, an Adenosine Triphosphate-Sensitive Potassium Channel Opener, Dilates Extracerebral but not Cerebral Arteries.
Al-Karagholi, MA, Ghanizada, H, Hansen, JM, Skovgaard, LT, Olesen, J, Larsson, HBW, Amin, FM, Ashina, M
Headache. 2019;(9):1468-1480
Abstract
BACKGROUND ATP-sensitive potassium (KATP ) channel opener levcromakalim induces migraine attacks in migraine patients. Underlying mechanisms responsible for headache and migraine induction after levcromakalim infusion are unknown. OBJECTIVE To investigate the effect of levcromakalim on the cranial arteries and to explore the possible relationship between the middle meningeal artery (MMA) dilation and headache. METHODS In a double-blind, randomized, placebo-controlled study, 20 healthy volunteers were scanned at the baseline and repeatedly after infusion of levcromakalim (n = 14) and placebo (n = 6). All participants received a subcutaneous injection of sumatriptan 6 mg before the last scanning. RESULTS The MMA circumference was significantly larger after levcromakalim compared with placebo (P < .0001). The MMA dilation lasted over 5 hours during observational period. We found a significant association between headache and MMA dilation (P < .0001). The superficial temporal artery (STA) circumference was significantly larger after levcromakalim compared with placebo (P = .03) over the initial period (110 minutes). Over the entire observational period, there was no difference in circumference of the STA and the middle cerebral artery (MCA) between levcromakalim and placebo. CONCLUSION Levcromakalim dilated the MMA but not MCA. The MMA dilation was associated with headache. Future studies should investigate whether opening of KATP channels can activate and sensitize the perivascular nociceptors.
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Apocynin and Tempol ameliorate dietary sodium-induced declines in cutaneous microvascular function in salt-resistant humans.
Ramick, MG, Brian, MS, Matthews, EL, Patik, JC, Seals, DR, Lennon, SL, Farquhar, WB, Edwards, DG
American journal of physiology. Heart and circulatory physiology. 2019;(1):H97-H103
Abstract
It has previously been shown that high dietary salt impairs vascular function independent of changes in blood pressure. Rodent studies suggest that NADPH-derived reactive oxygen species mediate the deleterious effect of high salt on the vasculature, and here we translate these findings to humans. Twenty-nine healthy adults (34 ± 2 yr) participated in a controlled feeding study. Participants completed 7 days of a low-sodium diet (LS; 20 mmol sodium/day) and 7 days of a high-sodium diet (HS; 300 mmol sodium/day) in random order. All participants were salt resistant, defined as a ≤5-mmHg change in 24-h mean BP determined while on the LS and HS diets. Laser Doppler flowmetry was used to assess cutaneous vasodilation in response to local heating (42°C) during local delivery of Ringer's (n = 29), 20 mM ascorbic acid (AA; n = 29), 10 µM Tempol (n = 22), and 100 µM apocynin (n = 22). Additionally, endothelial cells were obtained in a subset of participants from an antecubital vein and stained for nitrotyrosine (n = 14). Cutaneous vasodilation was attenuated by the HS diet compared with LS [LS 93.0 ± 2.2 vs. HS 86.8 ± 2.0 percentage of maximal cutaneous vascular conductance (%CVCmax); P < 0.05] and was restored by AA during the HS diet (AA 90.7 ± 1.2 %CVCmax; P < 0.05 vs. HS). Cutaneous vasodilation was also restored with the local infusion of both apocynin (P < 0.01) and Tempol (P < 0.05) on the HS diet. Nitrotyrosine expression was increased on the HS diet compared with LS (P < 0.05). These findings provide direct evidence of dietary sodium-induced endothelial cell oxidative stress and suggest that NADPH-derived reactive oxygen species contribute to sodium-induced declines in microvascular function. NEW & NOTEWORTHY High-sodium diets have deleterious effects on vascular function, likely mediating, in part, the increased cardiovascular risk associated with a high sodium intake. Local infusion of apocynin and Tempol improved microvascular function in salt-resistant adults on a high-salt diet, providing evidence that reactive oxygen species contribute to impairments in microvascular function from high salt. This study provides insight into the blood pressure-independent mechanisms by which dietary sodium impairs vascular function. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/dietary-sodium-oxidative-stress-and-microvascular-function/ .
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Effects of dietary sports supplements on metabolite accumulation, vasodilation and cellular swelling in relation to muscle hypertrophy: A focus on "secondary" physiological determinants.
Cholewa, J, Trexler, E, Lima-Soares, F, de Araújo Pessôa, K, Sousa-Silva, R, Santos, AM, Zhi, X, Nicastro, H, Cabido, CET, de Freitas, MC, et al
Nutrition (Burbank, Los Angeles County, Calif.). 2019;:241-251
Abstract
Increased blood flow via vasodilation, metabolite production, and venous pooling contribute to the hyperemia and cellular swelling experienced during resistance training. It has been suggested that these effects play a role in hypertrophic adaptations. Over the past 2 decades, sport supplement products have been marketed to promote exercise hyperemia and intracellular fluid storage, thereby enhancing hypertrophy via acute swelling of myocytes. The three main classes of supplements hypothesized to promote exercise-induced hyperemia include vasodilators, such as nitric oxide precursor supplements; anaerobic energy system ergogenic aids that increase metabolite production, such as β-alanine and creatine; and organic osmolytes, such as creatine and betaine. Previous studies indicated that these dietary supplements are able to improve muscle performance and thus enhance muscle hypertrophy; however, recent evidences also point to these three classes of supplements affecting "secondary" physiological determinants of muscle mass accretion such as vasodilation, metabolite accumulation, and muscle cellular swelling. Although we recognize that the literature is relatively scarce regarding these topics, a better comprehension and discussion of these determinants can lead to increased knowledge and might guide further research regarding the proposed mechanisms of action of the identified compounds. In this case, increased knowledge may contribute to the development of improved efficacy, new products, or direct new research to specifically investigate those secondary effects. The aim of this review was to bring into focus new perspectives associated with secondary physiological effects induced by supplementation and to determine their relevance.
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Effects of aronia berry (poly)phenols on vascular function and gut microbiota: a double-blind randomized controlled trial in adult men.
Istas, G, Wood, E, Le Sayec, M, Rawlings, C, Yoon, J, Dandavate, V, Cera, D, Rampelli, S, Costabile, A, Fromentin, E, et al
The American journal of clinical nutrition. 2019;(2):316-329
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Abstract
BACKGROUND Aronia melanocarpa is a rich source of (poly)phenols. Previous research has demonstrated that these berries may provide cardiovascular health benefits in high-risk populations. However, very few studies have investigated the effects of daily consumption of dietary achievable amounts of the berries in healthy subjects. OBJECTIVES The aim of this study was to investigate the effects of aronia berries on vascular function and gut microbiota composition in a healthy population. METHODS A double-blind, placebo-controlled, parallel designed study was conducted in 66 healthy men randomly allocated to consume a (poly)phenol-rich extract (116 mg, 75 g berries), a whole fruit powder (12 mg, 10 g berries), or placebo (maltodextrin) for 12 wk. Flow-mediated dilation (FMD), arterial stiffness, blood pressure, heart rate, and serum biochemistry were assessed. Plasma (poly)phenol metabolites were analyzed by LC-MS. Gut microbiota composition was determined via 16S rRNA sequencing in stool samples. RESULTS Consumption of aronia whole fruit and extract powder for 12 wk led to a significant increase in FMD over control of 0.9% ± 0.4% (95% CI: 0.13%, 1.72%) and 1.2% ± 0.4% (95% CI: 0.36%, 1.97%), respectively. Acute improvements in FMD were also observed 2 h after consumption of aronia extract on day 1 (1.1% ± 0.3%, P = 0.003) and 12 wk later (1.5% ± 0.4%, P = 0.0001). Circulating plasma phenolic metabolites increased upon consumption of the aronia treatments. Although no changes were found in gut microbiota diversity, consumption of aronia extract increased the growth of Anaerostipes (+10.6%, P = 0.01), whereas aronia whole fruit showed significant increases in Bacteroides (+193%, P = 0.01). Correlation analysis identified significant associations between changes in FMD, aronia-derived phenolic metabolites, and specific gut microbial genera. CONCLUSIONS In healthy men, consumption of aronia berry (poly)phenols improved endothelial function and modulated gut microbiota composition, indicating that regular aronia consumption has the potential to maintain cardiovascular health in individuals at low risk of cardiovascular disease. This trial was registered at CLINICALTRIALs.gov as NCT03041961.
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High-nitrate salad increased plasma nitrates/nitrites and brachial artery flow-mediated dilation in postmenopausal women: A pilot study.
Mayra, ST, Johnston, CS, Sweazea, KL
Nutrition research (New York, N.Y.). 2019;:99-104
Abstract
Cardiovascular disease risk is elevated in postmenopausal women relative to men of the same age or to younger, premenopausal women. This elevated risk is closely linked to the loss of estrogen, which is a potent stimulator of the vasodilator nitric oxide. While studies have largely supported dietary nitrate supplementation (typically concentrated beetroot juice) to augment plasma nitric oxide, these studies focused mainly on improving vascular fitness of athletes or patient populations. The purpose of this controlled crossover trial was to assess the feasibility of consuming a high-nitrate, leafy green salad twice daily for 10 consecutive days versus a low-nitrate, canned vegetable control (beans, corn, or peas) on plasma nitrate/nitrite concentration and measures of cardiovascular health in postmenopausal women. We hypothesized that plasma nitrate/nitrite concentration and flow-mediated dilation would improve following the leafy green salad treatment. Ten women (52.6 ± 4.9 y; 26.4 ± 6.4 kg/m2) completed the two 10-day treatment periods separated by 2-3 weeks washout. The mean fasting plasma nitrate/nitrite concentration was significantly increased following the high-nitrate salad treatment compared to the control (+156% and+ 16% respectively; P = .002, effect size = 0.661). Flow-mediated dilation responded favorably to the high nitrate salad in comparison to the canned vegetable condition (+17% versus -8% respectively; P = .047, effect size = 0.407); however, there were no treatment effects on peripheral or derived central-aortic blood pressure. These data suggest that daily ingestion of nitrate-rich, leafy green salads may prove a useful strategy for improving cardiovascular health in postmenopausal women.
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Effect of vitamin D supplementation on endothelial function - An updated systematic review with meta-analysis and meta-regression.
Pincombe, NL, Pearson, MJ, Smart, NA, King, N, Dieberg, G
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2019;(12):1261-1272
Abstract
BACKGROUND AND AIMS Atherogenesis and endothelial dysfunction contribute to cardiovascular risk and vitamin D has been implemented in endothelial repair. This systematic review, meta-analysis and meta-regression aims to establish the effect of vitamin D supplementation on endothelial function. METHODS AND RESULTS To conduct the systematic review we searched the Cochrane Library of Controlled Trials, PubMed, ProQuest and EMBASE for randomized controlled trials that investigated the effects of vitamin D supplementation on flow-mediated dilation (FMD%), pulse wave velocity (PWV), and central augmentation index (AIx). Meta-analysis was based on a random effects model and inverse-variance methods to calculate either mean difference (MD) or standardized mean difference (SMD) as effects sizes. This was followed by meta-regression investigating the effect of baseline vitamin D concentrations, vitamin D dosing and study duration. Risk of bias was assessed using the JADAD scale and funnel plots. We identified 1056 studies of which 26 studies met inclusion criteria for quantitative analysis. Forty-two percent of the 2808 participants had either deficient or insufficient levels of vitamin D. FMD% (MD 1.17% (95% CI -0.20, 2.54), p = 0.095), PWV (SMD -0.09 m/s (95% CI -0.24, 0.07), p = 0.275) and AIx (SMD 0.05% (95% CI -0.1, 0.19), p = 0.52) showed no improvement with vitamin D supplementation. Sub-analysis and meta-regression revealed a tendency for AIx and FMD% to increase as weekly vitamin doses increased; no other significant relationships were identified. CONCLUSIONS Vitamin D supplementation showed no improvement in endothelial function. More evidence is required before recommendations for management of endothelial dysfunction can be made.
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Low-Fat Diet Designed for Weight Loss But Not Weight Maintenance Improves Nitric Oxide-Dependent Arteriolar Vasodilation in Obese Adults.
Mahmoud, AM, Hwang, CL, Szczurek, MR, Bian, JT, Ranieri, C, Gutterman, DD, Phillips, SA
Nutrients. 2019;(6)
Abstract
Obesity is associated with microvascular dysfunction. While low-fat diet improves cardiovascular risk, its contributions on microvascular function, independent of weight loss, is unknown. We tested the hypothesis that nitric oxide (NO)-dependent vasodilation in microvessels is improved by low-fat diets designed for weight loss (LFWL) compared to low-fat weight maintenance (LFWM) diet. Obese adults were randomly assigned to either a LFWL diet (n = 11) or LFWM diet (n = 10) for six weeks. Microvessels were obtained from gluteal subcutaneous fat biopsies before and after the intervention for vascular reactivity measurements to acetylcholine (Ach) and flow, with and without L-NAME or indomethacin. Vascular and serum NO and C-reactive protein (CRP) were also measured. LFWL diet increased flow-induced (FID) and ACh-induced dilation (AChID); an effect that was inhibited by L-NAME. Conversely, LFWM diet did not affect FID or AChID. Indomethacin improved FID and AChID in the baseline and this effect was minimized in response to both diets. Serum NO or CRP did not change in response to either diet. In conclusion, LFWL diet improves microvascular reactivity compared to LFWM diet and increased vascular NO contribution to the improved microvascular dilation. These data suggest that weight reduction on low fat diet is critical for microvascular health.
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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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SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses.
Filippatos, TD, Liontos, A, Papakitsou, I, Elisaf, MS
Postgraduate medicine. 2019;(2):82-88
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors inhibit glucose re-absorption in the proximal renal tubules. Two trials have shown significant reductions of cardiovascular (CV) events with empagliflozin and canagliflozin, which could not be attributed solely to their antidiabetic effects. The aim of the review is the critical presentation of suggested mechanisms/hypotheses for the SGLT2 inhibitors' cardioprotection. The search of the literature revealed many possible cardioprotective mechanisms, because SGLT2 inhibitors (i) increase natriuresis and act as diuretics with unique properties leading to a reduction in preload and myocardial stretch (the diuretic hypothesis); (ii) decrease blood pressure and afterload (the blood pressure lowering hypothesis), (iii) favor the production of ketones, which can act as a 'superfuel' in the cardiac and renal tissue (the 'thrifty substrate' hypothesis), (iv) improve many metabolic variables (the metabolic effects hypothesis), (v) exert many anti-inflammatory effects (the anti-inflammatory effects hypothesis), (vi) can act through the angiotensin II type II receptors in the context of simultaneous renin-angiotensin-aldosterone-system (RAAS) blockade leading to vasodilation and positive inotropic effects (the RAAS hypothesis), (vii) directly decrease the activity of the upregulated in heart failure Na+-H+ exchanger in myocardial cells leading to restoration of mitochondrial calcium handling in cardiomyocytes (the sodium hypothesis). Additionally, some SGLT2 inhibitors exhibit also SGLT1 inhibitory action possibly resulting in an attenuation of oxidative stress in ischemic myocardium (the SGLT1 inhibition hypothesis). Thus, many mechanisms have been suggested (and possibly act cumulatively) for the cardioprotective effects of SGLT2 inhibitors.
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Evaluation of systemic microvascular reactivity in adults with congenital heart disease.
Marino, P, de Oliveira Lopes, G, Pereira Borges, J, Carolina Terra Cola, M, Arkader Kopiler, D, Tibirica, E
Congenital heart disease. 2018;(6):978-987
Abstract
OBJECTIVE Adults with congenital heart disease share some features with those with chronic heart failure. Although microvascular endothelial dysfunction has been described in chronic heart failure, evaluation of the microcirculation in adults with congenital heart disease is lacking. The present study aimed to investigate systemic microvascular reactivity in adults with congenital heart disease. INTERVENTIONS The patients initially underwent cardiopulmonary exercise testing. Then, the cutaneous microvascular reactivity was evaluated in these patients using a laser speckle contrast imaging system coupled with skin iontophoresis of endothelial-dependent (acetylcholine) or -independent (sodium nitroprusside) vasodilators and postocclusive reactive hyperemia (PORH) and compared with healthy controls matched for age and sex. RESULTS Thirty-one patients and 29 healthy controls were evaluated. The basal microvascular flow (P < .0001) and area under the curve in response to acetylcholine (P < .0001) were higher in the patients than in the healthy volunteers. The increase in cutaneous vascular conductance in response to sodium nitroprusside was reduced in the patients compared to the healthy volunteers (P = .0031). No difference in the microvascular response was observed during postocclusive reactive hyperemia. The basal microvascular flow of patients with peak oxygen consumption below 16.0 mL kg-1 min-1 was superior to that of patients with values greater than 16.0 mL kg-1 min-1 (P = .0046). CONCLUSIONS Adults with congenital heart disease present a higher baseline cutaneous microvascular blood flow than healthy controls and do not present systemic microvascular endothelial dysfunction. Nevertheless, endothelium-independent microvascular reactivity is blunted, suggesting an altered vascular smooth muscle response or vascular structural alterations. Finally, patients with a lower functional capacity presented a greater microvascular basal blood flow than subjects with a higher functional capacity.