Sickle cell anemia is a genetic disorder that affects hemoglobin leading to the production of an abnormal hemoglobin, called HbS. HbS has the property to polymerize under deoxygenated conditions, causing a mechanical distortion of red blood cells; a phenomenon called sickling. These sickle red blood cells are more fragile and rigid, leading to chronic hemolytic anemia and painful vaso-occlusive crises, as well as chronic vascular complications that can affect many organs. The abnormal functional properties of these sickle red blood cells are responsible for a wide range of clinical expression of the disease. HbS polymerization can be influenced by many factors, such as the hydration state of the red blood cells or the affinity of hemoglobin for oxygen. Moreover, the rheological characteristics of red blood cells, including their deformability and aggregation properties, are associated with specific clinical phenotypes. The pro-inflammatory and pro-oxidant state, as well as the repeated polymerization of HbS, accelerate the senescence of sickle red blood cells, promoting the release of microparticles and contributing to vascular dysfunction. Patients\' red blood cells also have molecular characteristics that promote their adhesion to the endothelium and other circulating cells, contributing to the onset of vascular complications. Massive intravascular hemolysis, due to increased erythrocyte fragility, is also responsible for chronic vascular complications. These different alterations are privileged therapeutic targets, leading to the emergence of new specific treatments. © 2023 Société nationale française de médecine interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.

The onset of menopause and accompanying changes to ovarian hormones often precedes endothelial dysfunction in women. In particular, accelerated impairments in macrovascular and microvascular function coincide with the loss of estrogen, as does impaired endothelial responses to ischemia-reperfusion (IR) injury. In healthy, early postmenopausal women (n = 12; 3.9 ± 1.5 years since menopause) we tested the hypothesis that acute dietary nitrate (NO3-) supplementation would improve endothelial function and attenuate the magnitude of endothelial dysfunction following whole-arm IR in comparison with placebo. In this randomized, double-blind, placebo-controlled, crossover study we tested participants before and after NO3--rich (BRnitrate) and NO3--depleted (BRplacebo) beetroot juice (BR) consumption, as well as following IR injury, and 15 min after IR to assess recovery. Analyses with repeated-measures general linear models revealed a condition × time interaction for brachial artery flow-mediated dilation (FMD; P = 0.04), and no interaction effect was found for the near-infrared spectroscopy-derived reperfusion slope (P = 0.86). Follow-up analysis showed a significant decline in FMD following IR injury with BRplacebo in comparison with all other timepoints (all, P < 0.05), while this decline was not present with BRnitrate (all, P > 0.05). Our findings demonstrate that a single dose of dietary NO3- minimizes IR-induced macrovascular endothelial dysfunction in healthy, early postmenopausal women, but does not improve resting macrovascular and microvascular function. Trial registration number: NCT03644472. Novelty: In healthy, early postmenopausal women, a single dose of NO3--rich BR can protect against IR-induced endothelial dysfunction. This protection may be due to nitric oxide bioactivity during IR rather than improved endothelial function prior to the IR protocol per se.

This study explored the cardiometabolic responses to sugar moieties acutely, and following a subsequent mixed meal tolerance test (MMTT). Twenty-one healthy adolescents (N = 10 female, 14.3 ± 0.4 years) completed 3 experimental and 1 control condition, in a counterbalanced order. These consisted of different drinks to compare the effect of 300 mL of water (control), or 300 mL of water mixed with 60 g of glucose, fructose or sucrose, on vascular function (flow-mediated dilation (FMD), microvascular reactivity (total hyperaemic response; TRH), and cerebrovascular reactivity (CVR)), and blood samples for uric acid, glucose, triglycerides and lactate concentrations. FMD increased 1 h after glucose and sucrose (P < 0.001, ES ≥ 0.92) but was unchanged following fructose and water (P ≥ 0.19, ES ≥ 0.09). CVR and TRH were unchanged 1 h following all conditions (P > 0.57, effect size (ES) > 0.02). Following the MMTT, FMD was impaired in all conditions (P < 0.001, ES > 0.40) with no differences between conditions (P > 0.13, ES < 0.39). Microvascular TRH was increased in all conditions (P = 0.001, ES = 0.88), and CVR was preserved in all conditions after MMTT (P = 0.87, ES = 0.02). Blood uric acid concentration was elevated following fructose consumption and the MMTT (P < 0.01, ES > 0.40). Consumption of a sugar sweetened beverage did not result in vascular dysfunction in healthy adolescents; however, the vascular and metabolic responses were dependent on sugar moiety. Novelty: Glucose consumption acutely increases peripheral vascular function in healthy adolescents. Acute sugar sweetened beverage consumption (sucrose) does not result in adverse vascular outcomes. Elevations in uric acid are observed with fructose consumption, which may have implications over repeated exposure.

Healthy males (n = 10; age: 24 ± 4 years; body mass index: 24 ± 2 kg·m-2) completed 2 randomized conditions separated by ≥48 h involving 6-8.5 h of sitting with (\"stair snacks\") and without (sedentary) hourly staircase sprint interval exercise (∼14-20 s each). Resting blood flow and shear rates were measured in the femoral artery, internal carotid artery, and vertebral artery (Duplex ultrasound). Flow-mediated dilation (FMD) was quantified as an index of peripheral endothelial function in the femoral artery. Neurovascular coupling (NVC; regional blood flow response to local increases in cerebral metabolism) was assessed in the posterior cerebral artery (transcranial Doppler ultrasound). Femoral artery hemodynamics were higher following the active trial with no change in the sedentary trial, including blood flow (+32 ± 23% vs. -10 ± 28%; P = 0.015 and P = 0.253, respectively), vascular conductance (+32 ± 27% vs. -15 ± 26%; P = 0.012 and P = 0.098, respectively), and mean shear rate (+17 ± 8% vs. -8 ± 28%; P = 0.004 and P = 0.310, respectively). The change in FMD was not different within or between conditions (P = 0.184). Global cerebral blood flow (CBF), conductance, shear patterns, and NVC were not different within or between conditions (all P > 0.05). Overall, exercise \"stair snacks\" improve femoral artery blood flow and shear patterns but not peripheral (e.g., FMD) or cerebral (e.g., CBF and NVC) vascular function following prolonged sitting. The study was registered at ClinicalTrials.gov (NCT03374436). Novelty: Breaking up 8.5 h of sitting with hourly staircase sprinting exercise \"snacks\" improves resting femoral artery shear patterns but not FMD. Cerebral blood flow and neurovascular coupling were unaltered following 6 h of sitting with and without hourly exercise breaks.

Human immunodeficiency virus (HIV) is associated with lower nitric oxide (NO) bioavailability and vascular dysfunction. Nitrate-rich beetroot juice (BJ) has been shown to acutely increase NO availability and vascular function in healthy and individuals at high risk for cardiovascular disease. Thus, we tested the effects of BJ ingestion on flow-mediated dilation (FMD) and pulse wave velocity (PWV) measurements in healthy and HIV-infected patients. Thirteen HIV-infected individuals (age, 36 ± 10 years) and 18 healthy (age, 27 ± 8 years) participated in the study. Individuals were submitted to vascular tests such as FMD and pulse PWV at pre (T0) and at 120 min (T120) after BJ and placebo (PLA) ingestion. The %FMD at T0 of the control group was significantly higher than the %FMD at T0 of the HIV individuals in both interventions. BJ improved the %FMD at T120 when compared with T0 in the HIV and control groups. There was no change in %FMD after PLA ingestion in the control and HIV groups. There were no differences between groups (control vs HIV), time points (T0 vs T120), and interventions (BJ vs PLA) for PWV. Our findings showed that nitrate-rich BJ ingestion acutely improved vascular function in healthy and HIV-infected patients. Clinical Trials Registry no. NCT03485248. Novelty: HIV is associated with lower NO bioavailability and vascular dysfunction. Acute supplementation with nitrate-rich BJ has been shown to acutely increases NO bioavailability. We showed for the first time that BJ acutely improves endothelial function in HIV-infected patients.

Metabolism and Function of High-Density Lipoproteins (HDL) Abstract. HDL has long been considered as \'good cholesterol\', beneficial to the whole body and in particular to cardio-vascular health. However, HDL is a complex particle that undergoes dynamic remodeling through interactions with various enzymes and tissue types throughout its life cycle. In this review, we explore the novel understanding of HDL as a multifaceted class of lipoprotein, with multiple subclasses of different size, molecular composition, receptor interactions, and functionality, in health and disease. Further, we report on emergent HDL based therapeutics tested in small and larger scale clinical trials and their mixed successes.
Zusammenfassung. HDL wurde lange Zeit als das «gute Cholesterin» angesehen, das für die Gesundheit des Gesamtorganismus und speziell des kardiovaskulären Systems essenziell ist. HDL ist jedoch komplex aufgebaut und durchläuft dynamische Umbauprozesse, an dem zahlreiche Komponenten, Enzyme und verschiedene Gewebe beteiligt sind. In dieser Übersichtsarbeit stellen wir HDL als eine Lipoproteinklasse vor, die zahlreiche Facetten hat, und deren verschiedene Unterklassen eine unterschiedliche Molekülgrösse und Zusammensetzung aufweisen, die unterschiedliche Rezeptor-Interaktionen und Funktionen ausüben. Ausserdem berichten wir von neuen auf HDL basierenden Therapie-Ansätzen, die bereits in klinischen Studien untersucht wurden, die allerdings nur zum Teil erfolgreich verliefen.

This study examined if the degree of aerobic training protects against the lower limb vascular dysfunction associated with a prolonged sitting bout. Ten young, aerobically trained (AT) and 10 young, untrained (UT) individuals completed a prolonged (3 h) sitting bout. Leg vascular function was measured prior to and at 1.5 and 3 h into the prolonged sitting bout using the passive leg movement (PLM) technique. PLM-induced hyperemia was significantly reduced from baseline at 1.5 and 3 h into the prolonged sitting bout in both groups when evaluated as peak change in leg blood flow from baseline (Δ LBF) (UT: 956 ± 140, 586 ± 80, and 599 ± 96 mL·min-1 at baseline, 1.5 h, and 3 h, respectively; AT: 955 ± 183, 789 ± 193, and 712 ± 131 mL·min-1 at baseline, 1.5 h, and 3 h, respectively) and LBF area under the curve (UT: 283 ± 73, 134 ± 31, and 164 ± 42 mL·min-1 at baseline, 1.5 h, and 3 h, respectively; AT: 336 ± 86, 242 ± 86, and 245 ± 73 mL·min-1 at baseline, 1.5 h, and 3 h, respectively), but no significant differences between groups were revealed. No significant correlations were observed when examining the relationship between maximal oxygen uptake (relative and absolute) and reductions in leg vascular function at 1.5 and 3 h into the prolonged sitting bout. This study revealed that aerobic training did not provide a protective effect against prolonged sitting-induced lower limb vascular dysfunction and further highlights the importance of reducing excessive sitting in all populations.

The beneficial effect of omega-3 polyunsaturated fatty acids (PUFA) supplementation on the cardiovascular (CV) system is well supported in CV patients; however, the effect of the consumption of omega-3 PUFA-enriched functional food in healthy individuals is still not fully elucidated. This study aimed to determine the effect of the consumption of omega-3 PUFA-enriched hen eggs on the microvascular reactivity (primary outcome), blood pressure (BP), and serum lipid profile in young healthy individuals. The control group (N = 16) ate 3 ordinary hen eggs (277 mg of omega-3 PUFAs/day), and the OMEGA-3 group (N = 20) ate 3 omega-3 PUFA-enriched eggs containing 259 mg of omega-3 PUFAs/egg daily (α-linolenic acid (ALA), 167 mg/egg; eicosapentaenoic acid (EPA), 7 mg/egg; docosahexaenoic acid (DHA), 84 mg/egg) for 3 weeks (777 mg of omega-3 PUFA/day). Postocclusive reactive hyperemia (PORH) in skin microcirculation assessed by laser Doppler flowmetry, serum lipid profile, fasting blood glucose, high-sensitivity C-reactive protein (hsCRP), and arterial BP were measured in all subjects before and after the protocol. PORH was significantly enhanced, and triglycerides, hsCRP, and BP were significantly decreased in the OMEGA-3 group compared with baseline measurements, whereas there was no significant difference in the control group after the protocol when compared with baseline. To the best of our knowledge, this is the first study to demonstrate that consumption of a mixture of omega-3 PUFA (ALA + EPA + DHA), provided via enriched hen eggs, elicits changes in the microvascular reactivity, BP, and triglyceride level in healthy subjects that are associated with CV benefits, thus suggesting that daily consumption of omega-3 PUFA-enriched eggs in healthy individuals may potentially contribute to CV risk factor attenuation and disease prevention.

Transient elevations in blood glucose level may lead to changes in vascular function. Herein, we investigated the effects of high-glucose or high-fructose challenge, as well as potential influence of juglone or resveratrol on vascular reactivity, Akt/eNOS, and insulin signaling effectors in rat aorta. Aortic segments of rats were incubated with high glucose (30 mmol/L) or high fructose (2 mmol/L) in the absence and presence of juglone (5 μmol/L) or resveratrol (10 μmol/L). Acute high-glucose incubation markedly decreased acetylcholine-induced relaxation, which is further inhibited by juglone, but ameliorated by resveratrol. Incubation with high glucose caused significant reduction in pAkt/total Akt and peNOS/total eNOS ratios, as well as in the expression of some genes involved in insulin signaling. Juglone produced a further impairment, whereas resveratrol resulted in an improvement on the expression profiles of these proteins and genes. Acute exposure of aortic segments to high glucose causes a reduction in acetylcholine-induced relaxation in association with suppression of Akt/eNOS pathway, as well as several genes in insulin signaling pathway. Juglone and resveratrol have opposite actions on vascular relaxation and the above signaling targets. These findings could be relevant for the treatment of hyperglycemia-induced vascular complications.

Despite the popularity of dietary nitrate supplementation and the growing evidence base of its potential ergogenic and vascular health benefits, there is no direct information about its effects on exercising limb blood flow in humans. We hypothesized that acute dietary nitrate supplementation from beetroot juice would augment the increases in forearm blood flow, as well as the progressive dilation of the brachial artery, during graded handgrip exercise in healthy young men. In a randomized, double-blind, placebo-controlled crossover study, 12 young (22 ± 2 years) healthy men consumed a beetroot juice (140 mL Beet-It Sport, James White Juice Company) that provided 12.9 mmol (0.8 g) of nitrate or placebo (nitrate-depleted Beet-It Sport) on 2 study visits. At 3 h postconsumption, brachial artery diameter, flow, and blood velocity were measured (Doppler ultrasound) at rest and during 6 exercise intensities. Nitrate supplementation raised plasma nitrate (19.5-fold) and nitrite (1.6-fold) concentrations, and lowered resting arterial pulse wave velocity (PWV) versus placebo (all p < 0.05), indicating absorption, conversion, and a biological effect of this supplement. The supplement-associated lowering of PWV was also negatively correlated with plasma nitrite (r = -0.72, p = 0.0127). Despite these systemic effects, nitrate supplementation had no effect on brachial artery diameter, flow, or shear rates at rest (all p ≥ 0.28) or during any exercise workload (all p ≥ 0.18). These findings suggest that acute dietary nitrate supplementation favorably modifies arterial PWV, but does not augment blood flow or brachial artery vasodilation during nonfatiguing forearm exercise in healthy young men.