Montmorency cherry supplementation attenuates vascular dysfunction induced by prolonged forearm occlusion in overweight, middle-aged men

Flavonoid supplementation improves brachial artery flow-mediated dilation (FMD), but it is not known whether flavonoids protect against vascular dysfunction induced by ischemia-reperfusion (IR) injury and associated respiratory burst. In a randomized, double-blind, placebo-controlled, crossover study, we investigated whether 4 wk supplementation with freeze-dried Montmorency cherry (MC) attenuated suppression of FMD after IR induced by prolonged forearm occlusion. Twelve physically inactive overweight, middle-aged men (52.8 ± 5.8 yr, BMI: 28.1 ± 5.3 kg/m2) consumed MC (235 mg/day anthocyanins) or placebo capsules for 4 wk, with supplementation blocks separated by 4 wk washout. Before and after each supplementation block, FMD responses and plasma nitrate and nitrite ([[Formula: see text]]) concentrations were measured at baseline and 15, 30, and 45 min after prolonged (20 min) forearm occlusion. FMD response was significantly depressed by the prolonged occlusion ( P < 0.001). After a 45-min reperfusion, FMD was restored to baseline levels after MC (ΔFMD presupplementation: −30.5 ± 8.4%, postsupplementation: −0.6 ± 9.5%) but not placebo supplementation (ΔFMD presupplementation: −11.6 ± 10.6, postsupplementation: −25.4 ± 4.0%; condition × supplement interaction: P = 0.038). Plasma [[Formula: see text]] decreased after prolonged occlusion but recovered faster after MC compared with placebo (Δ45 min to baseline; MC: presupplementation: −15.3 ± 9.6, postsupplementation: −6.2 ± 8.1; Placebo: presupplementation: −16.3 ± 5.9, postsupplementation: −27.7 ± 11.1 nmol/l; condition × supplement × time interaction: P = 0.033). Plasma peroxiredoxin concentration ([Prx2]) was significantly higher after MC (presupplementation: 22.8 ± 1.4, postsupplementation: 28.0 ± 2.4 ng/ml, P = 0.029) but not after placebo supplementation (presupplementation: 22.1 ± 2.2, postsupplementation: 23.7 ± 1.5 ng/ml). In conclusion, 4 wk MC supplementation enhanced recovery of endothelium-dependent vasodilatation after IR, in parallel with faster recovery of plasma [[Formula: see text]], suggesting NO dependency. These protective effects seem to be related to increased plasma [Prx2], presumably conferring protection against the respiratory burst during reperfusion. NEW & NOTEWORTHY This is the first study to demonstrate that 4 wk of Montmorency cherry powder supplementation exerted protective effects on endothelium-dependent vasodilation after transient ischemia-reperfusion injury in overweight, physically inactive, nonmedicated, hypertensive middle-aged men. These effects seem to be due to increased nitric oxide availability, as evidenced by higher plasma nitrite concentration and peak arterial diameter during the flow-mediated dilation measurement. This may be a consequence of increased concentration of peroxiredoxin and other antioxidant systems and, hence, reduced reactive oxygen species exposure.

Possible Modulation of Vascular Function Measures in Rheumatoid Arthritis by Homocysteine

The effect of homocysteine on cardiovascular diseases is still equivocal, especially in rheumatoid arthritis patients. In this investigation, the association between homocysteine with blood flow and vascular resistance in rheumatoid arthritis was examined. Serum levels of homocysteine were determined in thirty-one rheumatoid arthritis patients and nineteen apparently healthy subjects using ELISA. Additionally, strain-gauge plethysmography was used to determine both forearm blood flow and vascular function at rest and after occlusion. Forearm occlusion blood flow (patients: 21.9 ± 6.55 versus control: 25.5 ± 6.10ml/100mL/min) was lower (p < 0.05) while occlusion vascular resistance (patients: 4.77 ± 2.08 versus controls 3.05 ± 0.96U) was greater (p < 0.01) in rheumatoid arthritis than in the controls. Level of serum homocysteine was similar (p = 0.803) in rheumatoid arthritis group and healthy group. In addition, level of serum homocysteine was correlated with resting blood flow (r = −0.41; p < 0.02) and resting vascular resistance (r = 0.31, p < 0.05) in the patients group. The study confirms altered vascular function in rheumatoid arthritis. Uniquely, the results show that homocysteine was related to resting, but not postischemia, vascular measures. These relationships indicate that homocysteine might impact the vasculature in rheumatoid arthritis.

Chronic Transfusion Therapy in Sickle Cell Disease - Effect on Macrovascular Function, Microvascular Function, and Tissue Oxygenation Decreases the Potential for Ischemia

BACKGROUND: Sickle cell disease is an inheritable hemoglobinopathy that causes increased red blood cell (RBC) stiffness due to hemoglobin polymerization at low oxygen tension. This leads to microcirculatory occlusion as well as chronic hemolysis and chronic inflammation, resulting in a diffuse vasculopathy of bothmacrovascular and microvascular beds. Chronic transfusion therapy is used for both primary and secondary prevention of ischemic stroke, amacrovascular complication; however, there is limited knowledge of its effect on microvascular function. OBJECTIVE: To determine the effects of chronic transfusion therapy on microvascular function and tissue oxygenation. DESIGN/METHODS: We utilized a forearm, arterial and venous occlusion model, commonly used for flow-mediated dilation of the brachial artery, to simultaneously assess post occlusive reactive hyperemia (PORH) in the microcirculation and post hyperemic change in tissue oxygenation. PORH was measured using laser Doppler flowmetry placed over the third finger, proximal to the nailbed. Regional tissue oxygenation (rSO2) was measured using near infrared spectroscopy (NIRS) placed on the dorsal surface of the hand. FMD was measured using a linear ultrasound probe. Transfused patients were measured before and after a single transfusion. Kruskal-Wallis was used to test between group differences. Multivariate linear regression was used to model predictors of vascular function. RESULTS: We enrolled 18 control (CTL) patients, 75 non-transfused (NTR) SCD patients, and 26 chronically transfused (TR) SCD patients. Consistent with our previously published data, FMD was improved but not normalized by chronic transfusion and it was predicted by ln[plasma hgb], age and sex. PORH was reduced in both SCD patient groups when compared to the control group while resting flow by laser Doppler was elevated in both SCD groups (figure 1). PORH was also inversely related to resting flow, suggesting that basal conditions in the microcirculation are significant predictors of their response to forearm occlusion. Percent change in rSO2 was not different between the three groups. Lower baseline rSO2 was inversely associated with percent rSO2 increase following hyperemia; and, the baseline rSO2 was significantly decreased in the non-transfused SCD patients but normalized in the transfused SCD patients (Figure 2). Resting hypoxia was best predicted by RBC deformability in the non-transfused patients, even after correction for hemoglobin level, whereas resting hemoglobin levels predicted hypoxia in the transfused and healthy patients. DISCUSSION: With the goal to better understand the mechanism by which transfusion therapy decreases the risk of stroke, we tested the response to arterial and venous occlusion, simultaneously, at three different functional levels of the vascular system: 1.Conduit artery, 2.Pre-capillary arteriolar and capillary, 3.Tissue oxygen exchange. We confirm our previous findings that conduit vessel dysfunction is highly dependent on free hemoglobin, which is consistent with the hemolysis paradigm as a mechanism for sickle cell vasculopathy. This study extends our model to the microcirculation. Resting microcirculatory flow is increased in both transfused and non-transfused SCD patients; and while the resting rSO2 is near normal in the transfused SCD patients it is significantly lower in the non-transfused subjects. This creates the potential for severe hypoxia in the setting of a limited ability to augment flow through the microcirculation during periods of high demand, as in PORH. If there is also decreased conduit vessel reactivity upstream this creates the scenario over which large areas of tissue may rapidly become ischemic. This is a novel system, with simultaneous measurements in multiple vascular beds, allowing us to evaluate supply-demand matching. CONCLUSIONS: Chronic transfusion therapy improves both brachial artery endothelial function and regional tissue oxygenation but it does not significantly improve microcirculatory function, which may be near its maximal flow at rest. Hemoglobin determines resting tissue saturation in healthy and transfused SCD patients, but high shear RBC deformability determines rSO2 in non-transfused SCD patients. Figure 1. Laser Doppler resting flow is higher but post occlusive hyperemia is lower in SCD Figure 1. Laser Doppler resting flow is higher but post occlusive hyperemia is lower in SCD Figure 2. NIRS repsonse to forearm occlusion. Figure 2. NIRS repsonse to forearm occlusion. Disclosures Wood: World Care Clinical: Consultancy; Vifor: Consultancy; AMAG: Consultancy; Ionis Pharmaceuticals: Consultancy; Biomed Informatics: Consultancy; World Care Clinical: Consultancy; Ionis Pharmaceuticals: Consultancy; Apopharma: Consultancy; Vifor: Consultancy; Apopharma: Consultancy; AMAG: Consultancy; Biomed Informatics: Consultancy; Celgene: Consultancy; Celgene: Consultancy.

Impaired handgrip exercise-induced brachial artery flow-mediated dilation in young obese males

Flow mediated dilation (FMD) stimulated by different shear stress stimulus profiles may recruit distinct transduction mechanisms, and provide distinct information regarding endothelial function. The purpose of this study was to determine whether obesity influences brachial artery FMD differently depending on the shear stress profile used for FMD assessment. The FMD response to a brief, intermediate, and sustained shear stress profile was assessed in obese (n = 9) and lean (n = 19) young men as follows: brief stimulus, standard reactive hyperemia (RH) following a 5 min forearm occlusion (5 min RH); intermediate stimulus, RH following a 15 min forearm occlusion (15 min RH); sustained stimulus, 10 min of handgrip exercise (HGEX). Brachial artery diameter and mean shear stress were assessed using echo and Doppler ultrasound, respectively, during each FMD test. There was no group difference in HGEX shear stress (p = 0.390); however, the obese group had a lower HGEX-FMD (5.2 ± 3.0% versus 11.5 ± 4.4%, p < 0.001). There was no group difference in 5 min RH-FMD (p = 0.466) or 15 min RH-FMD (p = 0.181); however, the shear stress stimulus was larger in the obese group. After normalization to the stimulus the 15 min RH-FMD (p = 0.002), but not the 5 min RH-FMD (p = 0.118) was lower in the obese group. These data suggest that obesity may have a more pronounced impact on the endothelium’s ability to respond to prolonged increases in shear stress.

Impact of controlling shear rate on flow-mediated dilation responses in the brachial artery of humans

The reactive hyperemia test (RHtest) evokes a transient increase in shear stress as a stimulus for endothelial-dependent flow-mediated vasodilation (EDFMD). We developed a noninvasive method to create controlled elevations in brachial artery (BA) shear rate (SR, estimate of shear stress), controlled hyperemia test (CHtest), and assessed the impact of this vs. the RHtest approach on EDFMD. Eight healthy subjects participated in two trials of each test on 3 separate days. For the CHtest, SR was step increased from 8 to 50 s−1, created by controlled release of BA compression during forearm heating. For the RHtest, transient increases in SR were achieved after 5 min of forearm occlusion. BA diameter and blood flow velocity (ultrasound) were measured upstream of compression and occlusion sites. Both tests elicited significant dilation (RHtest: 6.33 ± 3.12%; CHtest: 3.00 ± 1.05%). The CHtest resulted in 1) reduced between-subject SR and EDFMD variability vs. the RHtest [SR coefficient of variation (CV): 4.9% vs. 36.6%; EDFMD CV: 36.16% vs. 51.80%] and 2) virtual elimination of the impact of BA diameter on the peak EDFMD response (peak EDFMD vs. baseline diameter for RHtest, r2 = 0.64, P < 0.01, vs. CHtest, r2 = 0.14, P < 0.01). Normalization of the RHtest EDFMD response to the magnitude of the SR stimulus eliminated test differences in between-subject response variability. Reductions in trial-to-trial and day-to-day SR variability with the CHtest did not reduce EDFMD variability. Between-subject SR variability contributes to EDFMD variability with the RHtest. SR controls with the CHtest or RHtest response normalization are essential for examining EDFMD between groups differing in baseline arterial diameter.