Reduction In Flow-mediated Dilation Research Articles

Acute Effects of Breaking up Sitting Time With Isometric Wall Squat Exercise on Vascular Function and Blood Pressure in Sedentary Adults: Randomized Crossover Trial.

The World Health Organization has recommended breaking up sitting time to improve cardiovascular health. However, whether isometric exercise can be effectively used as a strategy to break up sitting time remains unclear. Thus, the aim of this study was to analyze the acute effects of breaking up prolonged sitting with isometric wall squat exercise (IWSE) on vascular function and blood pressure (BP) in sedentary adults. This randomized crossover trial included 17 adults (53% male, 26±6yr, 22.4±3.6 kg/m 2 ) with high sedentary behavior (≥ 6hr/d). The participants completed 2 experimental sessions in a randomized order, both sharing a common sitting period of 180min: Breaks (2-min breaks were incorporated into the IWSE, with participants maintaining their knees at the angle determined by the incremental test, which occurred every 30min) and Control (sitting for 180min continuously). Popliteal artery flow-mediated dilation (FMD) and brachial BP were measured before and at 10 and 30min after the experimental sessions. The results did not indicate significant session vs time interaction effects on popliteal FMD and brachial BP ( P >.05). A subanalysis including only participants with popliteal FMD reduction after the Control session (n=11) revealed that Breaks enhanced popliteal FMD after 10min (1.38±6.45% vs -4.87±2.95%, P =.002) and 30min (-0.43±2.48% vs -2.11±5.22%, P =.047). Breaking up prolonged sitting with IWSE mitigates impaired vascular function resulting from prolonged sitting but has no effect on BP in sedentary adults.

Does perceived caloric and nutrient intake influence the acute effect of beverage consumption on cardiovascular function?

Our objective was to explore whether consuming the same high-fat/sugar beverage affects endothelial function differently depending on whether it is presented as "unhealthy" [accurate high calorie (kcal), fat, and sugar information displayed] versus "healthy" (inaccurate low kcal, fat, and sugar information displayed). Twenty-five, young (21 ± 2 yr), healthy, food-stress/shame-prone women completed three conditions: milkshake consumption (540 kcal, 80 g sugar, and 14 g fat) where correct, "unhealthy" nutritional information was shown to participants (milkshake condition), consumption of the same milkshake but with incorrect, "healthy" information shown to participants (100 kcal, 3 g sugar, and 4 g fat; sham-nutrishake condition), and water consumption (control condition). Pre- and postbeverage we assessed 1) endothelial function via standard brachial artery flow-mediated dilation (FMD); 2) perceived shame, stress, beverage healthiness, and harm; and 3) blood (plasma) glucose, insulin, triglycerides and oral fluid cortisol, and tumor necrosis factor-alpha (TNFα) receptor binding. Glucose, triglycerides, and insulin increased in the milkshake and sham-nutrishake conditions (P < 0.05). The milkshake was perceived as less healthy (P < 0.001) and more harmful (P < 0.001) than the sham-nutrishake. Shame, stress, oral fluid cortisol and TNFα receptor binding did not increase postconsumption. FMD decreased after the milkshake condition (pre: 7.4 ± 3.3%; post-60 min: 4.9 ± 2.9%; post-90 min: 4.5 ± 3.1%, P < 0.001) but not the sham-nutrishake (pre: 5.7 ± 2.2%; post-60 min: 5.5 ± 2.6%; post-90 min: 5.0 ± 2.4%, P = 0.43) or control conditions (pre: 7.0 ± 2.6%; post-60 min: 6.6 ± 4.1%; post-90 min: 6.0 ± 3.2%, P = 0.29). Shear rate stimulus covariation did not alter FMD results. Lower perceived beverage healthiness was significantly associated with a greater reduction in FMD (ρ = 0.36, P = 0.002). In conclusion, a high-fat/sugar milkshake reduced FMD only when presented as high in fat, sugar, and calories. This suggests that perceptions about nutritional information contribute to the impact of food intake on endothelial function and that nocebo effects could be involved in cardiovascular disease etiology.NEW & NOTEWORTHY This was the first study to investigate how perceived nutritional content influences the impact of a high-sugar/fat beverage on endothelial function. We found that a high-sugar/fat beverage only reduced endothelial function when it was presented to participants as high in calories, fat, and sugar. This suggests that perceived nutritional information contributes to the impact of high sugar and fat intake on endothelial function.

Assessment of Low-density Lipoprotein Cholesterol Levels and Non-invasive Vascular Health in School-aged Children: A Study in Ogasa District, Shizuoka Prefecture.

The present study assessed low-density lipoprotein cholesterol (LDL-C) levels in school-aged children from the Ogasa District of Shizuoka Prefecture and evaluated the utility of non-invasive vascular tests, namely flow-mediated dilation (FMD) and intima-media thickness (IMT), in pediatric patients with familial hypercholesterolemia (FH). We analyzed the lipid test results of 8,568 students screened for prevention of lifestyle-related diseases and 78 children under 15 years old with cholesterol levels exceeding 220 mg/dL who visited Chutoen General Medical Center. We examined the LDL-C distribution from school-age screenings and conducted FMD and IMT assessments on those meeting the 2022 Pediatric FH Guidelines criteria. Among the screened students, 186 (2.2%) exhibited LDL-C levels above 140 mg/dL, including 123 fourth-graders (2.8%) and 63 first-year junior high students (1.5%). The mean LDL-C level across all students was 90.0 mg/dL (standard deviation: 21.3 mg/dL), with the 95th percentile at approximately 125.0 mg/dL. Of the 78 children who visited the hospital, 65 met the FH diagnostic criteria. In children ≥ 10 years old, no significant IMT differences were observed between the Definitive and Probable FH groups and the Possible FH group; however, a significant difference in the FMD percentage was noted between these groups (9.9% [8.1%-11.9%] vs. 14.2% [11.6%-16.3%], P=0.003). Our findings highlight the LDL-C distribution in FH screening and suggest a potential reduction in FMD in pediatric FH patients ≥ 10 years old. These results emphasize the importance of initiating pharmacological interventions in school-aged children to maintain optimal LDL-C levels for lifelong cardiovascular health.

Varied effects of tobacco smoke and e-cigarette vapor suggest that nicotine does not affect endothelium-dependent relaxation and nitric oxide signaling

Chronic smoking causes dysfunction of vascular endothelial cells, evident as a reduction of flow-mediated dilation in smokers, but the role of nicotine is still controversial. Given the increasing use of e-cigarettes and other nicotine products, it appears essential to clarify this issue. We studied extracts from cigarette smoke (CSE) and vapor from e-cigarettes (EVE) and heated tobacco (HTE) for their effects on vascular relaxation, endothelial nitric oxide signaling, and the activity of soluble guanylyl cyclase. The average nicotine concentrations of CSE, EVE, and HTE were 164, 800, and 85 µM, respectively. At a dilution of 1:3, CSE almost entirely inhibited the relaxation of rat aortas and porcine coronary arteries to acetylcholine and bradykinin, respectively, while undiluted EVE, with a 15-fold higher nicotine concentration, had no significant effect. With about 50% inhibition at 1:2 dilution, the effect of HTE was between CSE and EVE. Neither extract affected endothelium-independent relaxation to an NO donor. At the dilutions tested, CSE was not toxic to cultured endothelial cells but, in contrast to EVE, impaired NO signaling and inhibited NO stimulation of soluble guanylyl cyclase. Our results demonstrate that nicotine does not mediate the impaired endothelium-dependent vascular relaxation caused by smoking.

Endothelin-1 Contributes to Reduced Endothelial Function in Middle-aged/Older Men with Low Testosterone

Male aging is associated with a general decline in serum testosterone (T) concentrations. Low endogenous T is associated with increased cardiovascular disease risk, and we recently demonstrated accelerated age-related endothelial dysfunction, measured by brachial artery flow mediated dilation (FMD), in middle-aged/older (MA/O) men with low T compared with age-matched men with normal T. Endothlin-1 (ET-1) is a potent vasoconstrictor that is modulated by sex hormones and contributes to age-associated endothelial dysfunction. However, whether ET-1 contributes to reduced FMD in MA/O men with low T has yet to be determined. PURPOSE: to determine if ET-1 contributes to reduced FMD in MA/O men with low T. HYPOTHESIS: we hypothesized that MA/O men with low T would have higher ET-1 concentrations compared with young and MA/O men with normal T. Additionally, we hypothesized that there would be an inverse relation between ET-1 and FMD. METHODS: 60 men were categorized as either young (18-40 years, T: 400-1000 ng/dL) or MA/O (50-75 years) with low (&lt;300ng/dL) or normal (400-1000 ng/dL) serum total T. T was determined from a venous blood draw using a one-step competitive enzyme linked immunosorbent assay. Endothelial function was determined using brachial artery FMD and ET-1 concentrations were determined using radioimmunoassay from a venous blood sample. RESULTS: T concentrations were significantly lower in MA/O men with low T (269±48 ng/dL) compared to young (500±58 ng/dL; p&lt;0.001) or MA/O men with normal T (512±115, ng/dL; p&lt;0.001). There was no difference in T between MA/O men with normal T and young men (p=0.995). MA/O men were similar in age (low T=59±8, normal T=60±6 years; p=0.996) and older than young men (29±4 years; p&lt;0.001 compared to MA/O with both low and normal T). Age-associated reductions in FMD (young=7.3±1.3 vs. MA/O normal T=5.7±2.2%; p=0.019), were exaggerated in MA/O men with low T (4.0±1.7%; p=0.010 vs. MA/O normal T, p&lt;0.001 vs. young). ET-1 concentrations were similar between young and MA/O men with normal T (young= 5.6±0.9 vs. MA/O normal T=6.0±1.4 pg/mL; p=0.768), and higher in MA/O men with low T (7.7±2.8 pg/mL; p=0.002 vs. young, p=0.016 vs. MA/O normal T). There was a moderate inverse association between FMD and ET-1 (r=-0.374, p=0.003). CONCLUSIONS: These data suggest that the greater age-associated endothelial dysfunction in MA/O men with low T may be related to elevations in ET-1. Future studies should examine the effects of low T on endothelin receptors ETA and ETB, as well as factors that could explain the increase in ET-1 in MA/O men with low T. Supported by NIH Grants R01AG049762, U54AG062319, and T32AG000279-16A1 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impaired endothelial function via fatty acids and the potential role of oxidative stress

Purpose: Excess plasma lipids promote oxidative stress and impaired vascular function. Therefore, we tested the hypothesis that a water-soluble antioxidant (ascorbic acid, AA) would attenuate reductions in endothelium-dependent dilation resulting from acutely elevated plasma fatty acids. Methods: A 20% IV fat emulsion (Intralipid) was administered for 2 hours to 8 healthy, middle-aged adults (2 men/6 women) with and without co-infusion of ascorbic acid (separate visits) in a double-blinded, crossover study design. Co-infusion of AA was administered at 0.06g/kg fat free mass in 100 ml saline at 5 mL/min over 20 min (bolus) followed by a drip infusion at 0.02 g/kg fat-free mass in 30 ml saline at 0.33 mL/min over 90 min. Endothelium-dependent dilation was assessed via brachial artery flow-mediated dilation (FMD) and expressed as % increase in diameter from baseline before forearm occlusion. Results: Lipid infusion significantly increase plasma fatty acid concentrations (w/o AA: +36 ± 18 vs. with AA: +41 ± 13 vs. μmol/L, P=0.84). AA infusion significantly increased plasma ascorbic acid concentrations (w/o AA: -1 ± 7 vs. with AA: +26 ± 11 μmol/L, P=0.04). Compared with baseline, FMD was significantly reduced following lipid infusion at (Baseline: 9.3 ± 1.1 vs. 20 min: 4.4 ± 1.3 vs. End: 5.3 ± 2.9 %, P=0.03), and when statistically adjusting for the stimulus (shear rate area under the curve) via analysis of covariance (P=0.02). FMD was also significantly reduced following lipid infusion with co-infusion of AA (Baseline: 8.9 ± 1.0 vs. 20 min: 5.3 ± 1.0 vs. End: 6.4 ± 3.8 %, P=0.02), but not when statistically adjusting for shear rate under the curve (P=0.08). Conclusions: Elevated plasma fatty acids impair endothelium-dependent dilation in healthy adults. However, co-administration of an antioxidant (ascorbic acid) limited the reduction in FMD when correcting for shear rate. Therefore, these preliminary data suggest that fatty acids may reduce endothelium-dependent dilation via an oxidative stress mechanism. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or CTSA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The effect of ozone short-term exposure on flow-mediated dilation: Using data before and after COVID-19 lockdown in Shanghai

BackgroundShort-term ambient ozone exposure has been shown to have an adverse impact on endothelial function, contributing to major cardiovascular diseases and premature death. However, only limited studies have focused on the impact of short-term ozone exposure on Flow-mediated Dilation (FMD), and their results have been inconsistent. The current study aims to explore the relationship between short-term ambient ozone exposure and FMD. In addition, the study aims to investigate how lockdown measures for COVID-19 may influence ozone concentration in the atmosphere. MethodsParticipants were recruited from a hospital in Shanghai from December 2020 to August 2022. Individuals' ozone exposure was determined using residential addresses. A distributed lag nonlinear model was adopted to assess the exposure-response relationship between short-term ozone exposure and FMD. A comparison was made between ambient ozone concentration and FMD data collected before and after Shanghai's lockdown in 2022. ResultsWhen ozone concentration was between 150 and 200 μg/m3, there was a significant reduction in FMD with a 2-day lag. Elderly individuals (age ≥ 65), females, non-drinkers, and non-smokers were found to be more susceptible to high concentrations of ozone exposure. The lockdown did elevate ambient ozone concentration compared to the same period previously. InterpretationThis study proposes that an ambient ozone concentration of 150–200 μg/m3 is harmful to endothelial function, and that a reduction in human activity during lockdown increased the concentration, which in turn reduced FMD. However, the underlying mechanism requires further research.

The Role of Rehabilitation in Arterial Function Properties of Convalescent COVID-19 Patients.

Coronavirus disease (COVID-19) is a respiratory disease, although arterial function involvement has been documented. We assess the impact of a post-acute COVID-19 rehabilitation program on endothelium-dependent vasodilation and arterial wall properties. We enrolled 60 convalescent patients from COVID-19 and one-month post-acute disease, who were randomized at a 1:1 ratio in a 3-month cardiopulmonary rehabilitation program (study group) or not (control group). Endothelium-dependent vasodilation was evaluated by flow-mediated dilation (FMD), and arterial wall properties were evaluated by carotid-femoral pulse wave velocity (cf-PWV) and augmentation index (AIx) at 1 month and at 4 months post-acute disease. FMD was significantly improved in both the study (6.2 ± 1.8% vs. 8.6 ± 2.4%, p < 0.001) and control groups (5.9 ± 2.2% vs. 6.6 ± 1.8%, p = 0.009), but the improvement was significantly higher in the study group (rehabilitation) (p < 0.001). PWV was improved in the study group (8.2 ± 1.3 m/s vs. 6.6 ± 1.0 m/s, p < 0.001) but not in the control group (8.9 ± 1.8 m/s vs. 8.8 ± 1.9 m/s, p = 0.74). Similarly, AIx was improved in the study group (25.9 ± 9.8% vs. 21.1 ± 9.3%, p < 0.001) but not in the control group (27.6 ± 9.2% vs. 26.2 ± 9.8 m/s, p = 0.15). Convalescent COVID-19 subjects of the study group (rehabilitation) with increased serum levels of circulating IL-6 had a greater reduction in FMD. Conclusively, a 3-month cardiopulmonary post-acute COVID-19 rehabilitation program improves recovery of endothelium-dependent vasodilation and arteriosclerosis.

Impairment of Endothelial Function by Cigarette Smoke Is Not Caused by a Specific Smoke Constituent, but by Vagal Input From the Airway.

Exposure to tobacco or marijuana smoke, or e-cigarette aerosols, causes vascular endothelial dysfunction in humans and rats. We aimed to determine what constituent, or class of constituents, of smoke is responsible for endothelial functional impairment. We investigated several smoke constituents that we hypothesized to mediate this effect by exposing rats and measuring arterial flow-mediated dilation (FMD) pre- and post-exposure. We measured FMD before and after inhalation of sidestream smoke from research cigarettes containing normal and reduced nicotine level with and without menthol, as well as 2 of the main aldehyde gases found in both smoke and e-cigarette aerosol (acrolein and acetaldehyde), and inert carbon nanoparticles. FMD was reduced by all 4 kinds of research cigarettes, with extent of reduction ranging from 20% to 46% depending on the cigarette type. While nicotine was not required for the impairment, higher nicotine levels in smoke were associated with a greater percent reduction of FMD (41.1±4.5% reduction versus 19.2±9.5%; P=0.047). Lower menthol levels were also associated with a greater percent reduction of FMD (18.5±9.8% versus 40.5±4.8%; P=0.048). Inhalation of acrolein or acetaldehyde gases at smoke-relevant concentrations impaired FMD by roughly 50% (P=0.001). However, inhalation of inert carbon nanoparticles at smoke-relevant concentrations with no gas phase also impaired FMD by a comparable amount (P<0.001). Bilateral cervical vagotomy blocked the impairment of FMD by tobacco smoke. There is no single constituent or class of constituents responsible for acute impairment of endothelial function by smoke; rather, we propose that acute endothelial dysfunction by disparate inhaled products is caused by vagus nerve signaling initiated by airway irritation.

Electronic hookah vaping reduces plasma concentrations of nitrate/nitrite and increases systemic oxidative stress

Abstract Background Electronic (e-) hookah–a new category of vaping devices–has increased in use among young adults in recent years. E-hookahs utilize the placement of e-bowls on traditional water pipes, allowing the flavored aerosol to pass through a water-filled base before being inhaled. Though advertised as a safe tobacco alternative, e-hookahs deliver flavored nicotine by creating an aerosol of fine particles and other free radicals that may increase cardiovascular disease risk. While acute e-hookah vaping impairs endothelial function, the underlying mechanism is not completely understood. Purpose To determine the mechanistic involvement of nitric oxide (NO) and oxidative stress underlying the acute e-hookah induced endothelial dysfunction. Methods Healthy young adult chronic hookah smokers (n=7; 26±1 years of age, 24.4±0.8 kg-m2; mean ±SE) were randomized to vape two 30-minute sessions of flavored e-hookah and sham vaping, separated by a 7-day washout period. Flow-mediated dilation (FMD) of the brachial artery was performed with the use of ultrasound. Circulating plasma nitrite/nitrate (NOx), as an index of nitric oxide (NO) concentration, and lipid peroxidation marker 8-isoprostane concentrations, as well as smoking exposure biomarkers (plasma nicotine and exhaled carbon monoxide) were measured before and after the vaping sessions. Results As compared to unchanged parameters with sham vaping (p=ns), e-hookah vaping induced an acute reduction in FMD by −27±3% (pre- vs. post-vaping, p&amp;lt;0.001), suggesting impairment in endothelial function. These vascular changes were accompanied by significant reductions in circulating plasma levels of NOx and increases in 8-iso prostaglandin F2a levels (−41±11% and +28±11%, respectively; p&amp;lt;0.001). Plasma nicotine concentrations increased 4-fold more after vaping e-hookah, whereas exhaled CO levels did not change (p=ns). Conclusions Our data demonstrate that e-hookah vaping transiently increases systemic oxidative stress and decreases NOx levels, the latter implies reduced NO bioavailability and is in line with the observed impairment in endothelial function, expressed by acute FMD reductions. Thus, in contrast to the unsubstantiated beliefs that e-hookah vaping is benign, in overtly healthy young adults, e-hookah vaping causes acute vascular functional impairment, likely mediated by oxidative stress. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): University of California Tobacco-Related Disease Research Program, University of California

Hypoxic Preconditioning Attenuates Ischemia‐Reperfusion Injury in Older Adults

Sudden restoration of blood flow to an ischemic vessel paradoxically damages endothelial cells. In young healthy adults, ischemic preconditioning, caused by repeated periods of brief ischemia induced by local cuff inflation prior to reperfusion, attenuates endothelial dysfunction following an ischemia‐reperfusion injury. However, ischemic preconditioning does not consistently protect against ischemia‐reperfusion injury in older adults. Intermittent systemic hypoxemia, induced via brief bouts of breathing low levels of oxygen, attenuates endothelial dysfunction following an ischemia‐reperfusion injury in young healthy adults. Therefore, the aim of the present study was to determine whether intermittent hypoxia protects against ischemia‐reperfusion injury in older adults. Eleven older adults (4 women, age: 57±9 years, height: 173±8 cm, body weight: 76±13 kg) visited the laboratory on two separate occasions. Endothelium‐dependent vasodilation was assessed by brachial artery flow‐mediated dilation using a semiautomated diagnostic ultrasound system before and after 20 minutes of blood flow occlusion to induce an ischemia‐reperfusion injury. Blood flow occlusion was preceded by either intermittent hypoxia (IH), consisting of three 4‐min hypoxic cycles at a targeted arterial oxygen saturation of 80% interspersed with 4‐min room air cycles, or intermittent normoxia (IN), consisting of three 4‐min normoxic cycles separated by 4‐min room air cycles. Intermittent hypoxia resulted in an arterial oxygen saturation of 80±2%, which corresponded to oxygen levels of 11.6±1.0%. When preceded by intermittent normoxia, blood flow occlusion reduced flow‐mediated dilation by 4.0±2.6% (6.4±1.7 to 2.4±1.8%). In contrast, flow‐mediated dilation was reduced by 1.8±1.5% when blood flow occlusion was preceded by intermittent hypoxia (5.6±1.8 to 3.7±2.4%: p=0.05). Intermittent hypoxia increased cardiac output (5.2±1.5 to 5.7±1.8 L·min‐1, p=0.03) mainly due to an increase in heart rate (61±12 to 69±10 bpm, p&lt;0.01). In conclusion, hypoxic preconditioning attenuated the reduction in flow‐mediated dilation induced by blood flow occlusion in older adults. Thus, exposure to intermittent hypoxia represents a potential strategy to protect against ischemia‐reperfusion injury in populations at risk for ischemic events.

Impaired Endothelial Function in Convalescent Phase of COVID-19: A 3 Month Follow Up Observational Prospective Study.

Background: Endothelial dysfunction has a role in acute COVID-19, contributing to systemic inflammatory syndrome, acute respiratory distress syndrome, and vascular events. Evidence regarding COVID-19 middle- and long-term consequences on endothelium are still lacking. Our study aimed to evaluate if COVID-19 severity could significantly affect the endothelial function after three months from the acute phase. Methods: We assessed endothelial function in outpatients with previous COVID-19 three months after negative SARS-CoV-2 molecular test by measuring flow-mediated dilation (FMD) in patients categorized according to a four-variable COVID-19 severity scale (“home care”; “hospital, no oxygen”; “hospital, oxygen”; “hospital requiring high-flow nasal canula, non-invasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation”). FMD difference among COVID-19 severity categories was assessed with analysis of variance; we further clarified the relationship between FMD and previous COVID-19 severity with multivariate logistic models. Results: Among 658 consecutive COVID-19 subjects, we observed a significant linear trend of FMD reduction with the increase of the COVID-19 category (p < 0.0001). The presence of endothelial dysfunction was more frequent among hospitalized patients (78.3%) with respect to home-care patients (21.7%; p < 0.0001). COVID-19 severity was associated with increased endothelial dysfunction risk (OR: 1.354; 95% CI: 1.06–1.71; p = 0.011) at multivariate binary logistic analysis. FMD showed a significant direct correlation with PaO2 (p = 0.004), P/F ratio (p = 0.004), FEV1 (p = 0.008), and 6MWT (p = 0.0001). Conclusions: Hospitalized COVID-19 subjects showed an impaired endothelial function three months after the acute phase that correlated with pulmonary function impairment. Further studies are needed to evaluate if these subjects are at higher risk of developing pulmonary disease or future cardiovascular events.

Effects of Postprandial Lipemia Combined With Disturbed Blood Flow on the Flow-Mediated Dilation, Oxidative Stress, and Endothelial Microvesicles in Healthy Subjects.

AimsBoth postprandial lipemia (PPL) and disturbed blood flow (DBF) induce endothelial dysfunction. However, the interactive effect of these stimuli on endothelial function is currently unknown. In the present study, we tested whether PPL plus DBF causes a greater reduction in flow-mediated dilation (FMD) than PPL and if this response is associated with elevations in oxidative stress and endothelial microvesicles (EMVs).MethodsEighteen individuals (aged 28 ± 1yrs, 3 females, and BMI 24.43 ± 0.8kg/m2) randomly underwent two experimental sessions: PPL and PPL plus DBF. FMD and venous blood samples were obtained at baseline and 30, 70, and 110 min after stimulation. PPL was induced by fat overload via mozzarella pizza ingestion and DBF by forearm cuff inflation to 75 mm Hg per 30 min. Lipidic profile, oxidative stress (thiobarbituric acid reactive substances, TBARS; ferric reducing/antioxidant power, FRAP; hydrogen peroxide, H2O2) and EMVs were measured in blood samples.ResultsHypertriglyceridemia was observed in both sessions. Retrograde shear rate and oscillatory index responses were significantly higher in the PPL plus DBF compared with PPL. PPL plus DBF evoked a greater reduction in FMD than did PPL and EMVs, NADPH oxidase, and H2O2 similarly increased in both sessions, but TBARS and FRAP did not change.ConclusionThese data indicate that the association of PPL plus DBF additively impairs endothelium-dependent function in 110 min after stimulus in healthy individuals, despite a similar increase in oxidative stress and EMVs. Further studies are needed to understand the mechanisms associated with the induced-endothelial dysfunction by association of PPL and DBF.

Membrane estrogen receptor alpha (ERα) participates in flow-mediated dilation in a ligand-independent manner.

Estrogen receptor alpha (ERα) activation by estrogens prevents atheroma through its nuclear action, whereas plasma membrane-located ERα accelerates endothelial healing. The genetic deficiency of ERα was associated with a reduction in flow-mediated dilation (FMD) in one man. Here, we evaluated ex vivo the role of ERα on FMD of resistance arteries. FMD, but not agonist (acetylcholine, insulin)-mediated dilation, was reduced in male and female mice lacking ERα (Esr1-/- mice) compared to wild-type mice and was not dependent on the presence of estrogens. In C451A-ERα mice lacking membrane ERα, not in mice lacking AF2-dependent nuclear ERα actions, FMD was reduced, and restored by antioxidant treatments. Compared to wild-type mice, isolated perfused kidneys of C451A-ERα mice revealed a decreased flow-mediated nitrate production and an increased H2O2 production. Thus, endothelial membrane ERα promotes NO bioavailability through inhibition of oxidative stress and thereby participates in FMD in a ligand-independent manner.

Abstract 11207: Electronic Hookah Vaping with and Without Nicotine: Insights into Vascular Function and Plasma Fibrinogen

Introduction: Electronic nicotine delivery systems (ENDS) are growing quickly in the United States, particularly among youth. Electronic (e-) hookahs are a new category of vaping devices in which the e-bowl is combined with and placed on a traditional waterpipe, allowing the flavored aerosol to pass through a water-filled base before being carried through the hose into the user’s mouth. E-hookah vaping with flavored nicotine acutely impairs endothelial function. However, the relative contribution of flavorings vs. nicotine on e-hookah vaping associated vascular dysfunction is unclear. Methods: In a randomized cross-over design study, we investigated the acute effect of flavored e-hookah with and without nicotine and sham vaping, among a cohort of 9 healthy young adult chronic hookah smokers (27±1 years, mean ±SE), on endothelial function, measured by brachial artery flow-mediated dilation (FMD). Fibrinogen, a major plasma protein coagulation factor, as well as smoking exposure biomarkers (plasma nicotine and expired carbon monoxide levels) were collected before and after the sessions. Results: Vaping e-hookah with nicotine induced an acute reduction in FMD (from 6.9±0.9 to 5.2±0.8%, pre- vs. post- vaping, p&lt;0.001), suggesting impairment in endothelial function and increased plasma fibrinogen (+14.5±4.1 mg/dL, p&lt;0.001). Though vaping e-hookah in the absence of nicotine did not significantly impair endothelial function (p = ns), it significantly induced an increase in plasma fibrinogen levels (+20.9±7.4 mg/dL, p&lt;0.001), higher than levels induced after vaping e-hookah with nicotine. Plasma nicotine concentrations increased 4-fold more after vaping e-hookah with nicotine, whereas no changes were observed after vaping e-hookah without nicotine or sham-vaping (p = ns). Exhaled CO levels did not change across all three vaping sessions. Conclusions: In healthy young adults, our findings to date suggest that while vaping e-hookah with nicotine induces an unfavorable effect on the vasculature, non-nicotine constituents generated from heating the flavored e-hookah aerosol cannot be ignored. Further plans are needed to elucidate the long-term vascular implications of vaping non-nicotine flavored constituents.

Abstract 13273: Late Senolytic Therapy Improves Cerebrovascular Endothelial Function but Not Cognition in Middle-Aged Severely Atherosclerotic Mice

Introduction: Age-related and atherosclerosis-related vascular dysfunction contributes to neuro-vascular uncoupling, which induces neuronal damage and leads to precocious cognitive loss. This dysfunction could be partially explained by the accumulation of senescent cells (SnC) that remain metabolically active and release many pro-inflammatory factors. Hypothesis: Targeted elimination of SnC with a senolytic restores cerebrovascular function, maintains neuro-vascular coupling and slows cognitive decline. Methods and Results: Nine-month old male atherosclerotic mice (ATX, LDLR -/- ;hApoB +/+ ) were treated (n=13), or not (n=11), for 3 months with navitoclax (50mg/kg), a Bcl2 inhibitor that stimulates global elimination of SnC overexpressing this antiapoptotic pathway. Twelve-month old vehicle-treated ATX mice developed atheroma plaques up to the upper neck portion of the carotid arteries, but not in the cerebral circulation. Three months treatment with navitoclax reduced aortic plaques size (-32%, p&lt;0.001) from 40±2% in vehicle-treated mice to 27±2% in navitoclax mice. At 12 months, endothelial dysfunction was severe in vehicle-treated ATX mice, as evidenced by a strong reduction in flow-mediated dilation (FMD) of pressurized posterior cerebral arteries ex vivo ; navitoclax improved endothelium-dependent dilatation by 50% (for example, FMD at 20 dyn/cm 2 : 58±10%) compared to vehicle-treated mice (FMD: 29±7%; p&lt;0.05). Two cognitive tests were performed: the Y-maze and the novel object recognition tests, to assess exploratory behavior and executive function, respectively. A gradual decline of both exploratory and executive memory was observed from 3 to 6, 9 and 12 months in vehicle-treated ATX mice; navitoclax, however, did not prevent this cognitive decline. Conclusion: Global elimination of SnC slowed atherosclerotic plaque development and restored cerebral endothelial function, demonstrating that senescence contributes to vascular dysfunction. The absence of cognitive improvement with navitoclax suggests an irreversible state of neuronal damage that could not be affected by the late senolytic treatment. To demonstrate the role of SnC in cognitive impairment, an earlier senolytic therapy will be needed.

A Single High Fat Meal Adversely Affects Postprandial Endothelial Function: A Systematic Review and Meta-Analysis

Abstract Objectives High-fat diets are associated with endothelial dysfunction, the first step in the progression to atherosclerosis and cardiovascular disease. We aimed to determine the postprandial endothelial response (flow-mediated dilation (FMD)) to a high-fat meal in various populations and define how the response varies by conducting a systematic review of the literature. Methods Six electronic databases were systematically searched for original research published from database inception to May 2020. Eligible studies measured both fasting and postprandial FMD following consumption of a meal containing ≥ 30 g fat or ≥ 40% energy from fat. A random-effects model was used to analyse the pooled effect size change from the fasting FMD, presented as mean difference. Moderator variables were analysed by meta-regression. Results One-hundred and twenty articles reporting on 3821 adults were included in the review. High fat meal consumption significantly attenuated FMD at 2 hours (MD: −1.61; 95% CI −2.02 −1.19, p &amp;lt; 0.001), 3 hours (−1.73; −2.30 −1.17, p &amp;lt; 0.001) and 4 hours (−1.54; −1.88 −1.20, p &amp;lt; 0.001), though heterogeneity (I2) was &amp;gt; 90%. Meta-regression revealed that fasting FMD significantly impacted the reported effect size (p &amp;lt; 0.0001) at all postprandial timepoints. Age and BMI were inversely correlated with FMD response at 2 and 4 hours (p &amp;lt; 0.0001). Conclusions Younger, healthy-weight participants exhibited a larger postprandial reduction in FMD compared to older, heavier groups after a high-fat meal. Vulnerable populations could be more likely to exhibit endothelial dysfunction, as evident through lower fasting FMD, together with impaired metabolic flexibility. A single high fat meal adversely impacts endothelial function and the magnitude of the impact on postprandial FMD was influenced by fasting FMD, participant age, and BMI. Funding Sources Monash University

The Acute Effect of Magnesium Supplementation on Endothelial Function: A Randomized Cross-Over Pilot Study

Magnesium (Mg) deficiency might be a catalyst in the process of endothelial dysfunction, an early event in the pathogenesis of atherosclerosis. The aim of this study was to determine the acute effect of an oral Mg supplement as compared to control on endothelial function assessed by flow-mediated dilatation (FMD). Nineteen participants (39 years, body mass index (BMI) 22.9 kg/m2) completed this randomized cross-over study. Blood pressure (BP) and FMD were measured and blood samples were taken before participants drank 200 mL water, with or without an over the counter Mg supplement (450 mg and 300 mg for men and women). Measurements were repeated at 60 and 120 min. There was a statistically significant two-way interaction between treatment and time on serum Mg (p = 0.037). A difference of −0.085 mm in FMD was observed 60-min post drink in the control group, as compared to baseline FMD, and no difference was observed in the supplement group as compared to baseline. Despite the non-significant interaction between treatment and time on FMD, once adjusted for baseline, the difference seen in the control group and the lack of change in the supplement group at 60 min post-drink suggests that Mg might attenuate the reduction in FMD post-prandially.

Acute Effect of Heat Exposure on Brachial Artery FMD: Impact of Modality and Measurement Timeline

Introduction Heat exposure is receiving a lot of attention for its potential to improve endothelial function, as measured by brachial artery flow-mediated dilation (FMD). Although most intervention studies have observed an improvement in brachial artery FMD, the acute effect of heat exposure has been inconsistent. This observation likely stems from the various modalities employed (local limb heating to whole-body heating) and the timing of FMD measurement following the heating intervention (immediately after up to 60 min post-heating). Identifying a heating modality that consistently improves brachial artery FMD and establishing the timeline of the response would facilitate investigations into potential mechanisms mediating heat-induced improvements in brachial artery FMD without the need of more challenging intervention studies. The aims of this study are to 1) determine the acute effect of four heating interventions on brachial artery FMD, and 2) characterize the time-dependent changes in brachial artery FMD following each intervention. Methods On separate days, 11 young and healthy adults (3F/8M; 29±6 y; 66.5±9.4 kg; 1.7±0.1 m) were exposed to: i) 10 minutes of forearm heating using an electric blanket (EB); ii) 30 minutes of forearm heating in 40˚C water (WI); iii) 60 minutes of whole-body heating where the arm used to assess brachial artery FMD was not covered by the water perfused suit (WHB-U), or; iv) was covered for the entire 60 minutes of whole-body heating with the suit (WBH-C). During each trial, brachial artery FMD was measured prior to the heating intervention (baseline), within 5 minutes following the end of the intervention, and every 30 minutes for two hours following the intervention. Results Mean shear rate increased from baseline during the WI (+78±43 s-1, P=0.02), WBH-U (+177±99 s-1, P<0.01) and WBH-C (+140±43 s-1, P<0.01) interventions, but not during EB (+18±35 s-1, P=0.37). Brachial artery FMD was unaffected by the EB intervention (P=0.39). Conversely, there was a main effect of time for FMD during the WI (P=0.03), WBH-U (P<0.01), and WBH-C (P<0.01) interventions. Specifically, FMD was greater relative to baseline, 90 minutes following the WI intervention (+3.7±3.3%, P=0.03, increase in 8/11 participants). A lower FMD relative to baseline was observed within 5 minutes of the end of the WBH-U (-4.5±3.7%, P<0.01, decrease in 9/11 participants) and WBH-C (WBH-C: -6.1±3.5%, P<0.01, decrease in 10/11 participants) interventions. Conclusion These results suggest that 10 minutes of local heating with an electric blanket may not modulate brachial FMD, whereas whole-body heating with or without local heating of the arm causes a temporary reduction in FMD. Forearm immersion in 40°C water for 30 minutes was the only intervention that consistently improved brachial artery FMD, but only when measured 90 minutes following the intervention.

Hypoxic preconditioning attenuates ischemia-reperfusion injury in young healthy adults.

Ischemic preconditioning attenuates the reduction in brachial artery endothelial function following an ischemia-reperfusion injury. Brief bouts of systemic hypoxemia could similarly mitigate the blunted vasodilatory response induced by an ischemia-reperfusion injury. The aim of the present study was to determine whether an acute bout of intermittent hypoxia protects against an ischemia-reperfusion injury in young healthy individuals. Brachial artery endothelial function was assessed by flow-mediated dilation in 16 young healthy individuals before and after a 20-min upper arm blood flow occlusion to induce ischemia-reperfusion injury. Blood flow occlusion was preceded by either intermittent hypoxia or intermittent normoxia. Intermittent hypoxia consisted of three 4-min hypoxic cycles at an arterial oxygen saturation of 87 ± 3% separated by 4-min normoxic cycles. Intermittent hypoxia resulted in a lower arterial oxygen saturation than intermittent normoxia (hypoxia: 87 ± 3% vs. normoxia: 99 ± 1%, P < 0.01), which was equivalent to a lower fraction of inspired oxygen (hypoxia: 0.123 ± 0.013 and normoxia: 0.210 ± 0.003, P < 0.01). When preceded by intermittent normoxia, blood flow occlusion resulted in a blunted flow-mediated dilation. In contrast, the reduction in flow-mediated dilation following blood flow occlusion was attenuated by prior exposure to intermittent hypoxia (hypoxia: 6.4 ± 1.9 to 4.4 ± 2.3% and normoxia: 7.1 ± 2.5 to 4.0 ± 2.4%, time × condition interaction P = 0.048). Exposure to intermittent hypoxia did not affect mean arterial pressure (hypoxia: 92 ± 9 mmHg and normoxia: 89 ± 8 mmHg, P = 0.19) or cardiac output (hypoxia: 5.8 ± 1.1 L·min-1 and normoxia: 5.3 ± 1.1 L·min-1, P = 0.29). In conclusion, hypoxic preconditioning attenuates the reduction in flow-mediated dilation induced by blood flow occlusion in young healthy individuals. Intermittent hypoxia represents a potential strategy to mitigate the effect of ischemia-reperfusion injury associated with ischemic events.NEW & NOTEWORTHY Ischemia-reperfusion injury induced by restoration of blood flow following occlusion impairs flow-mediated dilation, a marker of endothelium-dependent vasodilation. In young healthy adults, exposure to intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, before an ischemia-reperfusion injury significantly attenuated the reduction in flow-mediated dilation. Thus, hypoxic preconditioning represents a potential strategy to mitigate the effect of ischemia-reperfusion injury associated with ischemic events.