Endothelial Function In Humans Research Articles

The bottlenose dolphin (Tursiops truncatus): a novel model for studying healthy arterial aging.

Endothelial function declines with aging and independently predicts future cardiovascular disease (CVD) events. Diving also impairs endothelial function in humans. Yet, dolphins, being long-lived mammals adapted to diving, undergo repetitive cycles of tissue hypoxia-reoxygenation and disturbed shear stress without manifesting any apparent detrimental effects, as CVD is essentially nonexistent in these animals. Thus, dolphins may be a unique model of healthy arterial aging and may provide insights into strategies for clinical medicine. Emerging evidence shows that the circulating milieu (bioactive factors in the blood) is at least partially responsible for transducing reductions in age-related endothelial function. To assess whether dolphins have preserved endothelial function with aging because of a protected circulating milieu, we tested if the serum (pool of the circulating milieu) of bottlenose dolphins (Tursiops truncatus) induces the same arterial aging phenotype as the serum of age-equivalent humans. We incubated conduit arteries from young and old mice with dolphin and human serum and measured endothelial function ex vivo via endothelium-dependent dilation to acetylcholine. Although young arteries incubated with serum from midlife/older adult human serum had lower endothelial function, those incubated with dolphin serum consistently maintained high endothelial function regardless of the age of the donor. Thus, studying the arterial health of dolphins could lead to potential novel therapeutic strategies to improve age-related endothelial dysfunction in humans.NEW & NOTEWORTHY We demonstrate that, unlike serum of midlife/older adult humans, age-matched dolphin serum elicits higher endothelial function ex vivo in young mouse carotid arteries, suggesting that the circulating milieu of bottlenose dolphins may be geroprotective. We propose that dolphins are a novel model to investigate potential novel therapeutic strategies to mitigate age-related endothelial dysfunction in humans.

Variability of flow-mediated dilation across lower and upper limb conduit arteries

Endothelial dysfunction is an early predictor of atherosclerosis and cardiovascular disease. Flow-mediated dilation (FMD) is the gold standard to assess endothelial function in humans. FMD reproducibility has been mainly assessed in the brachial artery (BA) with limited research in lower limb arteries. The purpose of this study was to compare FMD reproducibility in the upper limb BA and lower limb superficial femoral artery (SFA) in young healthy adults.Fifteen young healthy adults (nine males; six females) underwent FMD, resting diameter, velocity, and shear rate measurements on three occasions to determine intra-and inter-day reproducibility in both BA and SFA, assessed by coefficient of variation (CV), intraclass correlation coefficient (ICC), and Bland–Altman plots.BA FMD CVs (intra-day: 4.2%; inter-day: 8.7%) and ICCs (intra-day: 0.967; inter-day: 0.903) indicated excellent reproducibility and reliability, while for SFA FMD, both CVs (intra-day: 11.6%; inter-day: 26.7%) and ICCs (intra-day: 0.898; inter-day: 0.651) showed good/moderate reproducibility and reliability. BA FMD was significantly more reproducible than SFA FMD (p < 0.05). Diameter reproducibility was excellent and similar between arteries, while resting velocity and shear rate have lower reproducibility in the BA compared to SFA. Bland–Altman plots displayed no proportional and fixed bias between measurements.In summary, SFA FMD is less reproducible than BA FMD, with identical volume of ultrasound training. Given the increasing interest in using SFA FMD to test the efficacy of interventions targeting lower limb’s vascular health and as a potential biomarker for peripheral arterial disease risk, future studies should ensure higher levels of training for adequate reproducibility.

Effects of exercise during water immersion on arterial function in humans.

Flow-mediated dilation (FMD) provides a valid bioassay of vascular function in humans. Although water immersion induces hemodynamic effects that modify brachial artery shear stress, it is unclear whether water-based exercise modifies FMD. We hypothesized that exercise in 32°C water would decrease brachial artery shear and FMD relative to land-based exercise, whereas exercise in 38°C would increase brachial shear and FMD. Ten healthy participants (8 males; 23.9 ± 3.3 yr) completed 30 min of resistance-matched cycle exercise in three separate conditions: on land and in 32°C and 38°C water. Brachial artery shear rate area under the curve (SRAUC) was measured throughout each condition, with FMD measured pre- and postexercise. Brachial SRAUC increased during exercise in all conditions and was highest across the 38°C condition compared with Land and 32°C conditions (38°C: 27,507 ± 8,350 vs. Land: 9,908 ± 4,738 vs. 32°C: 13,840 ± 5,861 1/s, P < 0.001). Retrograde diastolic shear was greater during 32°C than both Land and 38°C conditions (32°C:-3,869 ± 2,198 vs. Land:-1,602 ± 1,334 vs. 32°C:-1,036 ± 1,754, P < 0.01). FMD increased as a result of 38°C (6.2 ± 1.9 vs. 8.5 ± 2.7%, P = 0.03), with no change in the Land exercise (6.3 ± 2.4 vs. 7.7 ± 2.4%, P = 0.10) or 32°C condition (6.4 ± 3.2 vs. 6.7 ± 3.2%, P = 0.99). Our findings indicate that cycle exercise in hot water attenuates retrograde shear, increases antegrade shear, and FMD. Exercise in 32°C water induces central hemodynamic changes relative to land-based exercise, but these do not translate to increases in FMD in either condition, likely due to the impact of increased retrograde shear. Our findings indicate that modification of shear has direct acute impacts on endothelial function in humans.

Regulation of human endothelial cell migration by oral contraceptive estrogen receptor ligands

Ethinylestradiol (EE) and estetrol (E4) are the two main estrogenic agents used in combined oral contraceptives. These compounds have different binding affinity to and efficacy on estrogen receptors (ER) subtypes. We previously reported that treatment with estrogenic agents enhances angiogenesis via nongenomic, G protein-coupled estrogen receptor (GPER)-dependent mechanisms. However, the impact of EE and E4 on human endothelial function has been little investigated. EE and E4 (10−9– 10−7 M) significantly enhanced migration of human umbilical vein endothelial cells (HUVECs) using scratch and Boyden chamber assays. Mechanistically, both agents increased accumulation of phosphorylated protein tyrosine kinase 2 on tyrosine 397 (FAK Y397), a key player in endothelial cell motility, after 30-min treatment. Treatment with increasing concentrations of EE, but not E4, enhanced accumulation of the glycolysis activator PFKFB3. Of note, effects of EE and E4 on endothelial migration and signalling proteins were abolished by addition of the GPER antagonist G36 (10−6 M). Thus, EE and E4 induced comparable endothelial responses in vitro, suggesting no apparent alterations of vascular remodelling and regeneration capacity by oral contraceptives containing these agents.

S-11-5: CLINICAL IMPLICATION OF FMD

A healthy endothelium maintains vascular tone and structure by regulating the balance between vasodilation and vasoconstriction, growth inhibition and growth promotion, antithrombosis and prothrombosis, anti-inflammation and proinflammation, and also antioxidation and pro-oxidation. The vascular endothelium is involved in the release of various vasodilators, including nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor as well as vasoconstrictors. NO plays an important role in the regulation of vascular tone, the inhibition of platelet aggregation, and the suppression of smooth muscle cell proliferation. Cardiovascular diseases are associated with endothelial dysfunction. In addition, endothelial dysfunction is an early feature of atherosclerosis and vascular diseases in humans. Therefore, it is clinically important to estimate the degree of endothelial dysfunction. Several methods have been used to assess endothelial function in humans. Measurement of flow-mediated vasodilation (FMD) using an ultrasound is noninvasive and is an accurate indicator of NO production. Measurement of FMD is widely performed as an index of conduit artery endothelial function. Several investigators have shown that FMD is an independent predictor for cardiovascular outcomes. It is thought that FMD is useful for surrogate endpoint of cardiovascular outcomes and index of atherosclerotic treatment. However, the evaluation technique by the FMD measurement system still requires skills in measurement of the vessel diameter by an ultrasound system, and is difficult to handle. In addition, there is a problem in that the technique requires a large-scale apparatus and lacks in simplicity. In this session, we would like to explain in detail concerning the methods of assessing and clinical importance of endothelial function, especially FMD.

The health benefits of anthocyanins: an umbrella review of systematic reviews and meta-analyses of observational studies and controlled clinical trials.

Anthocyanins (ACNs) are phenolic compounds present in foods and have undefined health benefits. The present umbrella review aimed to analyze the effects of ACNs on multiple aspects of human health (from systematic reviews and meta-analyses [SRMs] of randomized controlled trials [RCTs]), and the associations of ACNs with the risk of various diseases (from SRMs of observational studies [OSs]). Following the PRISMA methodology, the PubMed, SCOPUS, and Cochrane databases were searched up to November 1, 2020 for OS-SRMs and RCT-SRMs that examined the effects of ACNs on health. The risk of bias of RCT-SRMs was assessed using the AMSTAR 2, and that of OS-SRMs was assessed using the Joanna Briggs Institute methodology. Based on 5 OS-SRMs (57 studies and 2 134 336 participants), ACNs of various sources were significantly associated with a reduction in the risks of hypertension and type 2 diabetes mellitus. According to 8 RCT-SRMs (139 interventions and >4984 participants), ACNs improved plasmatic lipids, glucose metabolism, and endothelial function, without affecting blood pressure. No associations between ACNs and breast or gastric cancer risks were found. ACN intake opens new pathways for the management of glucose metabolism, the plasmatic lipid profile, and the improvement of endothelial function in humans.

Comparison of the radial and brachial artery flow-mediated dilation in patients with hypertension.

Blood flow-mediated dilation (FMD) is a noninvasive assessment of vascular endothelial function in humans. The study of the FMD in hypertensive (HT) patients is an important factor supporting the recognition of the early mechanisms of cardiovascular pathologies, and also of the pathogenesis related to hypertension. To investigate whether FMD measured on the radial artery (FMD-RA) using high-frequency ultrasounds can be used as an alternative to FMD assessed with the lower frequency system on the brachial artery in patients with HT. The simultaneous measurements of FMD-RA and FMD measurements in the brachial artery (FMD-BA) were performed on 76 HT patients using 20 MHz and 7-12 MHz linear array probes, and were compared to the FMD measured in healthy groups. All quantitative data are presented as mean ± standard deviation (SD); the p-values of the normality and tests for variables comparisons are listed. The agreement of the FMD-RA and FMD-BA in HT patients was assessed with the Bland-Altman method, and using the intraclass correlation coefficient (ICC). In some statistical calculations, the FMD-RA values were rescaled by dividing them by a factor of 2. The mean FMD-RA and FMD-BA in HT patients were 5.16 ±2.18% (95% confidence interval (95% CI): [4.50%, 5.82%]) and 2.13 ±1.12% (95% CI: [1.76%, 2.49%]), respectively. The FMD-RA and FMD-BA values of HT patients were significantly different than those in respective control groups. The p-values of Mann-Whitney-Wilcoxon tests were less than 0.05. The Bland-Altman coefficient for both measurement methods, FMD-RA and FMD-BA, was 3%, and the ICC was 0.69. Our findings show that FMD-RA, supplementary to FMD-BA measurements, can be used to assess endothelial dysfunction in the group of HT patients. In addition, the FMD-RA measurements met the criteria of high concordance with the FMD-BA measurements.

Statistical Inferences Using Effect Sizes in Human Endothelial Function Research

IntroductionMagnitudes of change in endothelial function research can be articulated using effect size statistics. Effect sizes are commonly used in reference to Cohen’s seminal guidelines of small (d = 0.2), medium (d = 0.5), and large (d = 0.8). Quantitative analyses of effect size distributions across various research disciplines have revealed values differing from Cohen’s original recommendations. Here we examine effect size distributions in human endothelial function research, and the magnitude of small, medium, and large effects for macro and microvascular endothelial function.MethodsEffect sizes reported as standardized mean differences were extracted from meta research available for endothelial function. A frequency distribution was constructed to sort effect sizes. The 25th, 50th, and 75th percentiles were used to derive small, medium, and large effects. Group sample sizes and publication year from primary studies were also extracted to observe any potential trends, related to these factors, in effect size reporting in endothelial function research.ResultsSeven hundred fifty-two effect sizes were extracted from eligible meta-analyses. We determined small (d = 0.28), medium (d = 0.69), and large (d = 1.21) effects for endothelial function that corresponded to the 25th, 50th, and 75th percentile of the data distribution.ConclusionOur data indicate that direct application of Cohen’s guidelines would underestimate the magnitude of effects in human endothelial function research. This investigation facilitates future a priori power analyses, provides a practical guiding benchmark for the contextualization of an effect when no other information is available, and further encourages the reporting of effect sizes in endothelial function research.

Hesperidin in orange juice improves human endothelial function in subjects with elevated blood pressure and stage 1 hypertension: A randomized, controlled trial (Citrus study)

In a randomized, parallel, double-blind, placebo-controlled trial, participants with elevated blood pressure and stage 1 hypertension (n = 159) received 500 mL/day of control drink, orange juice (OJ), or hesperidin-enriched OJ (EOJ) for 12-weeks, and their ischaemic reactive hyperemia (IRH) was assessed at baseline and after 4, 8, and 12-weeks. Two dose–response studies were nested within the sustained-consumption study: at baseline and after 12-weeks, a single dose of 500 mL was administered. All treatments increased postpandrial IRH, and a higher increase was obtained with EOJ. Moreover, hs-CRP and IL6 increased but not after EOJ. After 12 weeks of sustained consumption: IRH values after EOJ increased versus control group; EOJ treatment increased DSP and decreased IEX-1 gene expression in PBMCs; and IRH directly correlated to NO and inversely to MPO and IEX1. Thus, hesperidin in OJ improves human endothelial function, lower inflammatory status at systemic level and changes at transcriptomic level might account for the increased IRH observed.

Tubulin-folding cofactor E deficiency promotes vascular dysfunction by increased endoplasmic reticulum stress.

AimsAssessment of endothelial function in humans by measuring flow-mediated dilation (FMD) risk-stratifies individuals with established cardiovascular disease, whereas its predictive value is limited in primary prevention. We therefore aimed to establish and evaluate novel markers of FMD at the population level.Methods and resultsIn order to identify novel targets that were negatively correlated with FMD and investigate their contribution to vascular function, we performed a genome-wide association study (GWAS) of 4175 participants of the population based Gutenberg Health Study. Subsequently, conditional knockout mouse models deleting the gene of interest were generated and characterized. GWAS analysis revealed that single-nucleotide polymorphisms (SNPs) in the tubulin-folding cofactor E (TBCE) gene were negatively correlated with endothelial function and TBCE expression. Vascular smooth muscle cell (VSMC)-targeted TBCE deficiency was associated with endothelial dysfunction, aortic wall hypertrophy, and endoplasmic reticulum (ER) stress-mediated VSMC hyperproliferation in mice, paralleled by calnexin up-regulation and exacerbated by the blood pressure hormone angiotensin II. Treating SMMHC-ERT2-Cre+/−TBCEfl/fl mice with the ER stress modulator tauroursodeoxycholic acid amplified Raptor/Beclin-1-dependent autophagy and reversed vascular dysfunction.ConclusionTBCE and tubulin homeostasis seem to be novel predictors of vascular function and offer a new drug target to ameliorate ER stress-dependent vascular dysfunction.

The effects of alcohol consumption on flow-mediated dilation in humans: A systematic review.

Changes in endothelial function may contribute to the positive and negative effects of alcohol consumption on cardiovascular conditions, such as hypertension and coronary artery disease. Numerous studies have used brachial artery flow‐mediated dilation (FMD) to examine the effects of alcohol consumption on endothelial function in humans. However, the findings are inconsistent and may be due to multiple factors such as heterogeneity in subject characteristics, the alcohol use pattern, and amount/dose of alcohol consumed. Therefore, the aim of this systematic review was to investigate the effect of alcohol consumption on brachial artery FMD in humans considering the above‐mentioned factors. This review found that while light to moderate alcohol consumption may have minimal effects on FMD, heavy alcohol consumption was associated with a decrease in FMD. However, most of the published studies included healthy, younger, and male individuals, limiting generalizability to other populations. Future studies should include more women, older subjects, and those from diverse and underrepresented backgrounds.

Sex‐specific associations of circulating soluble prorenin receptor with cardiometabolic risk factors among healthy women and men

The prorenin receptor (PRR), a component of the renin angiotensin system, is involved in blood pressure control, fluid homeostasis, tissue development and vesicular trafficking and play an important role in cardiovascular diseases. PRR can be cleaved to generate soluble PRR (sPRR) in plasma. sPRR concentrations vary with clinical conditions such as metabolic syndrome, pregnancy, chronic kidney disease and heart failure in humans. However, whether sPRR is associated with aging and healthy obesity in men and women is unknown. We aimed to evaluate if there are sex-specific associations of sPRR with cardiometabolic risk factors among healthy women and men varying in age and obesity. Circulating cardiometabolic, vascular and inflammatory risk factors and sPRR (via ELISA) were measured in unmedicated healthy men (n=55; age 39 ± 16 yrs; BMI 29 ± 4 kg/m2) and women (n=34; age 44 ± 16 yrs; BMI 30 ± 7 kg/m2) at the University of Iowa. Women were classified by menopausal status [non-menopausal, non-M (n=18) and post-menopausal, post-M (n=16)]. Independent t-test was used to compare means and pearson correlation was examined. In men, sPRR was not related to age, systolic blood pressure (SBP), BMI, cholesterol or endothelial function (brachial artery flow mediated dilation, FMD), but was correlated with plasma TNFα (r=0.50, P<0.05). sPRR was higher in overweight/obese (BMI ≥ 25 kg/m2) compared with non-obese men (n=48; 10.8 ± 0.4 vs. n=7; 8.3 ± 0.4 ng/ml, P<0.05). In women, sPRR did not correlate with BMI or SBP, but correlated with total cholesterol (r=0.49, P<0.05) and TNFα (r=0.49, P<0.05). sPRR correlated with age in women with a BMI<30 (r=0.54, P<0.05) but not a BMI ≥30 kg/m2. sPRR was significantly higher in post-M compared with non-M women independent of obesity or hypertension status (12.1 ± 0.5 vs. 10.1 ± 0.4 ng/ml, P<0.05). sPRR correlated with FMD only in obese women (%FMD: r=-0.50, P<0.05), indicating a relation of sPRR with endothelial dysfunction in obese women. Interestingly, sPRR was significantly higher in non-M compared with non-obese men, and menopause further exacerbated the difference. In conclusion, sPRR is associated with TNFα in both men and women, but there are sex differences in the relation with BMI, age, cholesterol and endothelial function in humans. sPRR concentrations were higher in post-M compared with non-M women, suggesting that PRR could contribute to cardiovascular risk in post-M women.

Inorganic Nitrite Supplementation Improves Endothelial Function With Aging: Translational Evidence for Suppression of Mitochondria-Derived Oxidative Stress.

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Adipocytokines in Diabetes Mellitus: A Study from a Rural Setting in Haryana, India

Introduction: Diabetes Mellitus (DM) and Obesity are the biggest public health challenges of 21st century. Both these disorders are associated with several co-morbidities like hypertension, hyperlipidemia, Cardiovascular Diseases (CVD) etc., that may be linked to the underlying insulin resistance, hyperglycaemia, dyslipidemia, hyperinsulinemia and altered levels of adipocyte- derived hormones. Furthermore, clinical studies in humans have suggested the possible correlation of plasma concentration of several adipocytokines and measures of adiposity, insulin resistance and endothelial function in humans. Aim: To estimate and compare the serum levels of leptin and adiponectin in patients with Type 2 Diabetes Mellitus (T2DM) and in non-diabetic subjects with and without obesity. Materials and Methods: In the study, 200 T2DM patients (with and without obesity) and 200 non-diabetic subjects (with and without obesity) aged between 30-70 years of either sex were included. In all the subjects included in the study, serum leptin and adiponectin levels were estimated using Enzyme Linked Immunosorbent Assay (ELISA) method. Results: It was observed that the serum adiponectin levels decreased while leptin levels increased significantly (p&lt;0.001) in obese than non-obese diabetics. Similarly, obese non-diabetics showed higher serum leptin and lower adiponectin levels than their non-obese counterparts (p&lt;0.001). Conclusion: Serum levels of leptin and adiponectin are altered in subjects with T2DM and obesity which may indicate the potential role of adipocytokines as an important link between increased fat mass, insulin resistance, deranged glucose metabolism and endothelial dysfunction especially in diabetic patients.

Overview of the Assessment of Endothelial Function in Humans.

The endothelium is recognized to play an important role in various physiological functions including vascular tone, permeability, anticoagulation, and angiogenesis. Endothelial dysfunction is increasingly recognized to contribute to pathophysiology of many disease states, and depending on the disease stimuli, mechanisms underlying the endothelial dysfunction may be markedly different. As such, numerous techniques to measure different aspects of endothelial dysfunction have been developed and refined as available technology improves. Current available reviews on quantifying endothelial dysfunction generally concentrate on a single aspect of endothelial function, although diseases may affect more than one aspect of endothelial function. Here, we aim to provide an overview on the techniques available for the assessment of the different aspects of endothelial function in humans, human tissues or cells, namely vascular tone modulation, permeability, anticoagulation and fibrinolysis, and the use of endothelial biomarkers as predictors of outcomes.

Abstract P246: Sex Differences In The Association Between Soluble Prorenin Receptor And Physiological And Cardiometabolic Risk Factors In Healthy Humans Varying In Age And Obesity

The prorenin receptor (PRR), which regulates renin-angiotensin system in multiple tissues, can be cleaved to generate soluble PRR (sPRR) in plasma. sPRR concentrations vary with clinical conditions such as metabolic syndrome, pregnancy, chronic kidney disease and heart failure in humans. However, whether sPRR is associated with aging and healthy obesity in men and women is unknown. We aimed to evaluate if there are sex-specific associations of sPRR with cardiometabolic risk factors among healthy women and men varying in age and obesity. Circulating cardiometabolic, vascular and inflammatory risk factors and sPRR (via ELISA) were measured in unmedicated healthy men (n=55; age 39 ± 16 yrs; BMI 29 ± 4 kg/m2) and women (n=34; age 44 ± 16 yrs; BMI 30 ± 7 kg/m2) at the University of Iowa. Women were classified by menopausal status [pre-menopausal, pre-M (n=18) and post-menopausal, post-M (n=16)]. Independent t -test was used to compare means and pearson correlation was examined. In men, sPRR was not related to age, systolic blood pressure (SBP), BMI, cholesterol or endothelial function (brachial artery flow mediated dilation, FMD), but was correlated with plasma TNFα (r=0.50, P&lt;0.05). sPRR was higher in overweight/obese (BMI ≥ 25 kg/m2) compared with non-obese men (n=48; 10.8 ± 0.4 vs. n=7; 8.3 ± 0.4 ng/ml, P&lt;0.05). In women, sPRR did not correlate with BMI or SBP, but correlated with total cholesterol (r=0.49, P&lt;0.05) and TNFα (r=0.49, P&lt;0.05). sPRR correlated with age in women with a BMI&lt;30 (r=0.54, P&lt;0.05) but not a BMI ≥30 kg/m2. sPRR was significantly higher in post-M compared with Pre-M women independent of obesity or hypertension status (12.1 ± 0.5 vs. 10.1 ± 0.4 ng/ml, P&lt;0.05). sPRR correlated with FMD only in obese women (%FMD: r=-0.50, P&lt;0.05), indicating a relation of sPRR with endothelial dysfunction in obese women. Interestingly, sPRR was significantly higher in Pre-M compared with non-obese men and menopause further exacerbated the difference. In conclusion, sPRR is associated with TNFα in both men and women, but there are sex differences in the relation with BMI, age, cholesterol and endothelial function in humans. sPRR concentrations were higher in post-M compared with pre-M women, suggesting that PRR could contribute to cardiovascular risk in post-M women.

Coffee and Endothelial Function: A Coffee Paradox?

Coffee is a popular beverage throughout the world. Coffee contains various chemical compounds (e.g., caffeine, chlorogenic acids, hydroxyhydroquinone, kahweol, cafestol, and complex chemical mixtures). Caffeine is also the most widely consumed pharmacological substance in the world and is included in various beverages (e.g., coffee, tea, soft drinks, and energy drinks), products containing chocolate, and drugs. The effects of coffee and caffeine on cardiovascular diseases remain controversial. It is well known that there are J-curve-type or U-curve-type associations of coffee consumption with cardiovascular events including myocardial infarction and stroke. However, there is little information on the direct and indirect effects of coffee consumption on endothelial function in humans. It is likely that the coffee paradox or caffeine paradox exists the association of coffee intake with cardiovascular diseases, cardiovascular outcomes, and endothelial function. This review focusses on the effects of coffee and caffeine on endothelial function from molecular mechanisms to clinical perspectives.

New Methods to Evaluate Endothelial Function: Non-invasive Method of Evaluating Endothelial Function in Humans

New Methods to Evaluate Endothelial Function: Non-invasive Method of Evaluating Endothelial Function in Humans

Shear stress and flow-mediated dilation in the normoxic and hypoxic human.

The endothelium is a single cell layer that plays a critical role in determining the health and function of blood vessels. Endothelial function is shaped by shear stress, the frictional force exerted by the speed of blood flow, and the thickness (viscosity) of the blood. Exposure to shear stress that reverses direction back-and-forth impairs endothelial function in young men. Whether women are equally susceptible to this perturbation and the isolated impact of a low level of shear stress with and without reversal of shear had not been investigated. Hypoxia, the low levels of oxygen that are experienced at high altitude, has been shown to influence flow reversal and impair endothelial function. However, no previous study had accounted for the changes in blood thickness, and hence shear stress that occur at high altitude. This may be especially important in the context of excessive erythrocytosis, a high-altitude disease characterized by exceptionally thick blood and increased cardiovascular risk. This thesis examined (i) whether there are sex differences in the impact of exposure to low and reversing shear stress on endothelial function; (ii) whether isolated low shear stress impairs endothelial function; (iii) the impact of reversing shear stress on endothelial function in short-term exposure to low levels of oxygen and after trekking to 5050 m in the Himalayas; and (iv) the role of high levels of blood viscosity on endothelial function in high-altitude natives in Cerro de Pasco, Peru (4330 m), with excessive erythrocytosis. We identified that (i) premenopausal women have some protection against reductions in endothelial function after being exposed to reversing shear stress; (ii) isolated low shear stress impaired endothelial function; (iii) short-term exposure to low levels of oxygen and sustained high-altitude exposure reduced endothelial function, while superimposing reversing shear stress had no effect; and (iv) high levels of hemoglobin and blood viscosity contributed to lower endothelial function in Andean high-altitude natives with excessive erythrocytosis. Altogether, this dissertation advances our understanding of how the components of shear stress (the pattern, magnitude, and blood viscosity) impact endothelial function in humans under normoxic (normal levels of oxygen) and hypoxic (low levels of oxygen, such as high-altitude) conditions.

Effect of Heating Duration on Brachial Artery Endothelial Function in Humans

Effect of Heating Duration on Brachial Artery Endothelial Function in Humans