Impaired Flow-mediated Dilation Research Articles

ARGININE METABOLISM AND ARTERIAL STIFFNESS IN HIGHLANDERS WITH HIGH ALTITUDE POLYCYTHEMIA

Objective: High altitude polycythemia (HAPC) is a health condition associated with hypoxemia and erythrocytosis. Patients with chronic hypoxemia often exhibit arterial stiffness. In the advanced stages of HAPC, patients can present changes in the pulmonary circulation, but limited information exists regarding arterial stiffness. Our study aims to investigate the relationship between HAPC and arterial stiffness, and explore the underlying mechanisms. Design and method: At an altitude of 3500m, we conducted a study examining arterial stiffness and vascular endothelial function in two groups of hypertensive highlanders with and without HAPC, each consisting of 30 participants. Plasma samples were measured using Ultra Performance Liquid Chromatography Tandem Mass Spectroscopy. Results: Hypertensive highlanders with HAPC exhibited notable vascular dysfunction, as indicated by significantly impaired flow-mediated dilation (FMD) (3.97±1.21% vs. 6.82±1.46%, P < 0.001), and higher brachial-ankle pulse wave velocity (BaPWV) (1556±239 cm/s vs. 1890±459 cm/s, P < 0.001). Metabolomics analysis revealed alterations in arginine/proline metabolism and the arginine biosynthesis pathway, involving L-arginine, L-ornithine, creatine and 4-guanidinobutanoic acid. The area under the curve (AUC) values for 4 metabolites and L-arginine/L-ornithine ratio were 0.753, 0.782, 0.720, 0.717 and 0.819, respectively. Pearson correlation analysis showed that L-arginine, L-ornithine, and L-arginine/L-ornithine ratio were associated with BaPWV (r=-0.4486, P=0.00032; r=0.3400, P=0.0078; r=0.3921, P=0.0019). L-arginine, L-ornithine, 4-guanidinobutanoic acid, creatine, and L-arginine/L-ornithine ratio were correlated with FMD. Multiple linear regression analysis revealed that L-arginine and L-arginine/L-ornithine ratio were independently correlated with BaPWV (beta= -0.370, t=-3.114, P=0.003; beta=-0.268, t=-2.211, P=0.032) and FMD (beta=0.434, t=3.114, P=0.003; beta= 0.457, t=3.445, P=0.001), but L-ornithine was not independently related to BaPWV and FMD. Conclusions: Our study indicates that HAPC may accelerate the progression of arterial stiffness in hypertensive patients. In fact, L-arginine takes an important role in the forming of NO in vascular endothelium. So The disorder of arginine metabolism may serve as the underlying metabolic mechanism.

Impaired brachial flow-mediated dilation may predict choroidal and retinal nerve fibre layer thickness changes in people with obesity

ABSTRACT Clinical relevance Choroidal thickness and peripapillary retinal nerve fibre layer (RNFL) changes are known to occur in obesity. Endothelial dysfunction and systemic atherosclerosis may play a role in the pathophysiology of these differences. Background Flow-mediated dilation (FMD) is reduced in patients with endothelial dysfunction, and the ankle-brachial index is a surrogate marker for atherosclerosis. This study was conducted to examine the relationship between systemic vascular parameters (FMD, and ankle-brachial index), subfoveal choroidal thickness, and peripapillary RNFL thickness in obese individuals. Methods This observational, cross-sectional study involved 108 total participants who were divided into two groups. One group consisted of 54 obese subjects who each had a body mass index of 30 kg/m2 or more. The other control group contained 54 participants who each had a body mass index of 25 kg/m2 or less but higher than 20 kg/m2 . For each participant, only one eye was examined in this study. Subfoveal choroidal thickness, RNFL thickness, ankle-brachial index, and ultrasound measurement of the brachial artery FMD were performed. FMD was categorised according to receiver operating characteristic analysis, and endothelial dysfunction was defined as an FMD ≤ 7.29%. Results Subfoveal choroidal and RNFL thicknesses in the temporal quadrant were significantly lower in the obese group (p < 0.05). Lower mean values of subfoveal choroidal and RNFL thicknesses in the temporal and inferior quadrants were observed in subjects with an FMD ≤ 7.29% (p < 0.05). In people with obesity, FMD was positively correlated with subfoveal choroidal thickness (r = 0.322, p = 0.001), inferior RNFL thickness (r = 0.259, p = 0.007), and temporal RNFL thickness (r = 0.297, p = 0.002). However, the ankle-brachial index was not correlated with obesity. Conclusions Impaired FMD was associated with reduced subfoveal choroidal and RNFL thicknesses in the temporal and inferior quadrants of people with obesity.

Brachial artery FMD and carotid artery IMT in glaucoma

Aims/Purpose: The purpose of the study was to assess the ultrasound measurements of the brachial artery flow‐mediated dilation (FMD) and carotid artery intima‐media thickness (IMT) and their relationship in glaucoma patients.Methods: Thirty‐seven patients with glaucoma and thirty‐one healthy controls were included in the study. All glaucoma patients and controls underwent ultrasound measurement of FMD of the brachial artery and ultrasound measurement of IMT of the carotid artery.Results: The mean values of brachial FMD were significantly lower among the glaucoma compared with controls (15.3 ± 9.5% vs 19.8 ± 9.3%, p = 0.04). No significant difference was found in carotid IMT (1.2 ± 0.4 vs. 1.1 ± 0.3, p = 0.4), and brachial artery diameter at rest (4.7 ± 0.6 vs. 4.9 ± 0.3, p = 0.2) between the glaucoma patients and controls. The significant difference in brachial artery diameter in hyperemia between the glaucoma patients and controls (5.4 ± 0.6 vs. 5.9 ± 0.4, p = 0.002) was found. A negative correlation among brachial FMD and carotid IMT as well as among brachial FMD and brachial artery diameter at rest was found.Conclusions: Impaired brachial FMD indicates presence of systemic vascular endothelial dysfunction in glaucoma; glaucoma patients with lower values of the brachial FMD are at increased risk of having thickened carotid IMT.

Impairment of Endothelial Function by Aerosol From Marijuana Leaf Vaporizers.

Marijuana leaf vaporizers, which heat plant material and sublimate Δ-9-tetrahydrocannabinol without combustion, are popular alternatives to smoking cannabis that are generally perceived to be less harmful. We have shown that smoke from tobacco and marijuana, as well as aerosol from e-cigarettes and heated tobacco products, impair vascular endothelial function in rats measured as arterial flow-mediated dilation (FMD). We exposed 8 rats per group to aerosol generated by 2 vaporizer systems (Volcano and handheld Yocan) using marijuana with varying Δ-9-tetrahydrocannabinol levels, in a single pulsatile exposure session of 2 s/min over 5 minutes, and measured changes in FMD. To model secondhand exposure, we exposed rats for 1 minute to diluted aerosol approximating release of uninhaled Volcano aerosol into typical residential rooms. Exposure to aerosol from marijuana with and without cannabinoids impaired FMD by ≈50%. FMD was similarly impaired by aerosols from Yocan (237 °C), and from Volcano at both its standard temperature (185 °C) and the minimum sublimation temperature of Δ-9-tetrahydrocannabinol (157 °C), although the low-temperature aerosol condition did not effectively deliver Δ-9-tetrahydrocannabinol to the circulation. Modeled secondhand exposure based on diluted Volcano aerosol also impaired FMD. FMD was not affected in rats exposed to clean air or water vapor passed through the Volcano system. Acute direct exposure and modeled secondhand exposure to marijuana leaf vaporizer aerosol, regardless of cannabinoid concentration or aerosol generation temperature, impair endothelial function in rats comparably to marijuana smoke. Our findings indicate that use of leaf vaporizers is unlikely to reduce the vascular risk burden of smoking marijuana.

The effect of anthracycline-based chemotherapy on endothelial function and arterial stiffness in breast cancer patients

Abstract Introduction Cardiotoxicity restricts anthracycline and trastuzumab treatment of Human Epidermal Growth Factor Receptor 2 positive early breast cancer. Endothelial dysfunction and arteriosclerosis are significant cardiovascular risk factors. Purpose We studied the effect of anthracycline-based chemotherapy, with or without trastuzumab, on endothelium and arteriosclerosis in patients with breast cancer. Methods In this case-control study, 52 women with breast cancer and 104 women without breast cancer were examined longitudinally up to 15 months following (in the breast cancer group) initiation of chemotherapy. Arterial stiffness was evaluated through pulse wave velocity (PWV), while endothelial function via flow-mediated dilatation (FMD) at baseline (T0), 3 (T1), 6 (T2), and 15 (T3) months later. Results There was no difference between subjects with breast cancer and control in PWV and FMD at baseline. Longitudinally, participants with breast cancer exhibited considerable impairment of PWV and FMD compared to the control group (p for interaction &amp;lt; 0.001 for both parameters). In breast cancer patient there was a significant increase from T0 to T3 in PWV (7.43 ± 1.68 m/sec vs. 8.18 ± 2.00 m/sec, p = 0.01) and decrease in FMD (6.95 ± 2.86 % vs. 5.03 ± 2.83 %, p = 0.006). The addition of trastuzumab in the treatment did not have any effect on PWV (p = 0.74) or FMD (p = 0.91). Conclusions In patients with breast cancer, there is progression of endothelial dysfunction and arteriosclerosis up to 15 months following initiation of anthracycline-based chemotherapy. Trastuzumab has no additive effect on endothelial function or arterial stiffness.Figure 1Figure 2

Fat intake impairs the recovery of endothelial function following mental stress in young healthy adults.

Mental stress has been identified as a trigger of cardiovascular events. A single episode of stress can induce acute impairments in endothelial function in healthy adults. Importantly, during stressful periods, individuals often resort to unhealthy behaviors, such as increased consumption of high-fat foods, which is also known to negatively impact endothelial function. Therefore, this study examined whether consumption of a high-fat meal would further exacerbate the negative effect of mental stress on vascular function. In a randomized, counterbalanced, cross- over, postprandial intervention study, 21 healthy males and females ingested a high-fat (56.5 g fat) or a low-fat (11.4 g fat) meal 1.5 h before an 8-min mental stress task (Paced-Auditory-Serial-Addition-Task, PASAT). Plasma triglyceride (TAG) concentration was assessed pre-and post-meal. Forearm blood flow (FBF), blood pressure (BP), and cardiovascular activity were assessed pre-meal at rest and post-meal at rest and during stress. Endothelial function, measured by brachial flow-mediated dilatation (FMD) was assessed pre-meal and 30 and 90 min following mental stress. Plasma TAG concentration was significantly increased following the high-fat meal compared to the low-fat condition. Mental stress induced similar increases in peripheral vasodilation, BP, and cardiovascular activity, and impaired FMD 30 min post-stress, in both conditions. FMD remained significantly impaired 90 min following stress in the high-fat condition only, suggesting that consumption of fat attenuates the recovery of endothelial function following mental stress. Given the prevalence of fat consumption during stressful periods among young adults, these findings have important implications for dietary choices to protect the vasculature during periods of stress.

Non-alcoholic fatty liver disease and compromised endothelial function in people with type 2 diabetes

IntroductionNonalcoholic fatty liver disease (NAFLD) frequently coexists with type 2 diabetes mellitus (T2DM) and synergistically contributes to the development of atherosclerosis. Flow-mediated dilation (FMD) is a commonly used noninvasive test for assessing endothelial function. The main objective of this study was to explore FMD in patients with T2DM with and without NAFLD.MethodsIn this cross-sectional study, conducted on people with T2DM, NAFLD was defined as controlled attenuation parameter (CAP) score > 302 dB/m. Endothelial dysfunction was detected when arterial FMD of brachial artery was equal or less than 0.7%. Regression analyses were applied to assess factors associated with impaired FMD.ResultA total of 147 patients (72 with NAFLD and 75 without NAFLD) were included in the final analysis. Patients with NAFLD were more likely to develop FMD ≤ 7% (77.8% vs. 58.7%, P = 0.01). In multivariate analysis, NAFLD (OR = 2.581, 95% CI (1.18–5.62), P = 0.017) and hypertension (HTN) (OR = 3.114, 95% CI (1.31–7.35), P = 0.010) were associated with an increased risk of impaired FMD. However, female sex was associated with a decreased risk of impaired FMD (OR = 0.371, 95% CI (0.15–0.87), P = 0.024).ConclusionNAFLD is associated with endothelial dysfunction in people with T2DM. This risk is comparable with the risk imposed by HTN, highlighting the importance of screening and management of NAFLD in these patients.

Oral inflammatory load predicts vascular function in a young adult population: a pilot study.

The periodontium is a highly vascularized area of the mouth, and periodontitis initiates negative functional and structural changes in the vasculature. However, mild oral inflammation, including levels experienced by many apparently healthy individuals, has an unclear impact on cardiovascular function. The purpose of this pilot study is to investigate the effects of objectively measured whole mouth oral inflammatory load (OIL) on vascular function in apparently healthy individuals. In this cross-sectional and correlational analysis, we recruited 28 young (18-30 years) and systemically healthy participants (16 male, 12 female). Using oral neutrophil counts, a validated measure for OIL, we collected participant's mouth rinse samples and quantified OIL. Blood pressure, arterial stiffness (pulse-wave velocity) and endothelial function (brachial artery flow-mediated dilation) were also measured. Only oral neutrophil count significantly predicted flow-mediated dilation % (p = 0.04; R2 = 0.16, β = - 1.05) and those with OIL levels associated with >2.5 × 105 neutrophil counts (n = 8) had a lower flow-mediated dilation % (6.0 ± 2.3%) than those with counts associated with gingival health with less than 2.5 × 105 neutrophil counts (10.0 ± 5.2%, p = 0.05). There were no significant predictors for arterial stiffness. We found that OIL was a predictor of reduced flow-mediated dilation. An impairment in flow-mediated dilation is an indicator of future possible risk of cardiovascular disease-one of the leading causes of death in North America. Therefore, this study provides evidence for the importance of oral health and that OIL may impact endothelial function.

Endothelial Dysfunction and Cardiometabolic Risk Factors in Mexican American Adults: The Cameron County Hispanic Cohort

Endothelial dysfunction assessed by impaired brachial flow-mediated dilation (FMD) predicts incident cardiovascular disease (CVD). We have previously shown that clustering of diabetes mellitus, obesity, and metabolic syndrome in young Hispanic patients was associated with subclinical atherosclerosis. This study aimed to assess determinants of impaired FMD response (%FMD), an earlier marker of atherosclerosis, in a population-based sample of asymptomatic Mexican Americans. Cardiometabolic biomarkers and FMD were obtained from 960 Cameron County Hispanic Cohort participants. Gender-specific median values of %FMD were used to categorize participants into those with %FMD below or above the median. The sample was further stratified into those younger and older than 55years. Survey-weighted logistic regression analyses were conducted to evaluate the effects of cardiometabolic biomarkers on the %FMD groups. The low %FMD group was significantly older, had higher visceral adipose tissue, systolic blood pressure, or plasma glucose, and had metabolic syndrome compared with those in the high %FMD group. Multivariable-adjusted age-stratified logistic regression analyses showed that in older participants, male gender (odds ratio [OR]=2.4 [1.4 to 4.2]) and having hypertension (OR=2.3 [1.3 to 4.3]) or prediabetes mellitus (OR=3.4 [1.5 to 7.5]) remained significantly associated with odds of low %FMD. In younger participants, high low-density lipoprotein (OR=2.8 [1.6 to 4.9]) or having the metabolic syndrome (OR=1.9 [1.1 to 3.6]) were significantly associated with odds of low %FMD. In conclusion, we found age-dependent associations between cardiometabolic biomarkers and an FMD response below the gender-specific median in a sample composed of Mexican Americans without previous CVD. Targeting specific risk factors by age may mitigate progression to incident CVD in this high-risk racial disparity group.

Prolonged impact of anti-cancer therapy on endothelial function and arterial stiffness in breast cancer patients

BackgroundCardiotoxicity restricts anthracycline and trastuzumab treatment of Human Epidermal Growth Factor Receptor 2 positive early breast cancer. Endothelial dysfunction and arteriosclerosis are significant cardiovascular risk factors. ObjectivesWe studied the effect of anthracycline-based chemotherapy, with or without trastuzumab, on endothelium and arteriosclerosis in patients with breast cancer. MethodsIn this case-control study, 52 women with breast cancer and 104 women without breast cancer were examined longitudinally up to 15 months following (in the breast cancer group) initiation of chemotherapy. Arterial stiffness was evaluated through pulse wave velocity (PWV), while endothelial function via flow-mediated dilatation (FMD) at baseline (T0), 3 (T1), 6 (T2), and 15 (T3) months later. ResultsThere was no difference between subjects with breast cancer and control in PWV and FMD at baseline. Longitudinally, participants with breast cancer exhibited considerable impairment of PWV and FMD compared to the control group (p for interaction <0.001 for both parameters). In breast cancer patients, there was a significant increase from T0 to T3 in PWV (7.43 ± 1.68 m/s vs. 8.18 ± 2.00 m/s, p = 0.01) and decrease in FMD (6.95 ± 2.86% vs. 5.03 ± 2.83%, p = 0.006). The addition of trastuzumab in the treatment did not have any effect on PWV (p = 0.74) or FMD (p = 0.91). ConclusionsIn patients with breast cancer, there is progression of endothelial dysfunction and arteriosclerosis up to 15 months following initiation of anthracycline-based chemotherapy. Trastuzumab has no additive effect on endothelial function or arterial stiffness.

The relationship between circadian rhythm of blood pressure and vascular dysfunction in essential hypertension

ABSTRACT Objective This study aimed to explore whether circadian rhythm of blood pressure is associated with brachial-ankle pulse wave velocity (baPWV) and brachial artery flow-mediated dilation (FMD) in patients with essential hypertension. Method This cross-sectional study included 4,217 patients with essential hypertension who completed 24-hour ambulatory blood pressure monitoring, baPWV, and FMD. BaPWV and FMD were measured to evaluate arterial stiffness and endothelial dysfunction. Participants were divided into dipper, non-dipper, and reverse dipping groups according to the nocturnal systolic blood pressure dipping percentage. Results In this study, baPWV was highest in the reverse dipping groups, followed by non-dipper and dipper groups (1667.11 ± 327.90 vs. 1613.88 ± 325.11 vs. 1577.45 ± 306.15 cm/s, P < .001) and FMD gradually increased (4.41 ± 2.87 vs. 4.70 ± 2.84 vs. 4.92 ± 2.79%, P = .001). baPWV and FMD were significantly associated with declining nocturnal systolic blood pressure (SBP). Interestingly, FMD (β = 0.042, P = .014) was only positively associated with a drop in nocturnal SBP decline in patients <65 years of age. Whereas baPWV was consistently negatively associated with nocturnal SBP decline regardless of age (β = -0.065, P < .001, age <65 years; β = -0.149, P = .002, age ≥ 65). Receiver operating characteristics (ROC) curves analysis showed areas under the curve (AUC) of baPWV/FMD for predicting circadian rhythm of blood pressure are 0.562/0.554 with a sensitivity of 51.7%/53.9% and specificity of 56.4%/53.4. Conclusion Impairment of baPWV and FMD were correlated with abnormal circadian rhythm of blood pressure in essential hypertension, suggesting a decrease in nighttime SBP may associate with endothelial function and arterial stiffness.

ENDOTHELIAL FUNCTION, AS ASSESSED BY FLOW MEDIATED DILATION AND ASYMMETRIC DIMETHYLARGININE IS IMPAIRED IN NEWLY DIAGNOSED TYPE 2 DIABETES MELLITUS

Objective: Endothelial dysfunction precedes the onset of clinically detectable atherosclerosis diabetes mellitus in type 2 (T2DM) and contributes significantly to the development of vascular complications and mortality. The aim of the present study was to investigate the endothelial function in patients with a recent diagnosis of T2DM. Design and method: We studied patients with newly diagnosed T2DM (&lt;6 months from diagnosis) that did not receive antidiabetic treatment (except for metformin) and otherwise healthy individuals matched for age and blood pressure (BP). We recorded somatometric, BP (office and 24-hour) and hematological (lipids, renal function, fasting glucose, HBA1c) data. We also calculate the 10-year atherosclerotic cardiovascular risk (ASCVD risk score). We determined endothelial dysfunction with 2 methods: Asymmetric Dimethylarginine (ADMA) by ELISA (enzyme-linked immunosorbent assay) and the gold standard non-invasive method Flow Mediated Dilation (FMD). Results: Ninety subjects were studied, 33 patients with T2DM and 57 controls. Twenty T2DM patients were enrolled within 1 month from diagnosis, while the rest 13 had been diagnosed 3.69±2.14 months before. Similarly, 16 (48.48%) had received metformin for a median of 3 (interquartile range 18) weeks. T2DM showed significantly impaired FMD [4.68 (4.58)% versus 7.85 (7)%, (p = 0.012)] and higher ADMA [0.926±0.569 μmol/l versus 0.468 (0.27) μmol/l, (p = 0.032)], compared to controls. There was also an independent association of T2DM and FMD (Beta = -0.278, p = 0.012). Results were similar in the sub-group analysis of patients without hypertension. In this cohort, FMD lower than 7.5% was able to predict T2DM diagnosis with 87.5% sensitivity and 70.8% specificity. Conclusions: Patients with a very recent diagnosis of T2DM show impaired endothelial function as demonstrated by FMD and ADMA findings. This assessment highlights the early severe, damaging effect of hyperglycemia on the endothelium, emphasizing the need for early detection and management.

Zanamivir infusion improves endothelial function and reduces arterial stiffness in diabetic mice

Endothelial dysfunction and arterial stiffening are consistently manifested in type 2 diabetes (T2D) and contribute to the development of cardiovascular disease. Consequently, there is an urgent need to identify novel therapies that improve endothelial function and reduce arterial stiffness in T2D. Endothelial dysfunction is characterized by a reduced capacity of the endothelium to induce vasodilation. Physiologically, this is evident as an impairment in flow-mediated dilation, a process in which the endothelial glycocalyx participates in the mechanosensation and mechanotransduction of shear that leads to the production of the vasodilator nitric oxide. Nitric oxide, in turn, has also been shown to be a potent regulator of vascular wall homeostasis, including arterial stiffness. In T2D, circulating neuraminidase activity is increased and implicated in glycocalyx degradation and endothelial dysfunction. Accordingly, we hypothesized that inhibition of neuraminidase activity would enhance endothelial function and reduce arterial stiffness in T2D. We tested this hypothesis in diabetic db/db mice infused with zanamivir (n=10) or vehicle control (n=10) for 4 weeks via subcutaneously implanted osmotic mini pumps. We chose to use the FDA approved neuraminidase inhibitor zanamivir to increase the translatability of our study. Treatment with zanamivir did not affect body weight or blood pressure. Nonetheless, it improved flow-mediated dilation in isolated mesenteric arteries assessed using pressure myography, with no associated changes in endothelium-independent vasodilation. Zanamivir also reduced stiffness in isolated mesenteric and femoral arteries, as well as aortic stiffness as assessed in vivo via pulse wave velocity and ex vivo via atomic force microscopy. These results indicate that zanamivir is a potential therapeutic to ameliorate vascular dysfunction in T2D. National Institutes of Health grant: R01HL153264 to LM-L and JP 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.

Treatment with the ADAM17 sheddase inhibitor, phosphatidylserine, improves endothelial function and reduces arterial stiffness in diabetic mice

Patients with type 2 diabetes (T2D) have an increased incidence of cardiovascular disease (CVD) morbidity and mortality. Indeed, CVD is the primary cause of death in T2D. Arterial stiffness and hypertension are both implicated in the progression of CVD in T2D. Moreover, arterial stiffening is posited to precede the development of hypertension and is associated with a higher risk for incidence of T2D. We propose that a central mediator of these pathologies is the aberrant upregulation of protein sheddase(s) that damage mechanosenstive structures in the endothelium leading to endothelial dysfunction and subsequent increased arterial stiffness. We have previously demonstrated that the sheddase/metallopeptidase, a disintegrin and matrix metalloproteinase (ADAM17), is upregulated in the vascular endothelium of patients with T2D, while others have shown that exogenous phosphatidylserine (PS) can work as a competitive inhibitor of ADAM17 sheddase activity. Therefore, we hypothesized that inhibition of ADAM17 with PS would ameliorate endothelial dysfunction in a mouse model of T2D (db/db) by improving endothelial mechanosensation, and that this effect would be associated with reductions in blood pressure and arterial stiffness. We tested this hypothesis in 20 db/db male mice aged 9 weeks that were randomized to receive a daily peanut butter pellet as vehicle control or the pellet with PS (200 mg/kg/day) for 28 days. A third group of 10 wild-type C57/Bl6 male mice served as untreated controls. All reported differences are significant at P&lt;0.05. Compared with wild-types, db/db control mice had elevated systolic blood pressure and pulse wave velocity, whereas PS treatment reduced both when compared with db/db controls. Excised mesenteric arteries were assessed for vasodilatory responses using pressure myography and db/db control mice showed impaired flow-mediated dilation (FMD) compared to wild-types. FMD was restored in PS-treated db/db mice. Aortas, femoral and mesenteric arteries were assessed for mechanical and structural characteristics. All of these arteries displayed increased incremental modulus of elasticity (increased stiffness) in db/db control mice compared with wilt-types. PS treatment reduced arterial stiffness across arteries in db/db mice. Our findings indicate that PS treatment improves endothelial function and reduces arterial stiffness in diabetic mice and suggest that PS may be a beneficial therapeutic approach to improve overall vascular function in the setting of T2D. R01HL151384 (to LAML and JP) and R01HL153264 (to LAML and JP) 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.

Endothelial dysfunction in children with newly diagnosed Graves’ disease

The most frequent cause of hyperthyroidism in children is Graves’ disease (GD). Vascular endothelium is a specific target of thyroid hormone. The purpose of this study is to assess flow-mediated dilatation (FMD)% and serum von Willebrand factor (vWF) levels in children with newly diagnosed GD to reflect the extent of endothelial dysfunction in those children. In this study, 40 children with newly discovered GD and 40 children who were healthy served as the control group. Both patients and controls had anthropometric assessment, as well as measurements of fasting lipids, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), TSH, and free thyroxine (FT4 and FT3), thyrotropin receptor antibodies TRAbs and vWF. Noninvasive ultrasound was utilized to quantify the carotid arteries’ intima-media thickness and the brachial artery’s FMD. Patients reported significantly reduced FMD response and greater vWF and hs-CRP levels compared to controls (P = 0.001 for each). In multivariate analysis, we reported that vWF was significantly correlated with TSH (OR 2.5, 95% CI 1.32–5.32, P = 0.001), FT3 (OR 3.4, 95% CI 1.45–3.55, P = 0.001), TRAb (OR 2.1, 95% CI 1.16–2.23, P = 0.01), and FMD% (OR 4.2, 95% CI 1.18–8.23, P = 0.001). Conclusions: Children with newly diagnosed GD have endothelial dysfunction, which is shown by impaired FMD and increased vWF. These findings support the idea that GD may need to be treated as soon as possible.What is Known:• Graves' disease is the most common cause of hyperthyroidism in children.• vWF is a reliable marker for detection of vascular endothelial dysfunction.What is New:• Children with newly diagnosed Graves' disease may have endothelial dysfunction as reflected by impairment of FMD and raised vWF level.• Measurement of vWF level in children with newly diagnosed Graves' disease can be used for early detection of endothelial dysfunction.

Association between High Pericoronary Adipose Tissue Computed Tomography Attenuation and Impaired Flow-Mediated Dilation of the Brachial Artery.

Pericoronary adipose tissue (PCAT) attenuation on coronary computed tomography angiography (CTA) is a noninvasive biomarker for pericoronary inflammation and is associated with cardiac mortality. We aimed to investigate the association between PCAT attenuation and endothelial dysfunction assessed using flow-mediated dilation (FMD). A total of 119 outpatients who underwent both coronary CTA and FMD measurements were examined. PCAT attenuation values were assessed at the proximal 40-mm segments of all three major coronary arteries on coronary CTA. Endothelial function was assessed using FMD. Patients were then classified into two groups: those with endothelial dysfunction (FMD ＜4%, n=44) and those without endothelial dysfunction (FMD ≥ 4%, n=75). In all three coronary arteries, PCAT attenuation was significantly higher in patients with endothelial dysfunction than in those without endothelial dysfunction. Multivariate logistic regression analysis revealed that PCAT attenuation in the right coronary artery (odds ratio [OR]=1.543; 95% confidence interval [CI]=1.004-2.369,p=0.048) and left anterior descending artery (OR=1.525, 95% CI=1.004-2.369, p=0.049) was an independent predictor of endothelial dysfunction. Subgroup analysis of patients with adverse CTA findings (significant stenosis and/or high-risk plaque) and those with coronary artery calcium score ＞100 showed that high PCAT attenuation in all three coronary arteries was a significant predictor of endothelial dysfunction. High PCAT attenuation was significantly associated with FMD-assessed endothelial dysfunction in patients with suspected coronary artery disease. Our results suggest that endothelial dysfunction is one of the pathophysiological mechanisms linking pericoronary inflammation to cardiac mortality.

Abstract P121: Varying Determinants of Endothelial Dysfunction by Age Group Among Mexican Americans

Endothelial dysfunction assessed by impaired brachial flow-mediated dilation (FMD) is a predictive factor of incident CVD. Most studies included small proportions of Hispanics or Latinos. We aimed to assess determinants of impaired FMD in a large population-based sample of asymptomatic Mexican-Americans. Methods: Cardiometabolic biomarkers, visceral adipose tissue (VAT), and FMD were obtained from 960 participants (57.9% females, mean age 52.1±0.9 years, age 18-85 years) from the Cameron County Hispanic Cohort. Sex-specific median values of %FMD were used to divide participants into two groups: those with FMD below (low %FMD) and above the median (high %FMD). The sample was further stratified into younger (age&lt;55 years) and older (age ≥ 55 years) age groups. Survey-weighted logistic regression analyses were conducted to evaluate the effects of factors on the %FMD groups. Results: There was a high prevalence of obesity (49.1%), hypertension (47.8%), diabetes (26.1%), hypercholesterolemia (46.7%), and metabolic syndrome (38.2%). The median FMD response was 4.2%±0.3% [3.8% (SE 0.4) in males and 4.5% (SE 0.4) in females]. Low %FMD group was significantly older, had higher VAT, SBP, or plasma glucose levels, and had metabolic syndrome compared to those in the high %FMD group. Multivariable-adjusted age-stratified logistic regression analyses showed that among older participants, male gender [OR =2.4 (1.4-4.2)] and having hypertension [OR=2.3 (1.3-4.3)] or pre-diabetes [OR=3.4 (1.5-7.5)] remained significantly associated with odds of low %FMD. Among younger participants, only high LDL [OR=2.8 (1.6-4.9)] or having metabolic syndrome [OR=1.9 (1.1-3.6)] were significantly associated with odds of low %FMD. Conclusion: We found age-dependent associations between cardiometabolic biomarkers and an FMD response below the gender-specific median in a population composed of Mexican-Americans without prior CVD. Targeting specific risk factors by age may mitigate progression to incident CVD in this high-risk group.

Myoglobinemia, Peripheral Arterial Disease, and Patient Mortality.

Peripheral arterial disease (PAD) causes leg muscle damage due to inadequate perfusion and increases cardiovascular events and mortality 2- to 3-fold. It is unclear if PAD is a biomarker for high-risk cardiovascular disease or if skeletal muscle injury harms arterial health. The objective of this work is to test if serum myoglobin levels (myoglobinemia) are a marker of PAD, and if so, whether myoglobin impairs vascular health. Patient blood samples were collected from PAD and control (no PAD) patients and interrogated for myoglobin concentrations and nitric oxide bioavailability. Patient mortality over time was captured from the medical record. Myoglobin activity was tested on endothelial cells and arterial function. Myoglobin is a biomarker for symptomatic PAD and was inversely related to nitric oxide bioavailability; 200 ng/mL myoglobin in vitro increased endothelial cell permeability in vitro and decreased nitrate bioavailability. Ex vivo, 100 ng/mL myoglobin increased vascular tone in naive murine aortas approximately 1.5 times, impairing absolute vessel relaxation. In vivo, we demonstrated that myoglobinemia caused impaired flow-mediated dilation in a porcine model. Patients presenting with myoglobin levels of 100 ng/mL or greater had significantly more deaths than those with myoglobin levels of less than 100 ng/mL. Using a combination of patient data, in vitro, ex vivo, and in vivo testing, we found that myoglobin is a biomarker for symptomatic PAD and a potent regulator of arterial health that can increase vascular tone, increase vascular permeability, and cause endothelial dysfunction, all of which may contribute to the vulnerability of PAD patients to cardiovascular events and death.

Abstract 10022: Marijuana Smoke or Vaporizer Aerosol Impairs Endothelial Function Regardless of Drying Regimen or Cannabinoid Profile

Introduction: Marijuana smoke and vaporizer aerosol adversely affect the cardiovascular system. Most US marijuana research has used research marijuana from the University of Mississippi supplied through the National Institute on Drug Abuse (NIDA). NIDA marijuana is dried at high temperature with maximum of 10% THC, but real-world material is gently dried and is ~20% THC. Because NIDA marijuana differs from what is currently used by the public in terms of THC content and drying regimen, skepticism regarding relevance to the real world is limiting the impact of results obtained from this material. Here, we validated the use of NIDA research marijuana in the study of vascular effects of cannabis. Hypothesis: Exposure to marijuana smoke or vaporizer aerosol, regardless of the cannabinoid profile or drying regimen, impairs endothelial function. Methods: We exposed groups of rats (n=8) to smoke or Volcano vaporizer aerosol from materials obtained from U Miss (Placebo (&lt;0.01% THC hot), 4.2% THC hot and gentle dried pair, 10% THC hot), from Biopharmaceutical Research Company (Castroville, CA) (20% THC gentle dried), commercial hemp with negligible THC content, and clean air. Exposure was pulsatile, 5s/min over 5 mins. Endothelial function was measured as flow-mediated dilation (FMD) and pre- vs. post-exposure FMD (10 and 30 mins after end of exposure) differences were analyzed. Results: We observed significant impairment of FMD after exposure to pulsatile smoke from marijuana with varied cannabinoid profiles and drying regimens (p≤.006), with no effect from clean air (p=.13). No significant recovery of FMD was observed in any group 30 mins after marijuana smoke exposure (p≥.32). Pulsatile exposure to aerosol generated from the same materials impaired FMD in all groups (p≤.001) except clean air (p=.23). Conclusions: Acute exposure to marijuana smoke/aerosol impairs endothelial function regardless of the drying regimens or the cannabinoid profile of the marijuana product.

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.