Conduit Artery Endothelial Function Research Articles

Vascular Dysfunction and Inflammation in Liver Transplant Recipients

INTRODUCTION Liver transplant (LT) recipients have an increased risk of developing cardiovascular disease (CVD) after transplant. The physiological mechanisms driving this risk are not fully understood. Vascular endothelial dysfunction is the initial pathophysiological step in the development of atherosclerosis. The objective of this study was to characterize vascular endothelial function in LT recipients. It was hypothesized that compared to matched healthy controls (HC), LT recipients would have impaired vascular function. METHODS. Conduit artery endothelial function was measured by flow-mediated dilation of the brachial artery (FMDBA) with duplex ultrasound in 40 LT patients (18 male, 22 female; mean ± SD: Age, 56±11 years) and 10 age matched HC (4 male, 6 female; Age 51±16 years). Central aortic blood pressures were derived from radial arterial tonometry and the use of the generalized transfer function. A venous blood sample was obtained for nuclear magnetic resonance spectroscopy assessment of the inflammation biomarker GlycA, and high-density lipoprotein (HDL) particle subspecies. A novel metabolic inflammation index was derived from plasma GlycA and HDL subparticle concentrations. RESULTS. LT recipients had higher peripheral (Median [IQR]: HC vs. LT, 119 [111-136] vs. 135 [124-147] mmHg, p=0.01) and central aortic (113 [102-126] vs. 124 [116-139] mmHg, p=0.03) systolic blood pressures. LT recipients had impaired vascular endothelial function (HC vs. LT, FMDBA: 6.08 [5.01-7.61] vs. 4.54 [3.31-6.24] %, p = 0.04). In LT recipients, the inflammation index (55 [45-62] AU) was negatively associated with vascular endothelial function ( r=-0.4, p=0.03). CONCLUSIONS. Despite optimal pharmacological intervention, LT recipients had higher systolic blood pressures and worse vascular endothelial dysfunction compared to HC. In LT recipients, a higher inflammation index was associated with worse endothelial function, suggesting that chronic low-grade inflammation may partly contribute to endothelial dysfunction in this patient population. These findings provide support for the vascular endothelium as a potential therapeutic target to improve cardiovascular health in LT recipients. Supported by CTSA award No. UM1TR004360 from the National Center for Advancing Translational Sciences. This is the full abstract presented at the American Physiology Summit 2024 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.

Sodium Loading Does Not Induce Oxidative Stress-Mediated Reductions in Vascular Function in Young Adults

Short-term, high sodium diets decrease dilation responses in conduit arteries and the microvasculature when compared to low sodium diets (e.g., 7000 vs. 500 mg/day). Supraphysiological antioxidant treatment mitigates these effects supporting a role for oxidative stress in sodium-induced vascular impairments. It is unclear whether these effects are present when high sodium conditions are compared to the sodium level of a typical American diet (~3400 mg/day). Therefore, we tested the hypotheses that sodium added to the habitual diet of young adults would reduce flow mediated dilation (FMD) and post-ischemic reactive hyperemia (RH) and that an acute infusion of the antioxidant ascorbic acid (AA) would attenuate the vascular consequences of excess sodium. Methods: Young adults (6M / 8F; age: 26 ± 4 y; BMI: 23.6 ± 2.5 kg/m2) were studied following 10 days of sodium loading (SL) via table salt-filled capsules (3900 mg sodium/day) and 10 days of placebo capsules in addition to their normal diet, in random order. Total sodium intake was estimated via 24-hour urinary sodium content on day 10. On day 11, brachial artery diameter and blood velocity were continuously measured via duplex ultrasound at baseline and after 5 min of forearm ischemia. FMD, the post-ischemic change in brachial artery diameter relative to baseline diameter, provided an index of conduit artery endothelial function. The total RH in the 2 min following ischemia was measured for an index of microvascular function. Within each condition, testing was performed before (pre-AA) and after (post-AA) a 20 min intravenous infusion of 0.06 g of AA/kg lean body mass. Results: Urinary sodium content was increased by SL compared to the placebo (285 ± 94 vs. 160 ± 75 mmol/24 h, p<0.001) indicating approximate sodium intakes of 6600 and 3700 mg/day, respectively. Mean arterial pressure did not differ across conditions pre-AA (SL: 77 ± 7; placebo: 75 ± 5 mmHg, P=0.40) or post-AA (SL: 79 ± 8; placebo: 76 ± 5 mmHg, P=0.17). Brachial artery FMD was not different across time or condition (SL pre-AA: 8.7 ± 3.6, post-AA: 8.8 ± 4.2% vs. placebo pre-AA: 8.8 ± 3.2, post-AA: 8.1 ± 3.5%, time x condition interaction P=0.48). RH was similar following SL and placebo (condition effect: P=0.38) but was reduced in both conditions post AA (SL: Δ-45 ± 44 ml, P=0.01; placebo: Δ-72 ± 59ml, p<0.001). Conclusion: Contrary to our hypothesis, 10 days of sodium loading did not decrease FMD or post- ischemic RH in young adults compared to their habitual diet. Likewise, acute antioxidant treatment did not augment FMD in either condition and paradoxically decreased total RH independent of sodium intake. These data suggest that a short-term increase in dietary sodium intake in healthy young adults does not elicit oxidative stress-induced reductions in vascular function. NIH 5R01HL104106 and 5P20GM113125; AHA 20POST35080171. This is the full abstract presented at the American Physiology Summit 2024 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.

Histamine H2-receptor antagonism improves conduit artery endothelial function and reduces plasma aldosterone level without lowering arterial blood pressure in angiotensin II–hypertensive mice

Aldosterone through the mineralocorticoid receptor MR has detrimental effects on cardiovascular disease. It reduces the bioavailability of nitric oxide and impairs endothelium-dependent vasodilatation. In resistance arteries, aldosterone impairs the sensitivity of vascular smooth muscle cells to nitric oxide by promoting the local secretion of histamine which activates H2 receptors. The present experiments tested in vivo and ex vivo the hypothesis that systemic H2-receptor antagonism reduces arterial blood pressure and improves vasodilatation in angiotensin II–induced chronic hypertension. Hypertension was induced by intravenous infusion of angiotensin II (60 ng kg−1 min−1) in conscious, unrestrained mice infused concomitantly with the H2-receptor antagonist ranitidine (27.8 µg kg−1 min−1) or vehicle for 24 days. Heart rate and arterial blood pressure were recorded by indwelling arterial catheter. Resistance (mesenteric) and conductance (aortae) arteries were harvested for perfusion myography and isometric tension recordings by wire myography, respectively. Plasma was analyzed for aldosterone concentration. ANGII infusion resulted in elevated arterial blood pressure and while in vivo treatment with ranitidine reduced plasma aldosterone concentration, it did not reduce blood pressure. Ranitidine improved ex vivo endothelial function (acetylcholine 10−9 to 10−6 mol L−1) in mesenteric resistance arteries. This was abolished by ex vivo treatment with aldosterone (10−9 mol L−1, 1 h). In aortic segments, in vivo ranitidine treatment impaired relaxation. Activation of histamine H2 receptors promotes aldosterone secretion, does not affect arterial blood pressure, and protects endothelial function in conduit arteries but promotes endothelial dysfunction in resistance arteries during angiotensin II–mediated hypertension. Aldosterone contributes little to angiotensin II–induced hypertension in mice.

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.

A systematic review and meta-analysis on the effect of selective serotonin reuptake inhibitors on endothelial function

Abstract Background Depression and atherosclerotic cardiovascular disease (ASCVD) are commonly clustered in affected patients. Endothelial dysfunction is an early marker of ASCVD while also reported in patients with depression. Emerging evidence suggests that selective serotonin receptor inhibitors (SSRIs) may improve endothelial function. However, clinical studies assessing flow-mediated dilation (FMD), the gold-standard method to evaluate conduit artery endothelial function, in response to SSRIs treatment included limited number of patients and did not provide consistent results. Purpose In the present study we aim to evaluate the effect of SSRIs treatment on endothelial function assessed by longitudinal changes in FMD. Methods We performed a systematic review to retrieve and subsequently meta-analyze eligible studies in patients with depression who received SSRIs and had available measurements of FMD change before and after treatment. Results In 5 studies and 323 individuals in total, SSRIs were associated with increased FMD at the end of follow-up compared to baseline measurement (pooled mean change 1.97%, 95% CI 0.17, 3.77, P=0.032, I2=87.4%). These results did not substantially change when analysis was restricted to patients with history of atherosclerotic cardiovascular disease (ASCVD). Similarly, FMD changes were higher in individuals receiving SSRIs compared to not-treated subjects (pooled mean difference 2.5%. 95% CI 0.7, 4.2, P<0.001, I2=82.7%). Substantial heterogeneity regarding with respect to follow-up duration, demographics, and SSRIs agents. Conclusion SSRIs significantly improve FMD, the gold-standard marker of endothelial function. Further investigation is warranted for the role of FMD as a possible therapeutic biomarker in patients with depression and established or subclinical ASCVD. Prospero registration: CRD42021252241 Funding Acknowledgement Type of funding sources: None.

The Influence of Covid‐19‐Based mRNA Vaccines on Measures of Conduit Artery and Microvascular Endothelial Function

With the emergence of severe acute respiratory syndrome 2 (SARS‐CoV‐2), leading to coronavirus disease 19 (COVID‐19), a new class of messenger RNA (mRNA) vaccines have been broadly used. These vaccines have been associated with inflammatory sides effects such as myo‐ and peri‐carditis. Despite the well‐known link between inflammation and endothelial dysfunction, it is unknown whether these vaccines may transiently impair endothelial function, and therefore increase cardiovascular risk. Aim: To evaluate the influence of COVID‐19‐based mRNA vaccines on macro‐ and micro‐vascular endothelial function in healthy adults. We hypothesized that macro‐ and micro‐vascular endothelial function would be reduced following vaccination.MethodsPrior to, and ~48 hrs following the second dose of COVID‐19‐based mRNA vaccines, brachial artery flow‐mediated dilation (FMD, macrovascular function), reactive hyperemia (microvascular function), and cutaneous intradermal microdialysis coupled with laser Doppler flowmetry (microvascular function) were measured in healthy young adults. For microdialysis, a standard local heating protocol (42⁰C) was utilized, followed by infusion of the Nitric Oxide Synthase inhibitor Nω‐Nitro‐L‐arginine methyl ester hydrochloride (L‐NAME, 15mM), and induction of maximum vasodilation (43⁰C+28mM Sodium Nitroprusside). Sites included: control (lactated Ringer’s), ascorbic acid (10 mM), l‐arginine (10 mM), and tetrahydrobiopterin (BH4,10 mM). C‐reactive protein (CRP), a marker of systemic inflammation, was measured from fasting serum samples at both time points.ResultsVaccination (mRNA‐1273, n=3 and BNT162b2, n=6, 5men/4women, 34±2yrs) induced an increase in CRP (pre: 0.2±0.1mg/dL vs. post: 2.1±0.5mg/dL, p=0.008, r‐statistic=‐0.89), but had no effect on FMD (pre: 3.6±0.9% vs. post: 4.6±1.1%, p=0.43, Cohen’s d=0.28) or reactive hyperemia (pre: 20178±3236 AU vs. post: 28426±4573 AU, p=0.14, Cohen’s d=0.55). There was no association between the change in FMD (r=‐0.07, p=0.87) or reactive hyperemia (r=‐0.48, p=0.19) and the change in CRP. Vaccination also had no effect on microvascular nitric oxide (NO)‐dependent dilation (pre: 77.0±2.5% vs post: 77.3±2.4%, p=0.91, ηp2=0.002), nor was there an effect of microdialysis treatment on NO‐dependent dilation (p=0.74, ηp2=0.05). Following vaccination, the difference in NO‐dependent dilation relative to control was unaffected by treatment (p=0.25, η2=0.11) with no difference in the effects of BH4 (6.3±4.9%), l‐arginine (8.3±5.2%), or ascorbic acid (‐2.6±4.2%, all p>0.05). The change in NO‐dependent dilation at the control site was not related to the change in CRP (r=0.32, p=0.40).ConclusionsThere was a significant inflammatory response to COVID‐19‐based mRNA vaccines ~48 hrs following the second vaccine dose. Despite this, macro‐ and micro‐vascular endothelial function and NO‐dependent dilation were preserved in healthy adults.

Conduit Artery and Forearm Microvascular Reactivity in Black and White Females: Examining the Role of Greater Superwoman Schema Endorsement

Among females in the United States, Black females suffer from the highest rates of hypertension, stroke, coronary artery disease, heart failure, and total cardiovascular disease (CVD) mortality. Importantly, vascular dysfunction precedes overt CVD and predicts CVD risk. In this regard, a recent study reported that upper limb microvascular but not macrovascular function was blunted in Black relative to White women. However, this is not always a consistent finding and such investigations have not incorporated psychosocial measures, which are known to contribute to race/ethnicity‐related disparities in cardiovascular health. Given the strong relationship between psychosocial stress and health, Woods‐Giscombe, et al. recently developed the Giscombe Superwoman Schema Questionnaire (G‐SWS‐Q), which operationalizes the Superwoman Schema (SWS) Conceptual Framework to quantify psychological stress processes specifically associated with being a Black woman. Accordingly, we tested the hypothesis that Black females would have blunted post‐occlusive upper limb microvascular and macrovascular vasodilation relative to White females and that greater SWS endorsement by Black females would be associated with blunted vascular responses.METHODSSeven Black (age: 22 ± 1 yr; BMI: 27.5 ± 1.6 kg/m2) and 6 White (age: 23 ± 1 yr; BMI: 25.9 ± 1.3 kg/m2) females participated. Post‐occlusive brachial artery flow‐mediated dilation (FMD) and forearm reactive hyperemia were assessed via well‐established procedures. Briefly, brachial artery diameter and blood velocity were measured continuously and recorded via Doppler ultrasound and a video capture system throughout a 2 min baseline, 5 min suprasystolic forearm cuff occlusion, and 3 min recovery. Offline analysis was performed via a continuous edge detection and blood velocity tracking software. Black participants also completed the G‐SWS‐Q, which is a 35‐item instrument designed to measure the cognitive, affective, and behavioral underpinnings associated with being a “Strong Black Woman” in the United States.RESULTSBrachial artery FMD was lower in Black relative to White females (3.99 ± 1.15 vs. 7.34 ± 1.10%; p = 0.03); however, after correcting for post‐occlusive shear rate AUC via ANCOVA, group differences in FMD were less apparent (p = 0.07). Post‐occlusive peak blood velocity and blood flow AUC were not different between groups (p = 0.43 and p = 0.42, respectively). A moderate negative correlation was observed between overall SWS and FMD (r = ‐0.58, p = 0.09). Among the SWS subscales, a strong negative correlation was observed between “Obligation to Present an Image of Strength” and FMD (r = ‐0.70, p = 0.04), whereas “Intense Motivation to Succeed” was moderately negatively correlated with FMD (r = ‐0.64, p = 0.06).CONCLUSIONThese preliminary data indicate that 1) upper limb macrovascular but not microvascular function may be blunted in young Black females and 2) stronger SWS endorsement may be associated with blunted vascular reactivity. Therefore, blunted conduit artery endothelial function in Black females may be partially attributable to greater SWS internalization.

Abstract TP65: Evaluation Of Leg Microvascular Function In Chronic Stroke Survivors Using Near Infrared Spectroscopy And The Vascular Occlusion Technique.

Background: Chronic stroke survivors have impaired conduit artery endothelial function, but little is known about peripheral microvascular function post-stroke. Near infrared spectroscopy (NIRS) can non-invasively measure tissue oxygen saturation (StO 2 ) of skeletal muscle, and when combined with a dynamic challenge like a vascular occlusion, can indirectly evaluate tissue oxygen utilization during the occlusion period and microvascular function during the post-occlusive hyperemic period. We hypothesized that microvascular function would be impaired in the tibialis anterior (TA) muscle of the affected leg of chronic stroke survivors compared to the non-affected leg as evidenced by a slower oxygen resaturation rate post-cuff release. Methods: Fifteen chronic stroke survivors completed this study. The mean age was 57±12 years, 10 were female, and the mean time since stroke was 12±10 years. After resting for fifteen minutes a NIRS sensor was placed over either the affected or non-affected TA. The opposite leg was tested one week later. After recording five minutes of baseline StO 2 , a cuff was placed around the proximal thigh and inflated to 225 mmHg for five minutes. StO 2 was continuously measured during cuff inflation and for five minutes post-cuff release. The rate of change in StO 2 was calculated during the five-minute cuff occlusion and the first 12 seconds post-cuff release. Results: There was no difference in baseline StO 2 between the affected and non-affected TA (68±11% vs. 67±6%, respectively; p=0.60). There was also no difference in the change in StO 2 during the occlusion period (affected ΔStO 2 = -31±12 % vs. non-affected -35±19%; p=0.76), or the rate of oxygen desaturation (affected -0.15±0.11 %·s -1 vs non-affected -0.10±0.04 %·s -1 ; p=0.39). After cuff release, there was a greater oxygen resaturation rate in the non-affected leg compared to the affected leg (3.13±2.08 %·s -1 vs. 1.60±1.11 %·s -1 , respectively; p=0.01). Conclusion: There was no difference in oxygen utilization between the affected and non-affected TA during the cuff occlusion period. The oxygen resaturation response in the affected TA post-cuff release was slower compared to the non-affected TA, suggesting microvascular function is impaired in the affected muscle.

Abstract 13153: Vascular Function and the Gut Microbiome in Liver Transplant Recipients

Introduction: Cardiovascular disease (CVD) risk is elevated in liver transplant (LT) patients. The underlying physiological mechanisms associated with LT related CVD are not yet fully understood. High levels of the gut microbiome metabolite trimethylamine N-oxide (TMAO) may contribute to an increased risk of atherosclerosis. The purpose of this study is to investigate if high circulating levels of TMAO contribute to vascular dysfunction in LT recipients. Hypothesis: We hypothesized that vascular dysfunction, including measures of conduit artery endothelial function, central systolic blood pressure and carotid intima media thickness (cIMT), would be correlated with higher TMAO levels. Methods: We enrolled 12 LT recipients (6 male; 6 female; Mean±SD: Age 58.75±8.45 yrs). Conduit artery endothelial function was measured via flow-mediated dilation with duplex ultrasound. Central aortic pressure waves were synthesized from radial artery waveforms acquired by applanation tonometry and the use of a generalized transfer function. Mean cIMT of the near and far wall was assessed via B mode ultrasound. Blood samples were analyzed for plasma TMAO by nuclear magnetic resonance spectroscopy. Results: As shown in Figure 1, conduit artery endothelial function (Mean±SD: 4.11±2.82%) was negatively associated with TMAO (10.94±9.65 μM; r = -0.87, p <0.001). There was no significant relationship between TMAO and central aortic pressure (131±17mmHg; r = 0.36, p =0.3) or cIMT (0.68±0.10mm; r = -0.08, p =0.8). Conclusions: Our results showed that LT recipients with higher levels of plasma TMAO had worse conduit artery endothelial function. Endothelial dysfunction is a well-established precursor to the development of atherosclerosis. Therefore, therapeutic strategies aimed at improving the health of the gut microbiome and subsequently reducing the levels of TMAO hold promise for preventing atherosclerosis in LT patients and should be investigated in future trials.

Abstract 14367: Elevated Creatinine Levels Are Associated With Vascular Dysfunction in Liver Transplant Recipients

Introduction: Liver transplant (LT) recipients have an increased risk of developing cardiovascular disease (CVD) after transplant. The physiological mechanisms driving LT-related CVD are not fully understood. Renal impairment post-transplant may contribute to CVD risk in LT recipients. The aim of this study was to investigate the relationship between plasma creatinine levels and vascular function in LT patients. Methods: Conduit artery endothelial function was measured via flow-mediated dilation of the brachial artery (FMD BA ) with duplex ultrasound in 13 LT patients (7 Male, 6 Female; Median [IQR]: Age 59 [56 - 64] years). Parameters of carotid artery function (distension, distensibility, compliance and stiffness) were assessed using B mode ultrasound and central aortic pressure waves that were synthesized from radial artery waveforms acquired by applanation tonometry in 13 LT patients (6 Male, 7 Female; Age 57 [56 - 64] years). Blood samples were analyzed for plasma creatinine by nuclear magnetic resonance spectroscopy. Results: Conduit artery endothelial function via FMD BA (4.07 [3.52 - 6.40] %) was negatively associated with plasma creatinine levels (1.30 [1.08 - 1.56] mg/dL; r = -0.63, p = 0.03). Plasma creatinine levels were also inversely associated with carotid artery distension (0.53 [0.35 - 0.61] mm, r = -0.74, p = 0.006), distensibility (25.62 [20.65 - 33.03] 10 -3 ·kPa -1 , r = -0.59, p = 0.04), and compliance (1.19 [0.82 - 1.41] 10 -6 ·m 2 ·kPa -1 , r = -0.66, p = 0.02), and positively associated with carotid stiffness (6.07 [5.35 - 6.76] m·s -1 , r = 0.59, p = 0.04) as shown in Figure 1. Conclusions: Our results indicate that LT patients with higher levels of creatinine have impaired conduit artery endothelial function and compromised carotid artery function, making these individuals more susceptible to the development of atherosclerosis and stroke. The presence of renal dysfunction after LT may contribute to CVD risk and warrants investigation in future trials.

A New Protocol for Controlling and Targeting Reactive Hyperemia Shear Stress to Assess Endothelial Function

Conduit artery endothelial function is most commonly assessed via measurement of flow mediated dilation (FMD) evoked by a transient post-limb occlusion increase in shear stress [reactive hyperemia (RH)]. A limitation of RH-FMD is the uncontrolled nature of the RH shear stress stimulus which produces RH-FMD response variability that is independent of conduit artery endothelial function. The purpose of this study was to develop a protocol to create a uniform, targeted, and transient (40 second) shear stress stimulus and compare it to the standard RH-FMD approach. We hypothesize that incorporating arterial compression in the controlled targeted RH (CTRH) protocol will allow us to achieve a uniform target shear rate (estimate of shear stress) within and between participants. Young, healthy men and women (females n = 4, age = 22 ± 1 years; males n = 2, age = 25 ± 3 years) underwent one trial of RH-FMD and two trials of CTRH-FMD with duplex ultrasound assessment. The CTRH protocol incorporated three-minutes of ischemic handgrip exercise at 30% of participants’ maximum voluntary contraction during a five-minute occlusion to create a large forearm vasodilation and hyperemic reserve. Upon cuff release, the ensuing hyperemia was controlled with manual brachial artery compression at the antecubital fossa. A live velocity readout permitted compression adjustments to achieve the velocity required to maintain a target shear rate of 120 s-1. The cuff was re-inflated after 40s of cuff release. The RH-FMD trial followed the standard five-minute forearm occlusion protocol. The 40s average shear rate was 116.0 ± 8.8s-1 in the CTRH test and 102.1 ± 15.4 s-1 in the RH test. The CTRH test shear rate was significantly closer to the 120s-1 target; calculated as the absolute distance from target in 3s time bins over the 40s period: CTRH = 19.0 ± 3.9s-1; RH = 36.5 ± 6.7 s-1 p = 0.002. The between participant coefficient of variation (CV) for the RH 40s average shear rate was lower in the CTRH test (CTRH CV = 8.1%; RH CV = 15.1%). The within subject trial to trial CV for the CTRH 40s average shear rate was 3.0 ± 4.6%. FMD responses were similar between tests (CTRH-FMD% = 8.3 ± 1.6%; RH-FMD% = 7.6 ± 4.8%, p=0.717). These preliminary findings demonstrate the capacity for RH stimulus control. CTRH-FMD is minimally impacted by stimulus variability and may provide a clearer reflection of brachial artery endothelial function.

Finnish Sauna Bathing and Vascular Function in Adults with Coronary Artery Disease: Preliminary Analysis of a Randomized Controlled Trial

Background Regular Finnish sauna use is associated with a reduced risk of cardiovascular mortality. However, mechanisms underlying this relationship remain unknown. Other forms of heat therapy have been shown to improve markers of vascular function in healthy young adults as well as in middle-aged adults with cardiovascular risk factors and older adults with chronic heart failure. Nevertheless, no experimental study has addressed the effects of regular Finnish sauna use on vascular function. This study tested the hypothesis that an 8-week Finnish sauna intervention improves vascular function in adults with stable coronary artery disease (CAD) Methods Fourteen middle-aged to older adults (61 ± 7 years, 12 men/2 women) with stable CAD and naïve to heat therapy were randomized to 8 weeks of Finnish sauna (4 sessions/week, 20-30 min/session) (SAUNA, n=7) or maintenance of habitual lifestyle (CTRL, n=7). Before and after the intervention, resting blood pressure, brachial artery flow-mediated dilation (FMD) and cutaneous vasodilation during local heating at 39°C were measured. Brachial artery FMD was used as an index of conduit artery endothelial function, peak and area under the curve (AUC) of forearm vascular conductance (FVC) during reactive hyperemia were used as indices of peripheral microvascular reactivity and the plateau of cutaneous vascular conductance, expressed as percentage of maximal (%CVC) during local heating, was used as an index of skin microvascular reactivity. Results Resting systolic (P for interaction = 0.55) and diastolic blood pressure (P for interaction = 0.56) were not different between interventions. Contrary to our hypothesis, no effect of the sauna intervention was observed on FMD (SAUNA pre to post: 4.2 ± 2.4 to 4.5 ± 2.1%, CTRL pre to post: 5.0 ± 1.8 to 4.3 ± 2.1%, P for interaction = 0.37). Peripheral microvascular reactivity decreased following the SAUNA intervention and increased following CTRL, according to peak FVC (SAUNA pre to post: 2.7 ± 1.2 to 2.3. ± 1.2 ml/min/mmHg, CTRL pre to post: 3.2 ± 0.6 to 3.9 ± 0.7 ml/min/mmHg, P for interaction = 0.03) and FVC-AUC (SAUNA pre to post: 1.4 ± 0.6 to 1.1 ± 0.6 ml/mmHg, CTRL pre to post: 1.7 ± 0.5 to 2.1 ± 0.5 ml/mmHg, P for interaction = 0.03). However, within group changes in both peak FVC and FVC-AUC were not significant (all P > 0.06). No effect of either intervention was observed on %CVC (P for interaction = 0.33). Conclusion These results suggest that 4 sessions of Finnish sauna bathing per week for 8 weeks does not improve markers of macro- or microvascular function in middle-aged to older adults with stable CAD.

Doxorubicin-Induced Oxidative Stress and Endothelial Dysfunction in Conduit Arteries Is Prevented by Mitochondrial-Specific Antioxidant Treatment

BackgroundDoxorubicin (DOXO) chemotherapy increases risk for cardiovascular disease in part by inducing endothelial dysfunction in conduit arteries. However, the mechanisms mediating DOXO-associated endothelial dysfunction in (intact) arteries and treatment strategies are not established. ObjectivesWe tested the hypothesis that DOXO impairs endothelial function in conduit arteries via excessive mitochondrial reactive oxygen species (ROS) and that these effects could be prevented by treatment with a mitochondrial-targeted antioxidant (MitoQ). MethodsEndothelial function (endothelium-dependent dilation [EDD] to acetylcholine) and vascular mitochondrial ROS were assessed 4 weeks following administration (10 mg/kg intraperitoneal injection) of DOXO. A separate cohort of mice received chronic (4 weeks) oral supplementation with MitoQ (drinking water) for 4 weeks following DOXO. ResultsEDD in isolated pressurized carotid arteries was 55% lower 4 weeks following DOXO (peak EDD, DOXO: 42 ± 7% vs. sham: 94 ± 3%; p = 0.006). Vascular mitochondrial ROS was 52% higher and manganese (mitochondrial) superoxide dismutase was 70% lower after DOXO versus sham (p = 0.0008). Endothelial function was rescued by administration of the mitochondrial-targeted antioxidant, MitoQ, to the perfusate. Exposure to plasma from DOXO-treated mice increased mitochondrial ROS in cultured endothelial cells. Analyses of plasma showed differences in oxidative stress-related metabolites and a marked reduction in vascular endothelial growth factor A in DOXO mice, and restoring vascular endothelial growth factor A to sham levels normalized mitochondrial ROS in endothelial cells incubated with plasma from DOXO mice. Oral MitoQ supplementation following DOXO prevented the reduction in EDD (97 ± 1%; p = 0.002 vs. DOXO alone) by ameliorating mitochondrial ROS suppression of EDD. ConclusionsDOXO-induced endothelial dysfunction in conduit arteries is mediated by excessive mitochondrial ROS and ameliorated by mitochondrial-specific antioxidant treatment. Mitochondrial ROS is a viable therapeutic target for mitigating arterial dysfunction with DOXO.

Acute High Phosphate Intake Impairs Endothelial‐Dependent Vasodilation in Young Premenopausal Women

In the United States, the growing abundance of processed foods has led to Americans consuming more than double the recommended dietary intake of inorganic phosphate (Pi). Chronic consumption of Pi is associated with a higher risk of cardiovascular disease in the general population; however, studies investigating underlying mechanisms are limited. Recently, our lab has reported an impairment in brachial artery flow‐mediated dilation (FMD) following acute high Pi consumption in young, healthy men. To our knowledge, the effect of acute high Pi on vascular function in women remains unknown. This becomes important, as previous longitudinal work suggests that women may be protected from the greater cardiovascular risk associated with high serum phosphorus. Therefore, the aim of this study was to determine the effect of acute high Pi consumption on vascular function in young, healthy women. Eight healthy premenopausal women ingested a high‐Pi drink containing 2,000 mg of phosphorus (23 ± 2 yrs; mean ± SEM). Heart rate (HR) (ECG) and arterial blood pressure (BP) (finger photoplethysmography and automated sphygmomanometer) were measured during a 10 min baseline. FMD was used to assess conduit artery endothelial function and microvascular function was quantified as reactive hyperemic velocity AUC following cuff release. In addition, Pulse Wave Velocity (PWV) was used to assess large artery stiffness. All measures were performed before (pre) and 60 min after (post) Pi drink consumption (a time period our lab has shown to elicit peak elevations in serum phosphate following Pi consumption). Resting mean arterial BP and HR were not different pre‐ vs. post‐ Pi consumption (BP= pre, 80 ± 1; post, 81 ± 2 mmHg; p=0.28; HR= pre, 62 ± 4; post, 62 ± 4 beats/min; p=0.64). In contrast, FMD was significantly attenuated post‐Pi consumption, (pre, 6.7 ± 0.5%; post, 4.8 ± 0.8%; p=0.04), whereas, reactive hyperemic velocity AUC remained unchanged (pre, 2590 ± 488 arbitrary units; post, 2056 ± 221 arbitrary units; p=0.30), indicating that acute high Pi consumption had no effect on microvascular function. In addition, PWV was also unaffected by acute high Pi (p=0.18). Collectively, our preliminary findings suggest that, similar to men, exposure to acute high Pi impairs conduit artery endothelial function, but not microvascular function, in young healthy women.Support or Funding InformationUniversity of Texas at Arlington College of Nursing and Health Innovation

Acute Systemic Rho‐kinase Inhibition Reduces Blood Pressure and Influences Peripheral Vascular Tone in Healthy Older Adults

Aging is the primary risk factor for cardiovascular disease (CVD), and Rho‐kinase has emerged as an important contributor to the pathogenesis of CVD in preclinical and clinical studies. Therefore, we tested the hypothesis that acute, systemic Rho‐kinase inhibition would improve measures of CVD risk in older adults. We studied healthy young (YA; 25 ± 1 yrs; 6M/6F) and older adults (OA; 65 ± 1 yrs; 6M/7F) under control conditions (CON, intravenous saline) and during inhibition of Rho‐kinase via intravenous fasudil administration (60 mg) in a double‐blind, randomized, crossover design. In separate visits to the laboratory, saline and fasudil were infused over the course of 1 h, after which we measured blood pressure, carotid‐femoral pulse wave velocity (cfPWV; index of arterial stiffness), and central augmentation index (AIx; SphygmoCor XCEL). In a subset of participants (YA: 5M/5F; OA: 6M/3F), we assessed reactive hyperemia (RH) and flow‐mediated dilation (FMD) to evaluate microvascular function and conduit artery endothelial function, respectively. We measured brachial artery diameter and mean blood velocity (MBV; Doppler ultrasound) to calculate forearm vascular conductance (FVC; forearm blood flow/mean arterial pressure · 100). FMD was quantified as the percent change in brachial artery diameter following 5 min of forearm ischemia. Shear rate (8 · MBV/diameter) was expressed as area under the curve (SRAUC) from cuff release to peak diameter to quantify the stimulus for FMD. In OA, fasudil reduced systolic (SBP, 127 ± 4 vs. CON: 134 ± 4 mmHg, P < 0.05), diastolic (DBP, 76 ± 2 vs. CON: 79 ± 1 mmHg, P < 0.05), and mean arterial pressure (MAP, 93 ± 2 vs. CON: 97 ± 2 mmHg, P < 0.05), and BP remained lower 1 and 2 h postinfusion. Although fasudil initially reduced SBP (114 ± 2 vs. CON: 119 ± 2 mmHg, P < 0.05), DBP (68 ± 2 vs. CON: 72 ± 2 mmHg, P < 0.05), and MAP (84 ± 2 vs. CON: 88 ± 2 mmHg, P < 0.05) in YA, BP returned to control levels and was not different from CON at 1 or 2 h post‐infusion. Fasudil lowered cfPWV in OA (7.6 ± 0.4 vs. CON: 7.8 ± 0.4 m/s, P < 0.05) and tended to lower cfPWV in YA (5.2 ± 0.2 vs. CON: 5.4 ± 0.2 m/s, P = 0.07). However, AIx was unchanged by the fasudil treatment in both OA (27 ± 2 vs. CON: 31 ± 2%, P = NS) and YA (−2 ± 2 vs. CON: −5 ± 5%, P = NS). Baseline brachial diameter increased with fasudil in OA (3.29 ± 0.23 vs. CON: 3.16 ± 0.20 mm, P < 0.05), whereas fasudil had no effect on baseline diameter in YA (3.19 ± 0.19 vs. CON: 3.16 ± 0.17 mm, P = NS). Similarly, resting FVC was elevated under fasudil conditions in OA (36 ± 4 vs. CON: 25 ± 3 ml/min/100 mmHg, P < 0.05), while FVC was unchanged with fasudil in YA (36 ± 9 vs. CON: 32 ± 5 ml/min/100 mmHg, P = NS). Following forearm ischemia, there was no effect of fasudil on peak blood flow (OA, 288 ± 30 vs. CON: 286 ± 31 ml/min, P = NS; YA, 346 ± 65 vs. CON: 346 ± 45 ml/min, P = NS) or on FMD (OA, 6.2 ± 1.1 vs. CON: 7.0 ± 1.1%, P = NS; YA, 6.5 ± 1.1 vs. CON: 7.9 ± 1.4%, P = NS). Fasudil did not affect SRAUC (OA, 29 ± 5 vs. CON: 29 ± 4 s−1 · 103, P = NS; YA, 32 ± 5 vs. CON: 36 ± 5 s−1 · 103) in either group. Collectively, these data suggest Rho‐kinase contributes to the age‐related elevation in blood pressure potentially via greater peripheral vasoconstrictor tone in healthy older adults.Support or Funding InformationHL119337

Fluctuation in shear rate, with unaltered mean shear rate, improves brachial artery flow-mediated dilation in healthy, young men.

Increase in mean shear stress represents an important and potent hemodynamic stimulus to improve conduit artery endothelial function in humans. No previous study has examined whether fluctuations in shear rate patterns, without altering mean shear stress, impacts conduit artery endothelial function. This study examined the hypothesis that 30-min exposure to fluctuations in shear rate patterns, in the presence of unaltered mean shear rate, improves brachial artery flow-mediated dilation. Fifteen healthy men (27.3 ± 5.0 yr) completed the study. Bilateral brachial artery flow-mediated dilation was assessed before and after unilateral exposure to 30 min of intermittent negative pressure (10 s, -40mmHg; 7 s, 0 mmHg) to induce fluctuation in shear rate, while the contralateral arm was exposed to a resting period. Negative pressure significantly increased shear rate, followed by a decrease in shear rate upon pressure release (both P < 0.001). Across the 30-min intervention, mean shear rate was not different compared with baseline (P = 0.458). A linear mixed model revealed a significant effect of time observed for flow-mediated dilation (P = 0.029), with exploratory post hoc analysis showing an increase in the intervention arm (∆FMD +2.0%, P = 0.008), but not in the contralateral control arm (∆FMD +0.5%, P = 0.664). However, there was no effect for arm (P = 0.619) or interaction effect (P = 0.096). In conclusion, we found that fluctuations in shear patterns, with unaltered mean shear, improves brachial artery flow-mediated dilation. These novel data suggest that fluctuations in shear pattern, even in the absence of altered mean shear, represent a stimulus to acute change in endothelial function in healthy individuals. NEW & NOTEWORTHY Intermittent negative pressure applied to the forearm induced significant fluctuations in antegrade and retrograde shear rate, while mean shear was preserved relative to baseline. Our exploratory study revealed that brachial artery flow-mediated dilation was significantly improved following 30-min exposure to intermittent negative pressure. Fluctuations in blood flow or shear rate, with unaltered mean shear, may have important implications for vascular health; however, further research is required to identify the underlying mechanisms and potential long-term health benefits.

Influence of Fitness on Vascular Function in Young Adults during Acute Inflammation

Acute inflammation is associated with increased risk of cardiovascular events and impairs vascular function. Vascular function in this setting is most often interrogated by assessing endothelial function in conduit arteries, however, less is known regarding the downstream vascular tree including resistance artery and microvasculature function. Vascular dysfunction during acute inflammation may be attenuated by high cardiorespiratory fitness due to its association with improved vascular function and cardiovascular health.PURPOSEDetermine the effect of acute inflammation and fitness on conduit artery, resistance artery, and microvascular function.METHODSVascular function was assessed in 11 low fit (6 male, 24 ± 5 yrs, 22.8 ± 4.3 kg/m2, 34.5 ± 2.9 ml/kg/min) and 12 high fit (5 male, 27 ± 4 yrs, 22.6 ± 1.9 kg/m2, 56.4 ± 9.7 ml/kg/min) participants at baseline and 24h after a typhoid vaccination. Fitness was determined using a maximal treadmill test and those with a VO2peak &gt;75th age‐ and sex‐specific percentile according to the American College of Sports Medicine were considered high fit. Vascular assessments included flow‐mediated dilation (FMD) of the brachial artery via ultrasonography, forearm reactive hyperemia (RH) via venous occlusion plethysmography, and near‐infrared spectroscopy (NIRS) during a 5‐min arterial occlusion. Blood pressure was measured using an oscillometric cuff and C‐reactive protein (CRP) and interleukin‐6 (IL‐6) were assessed via standard ELISA techniques.RESULTSAcute inflammation was induced, as evident by increases in IL‐6 and CRP (p&lt;0.01, see Table). Mean arterial pressure did not change in either group (low fit: 92 ± 9 to 91 ± 8; high fit: 92 ± 10 to 91 ± 7). FMD was lower in the high fit group, yet both groups reduced FMD at 24h, even after controlling for shear rate (p&lt;0.05). No effect of acute inflammation was observed for forearm RH or NIRS (p&gt;0.05). High fit individuals, however, had greater microvascular reactivity with a quicker ability to accommodate increased blood flow (time to peak, group effect, p&lt;0.05).CONCLUSIONFitness did not alter the vascular response to acute inflammation, regardless of the level along the vascular tree. Both groups showed reductions in conduit artery endothelial function and no change in resistance artery or microcirculatory function, suggesting acute inflammation has non‐uniform effects on vascular function. Cardiorespiratory fitness did not influence the arterial response to inflammation, at least in this young, healthy population. Future studies need to evaluate the effects of acute inflammation in older individuals including those who are healthy and those with chronic health conditions.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Comparison of Non‐Invasive Peripheral Vascular Function to Invasive Measures of Coronary Function in Patients with Suspected Coronary Microvascular Dysfunction

IntroductionThe purpose of this study is to compare non‐invasive vascular assessments to invasive gold standard measures of coronary flow and resistance in patients with suspected coronary microvascular dysfunction (CMD), a condition driven by systemic endothelial dysfunction. We hypothesize that non‐invasive measures will be associated with both coronary flow and resistance following pharmacological hyperemia.MethodsForty‐one patients with suspected CMD attended the Cardiovascular Integrative Physiology Clinic at Southlake Regional Health Centre. Patients underwent finger‐based arterial tonometry (RHPAT) to non‐invasively quantify microvascular endothelial function (EndoPAT). A subset of participants (n=15) also concurrently completed flow mediated dilation (FMD) of the brachial artery to assess conduit artery endothelial function. Briefly, a standard blood pressure cuff was positioned on the right arm of patients, distal to the elbow joint. Baseline recordings preceded 5 minutes of forearm ischemia, and was followed by cuff deflation, eliciting reperfusion. Within 4 months, patients underwent coronary reactivity testing using the Doppler guidewire method. Specifically, the coronary flow reserve (CFR), and the index of microvascular resistance (IMR) were calculated during pharmacologically‐induced hyperemia using adenosine, then acetylcholine, then dobutamine. Prior to each stimuli, baseline measures were obtained to ensure hemodynamics results to baseline.ResultsRHPAT was negatively correlated to the IMR during dobutamine (r=−0.39, p=0.04), but not the CFR (r=0.14, p=0.49). FMD was negatively correlated to the IMR during adenosine (r=−0.64, p=0.01), but not the CFR (r=0.29, p=0.30). RHPAT and FMD were not correlated to the IMR or CFR during acetylcholine.ConclusionThese preliminary results suggest that measures of non‐invasive peripheral vascular function can predict pharmacologically induced changes in coronary resistance, but not coronary flow.Support or Funding InformationSt. Jude MedicalThe Heart of Gold Cardiac Research FundYork UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Elevated high-density lipoprotein in adolescents with Type 1 diabetes is associated with endothelial dysfunction in the presence of systemic inflammation.

AimsHigh-density lipoprotein (HDL) function may be altered in patients with chronic disease, transforming the particle from a beneficial vasoprotective molecule to a noxious pro-inflammatory equivalent. Adolescents with Type 1 diabetes often have elevated HDL, but its vasoprotective properties and relationship to endothelial function have not been assessed.Methods and resultsSeventy adolescents with Type 1 diabetes (age 10–17 years) and 30 age-matched healthy controls supplied urine samples for the measurement of early renal dysfunction (albumin:creatinine ratio; ACR), blood samples for the assessment of cardiovascular risk factors (lipid profiles, HDL functionality, glycaemic control, and inflammatory risk score), and had their conduit artery endothelial function tested using flow-mediated dilation (FMD). HDL-c levels (1.69 ± 0.41 vs. 1.44 ± 0.29mmol/L; P < 0.001), and glycated haemoglobin (HbA1c) (8.4 ± 1.2 vs. 5.4 ± 0.2%; P < 0.001) were increased in all patients compared with controls. However, increased inflammation and HDL dysfunction were evident only in patients who also had evidence of early renal dysfunction (mean ± standard deviation for high-ACR vs. low-ACR and healthy controls: inflammatory risk score 11.3 ± 2.5 vs. 9.5 ± 2.4 and 9.2 ± 2.4, P < 0.01; HDL-mediated nitric-oxide bioavailability 38.0 ± 8.9 vs. 33.3 ± 7.3 and 25.0 ± 7.7%, P < 0.001; HDL-mediated superoxide production 3.71 ± 3.57 vs. 2.11 ± 3.49 and 1.91 ± 2.47nmol O2 per 250 000 cells, P < 0.05). Endothelial function (FMD) was impaired only in those who had both a high inflammatory risk score and high levels of HDL-c (P < 0.05).ConclusionIncreased levels of HDL-c commonly observed in individuals with Type 1 diabetes may be detrimental to endothelial function when accompanied by renal dysfunction and chronic inflammation.

Examining the acute effects of retrograde versus low mean shear rate on flow-mediated dilation.

Arterial endothelial function is acutely and chronically regulated by blood flow-associated shear stress. An acute intervention employing modest forearm cuff occlusion to simultaneously increase retrograde and decrease mean brachial artery shear rate for 30 min evokes transient impairments in flow-mediated dilation (FMD). However, the independent influence of the low mean versus the retrograde shear stress components is unclear. Healthy young adults [n = 24 (12 women, 12 men); 22 ± 2 yr, body mass index = 25 ± 2 kg/m2 (mean ± SD)] completed three laboratory visits within 1 wk. Visits consisted of 45 min of supine rest followed by a brachial artery FMD test (duplex ultrasound) before and after a 30-min intervention: control (shear rate unchanged), cuff (mean shear rate decreased, retrograde shear rate increased), or arterial compression (mean shear rate decreased, no increase in retrograde shear rate). The mean shear rate on the compression visit was targeted to match that achieved on the cuff visit. Cuff and compression trials decreased mean shear rate to a similar extent (cuff: 43 ± 22 s-1, compression: 43 ± 21 s-1; P = 0.850) compared with control (65 ± 21 s-1; both P < 0.001), with the retrograde component elevated only in the former (cuff: -83 ± 30 s-1, compression: -7 ± 5 s-1; P < 0.001). FMD decreased by 29 ± 30% (P < 0.001) after the cuff intervention and 32 ± 24% (P < 0.001) after the compression trial but was unchanged on the control visit (-0.3 ± 18%; P = 0.754). This was not altered by accounting for the shear rate stimulus. An increased retrograde shear stress does not appear to be obligatory for the transient reduction in FMD achieved after a 30-min exposure to low mean shear stress. These findings provide novel mechanistic insight on the regulation of endothelial function in vivo. NEW & NOTEWORTHY Low mean and retrograde shear stress are considered atherogenic; however, their relative contribution to the acute regulation of endothelial function in humans is unclear. Matched reductions in mean shear stress (30 min), with and without increases in retrograde shear stress, elicited equivalent reductions in flow-mediated dilation in men and women. These findings afford novel insight regarding the shear stress components governing the acute (dys)regulation of conduit artery endothelial function in vivo.