Vascular Function In Patients Research Articles

Leukotrienes E4 and B4 and vascular endothelium – New insight into the link between vascular inflammation and peripheral arterial

Leukotrienes are proinflammatory mediators that participate in the process of atherogenesis and contribute to the development of symptomatic peripheral arterial disease. The aim was to evaluate the relationship between leukotriene E4 (LTE4) and B4 (LTB4) with parameters reflecting endothelial vascular function in patients with chronic lower limb ischemia. This prospective observational study enrolled 50 consecutive patients undergoing endovascular treatment due to chronic lower limb ischemia (Rutherford 3). All participants were followed-up for one year (after 1, 3, 6 and 12 months), with a sequential assessment of urinary LTE4 and LTB4, as well as measures of endothelial and vascular function: Flow-Mediated Dilatation (FMD), Intima-Media Thickness (IMT), corrected Augmentation Index (AI75), Shear Rate (SR), Ankle-Brachial Index (ABI), Toe-Brachial Index (TBI). There was a significant relationship between LTE4 and measures of vascular function: FMD (R2 = 0.69, P < 0.001), IMT (R2 = 0.12, P < 0.01), AI75 (R2 = 0.43, P < 0.001), SR (R2 = 0.48, P < 0.001). Similar findings were noted for LTB4: FMD (R2 = 0.47, p < 0.001), IMT (R2 = 0.23, P < 0.001), AI75 (R2 = 0.61, P < 0.001) and SR (R2 = 0.33, P < 0.001). Alterations in parameters were significantly related: ΔLTE4 vs ΔFMD(R2 = 0.63, P < 0.001), ΔSR (R2 = 0.42, P < 0.001) and ΔLTB4 vs AI75(R2 = 0.40, P < 0.001), SR(R2 = 0. 29, P < 0.001). We conclude, that increasing concentrations of LTE4 and LTB4 are associated with impairment of vascular and endothelial function, which may lead to worse endovascular treatment clinical outcomes.

Effects of High Amylose-Resistant Starch on Gut Microbiota and Uremic Toxin Levels in Patients With Stage-G3a-G4 Chronic Kidney Disease: A Randomized Trial

ObjectiveThis study was designed to determine the effect of 16 weeks of supplementation with Hi-maize 260 resistant starch on the gut microbiota, uremic toxins (indoxyl sulfate and p-cresyl sulfate), markers of inflammation and oxidative stress along with vascular function in patients with stage G3a-G4 chronic kidney disease (CKD). Design& Methods: This was a double-blind, placebo-controlled, parallel-arm, randomized controlled trial. Sixty-eight patients with stage G3a-G4 CKD were randomized to either resistant starch with usual care or placebo and usual care. Patients attended four testing sessions: two baseline visits, and follow-up visits at 8 and 16 weeks. Fasting blood samples, resting brachial and central blood pressures, along with arterial stiffness, were collected at visits (1 or 2), and weeks 8 and 16. A stool sample was collected for analysis of microbial composition at baseline and week 16. Patients were randomized after the baseline visits. ResultsPatients receiving the resistant starch had a reduction in p-cresyl sulfate at week 16. This reduction was associated with a decrease in microbial α-diversity between baseline and week 16 (Chao1 p=0.014, Shannon p=0.017, PD p= 0.046, and Simpson p=0.017) as well as increases in Subdoligranulum (p=0.03) and Oscillospiraceae UCG 002 (p=0.02) and decreases in Bacteroides (p=0.009).There were no changes in microbial beta diversity and other biomarkers or markers of vascular function following the 16-week period Conclusion: Sixteen weeks of supplementation of resistant starch in patients with stage G3a-G4 CKD led to changes in microbial composition that were associated with a significant reduction in p-cresyl sulfate.

Vascular function in patients with advanced heart failure and continuous-flow or pulsatile ventricular assist devices.

A significant proportion of patients with heart failure (HF) progress to an advanced stage, which is associated with a substantial increase in morbidity and mortality. These patients may be eligible for advanced treatment strategies such as mechanical circulatory support with ventricular assist devices (VAD). Vascular dysfunction is a hallmark of heart failure pathophysiology and prognosis. However, whether and to what degree the hemodynamic benefits of VADs influence vascular function remain unknown. In this study, we evaluated endothelial vascular function with flow-mediated vasodilatation (FMD) and with flicker-light induced retinal vasodilatation (FID). 34 patients with a VAD (age 58 ± 10years, 85% male, 74% ischemic heart disease, 26 continuous-flow (CF)-LVAD, and 8 pulsatile biventricular (bi)-VAD) were compared to 34 propensity-matched patients (mean age 62 ± 9years, 68% male, 59% ischemic heart disease) with advanced HF (AdvHF). Endothelial function of larger arteries (FMD) was significantly better in patients after VAD implantation compared to matched AdvHF patients (7.2 ± 4.6% vs. 5.0 ± 3.2%, p = 0.03), whereas microvascular arteriolar function (FIDart) did not differ (0.99 ± 1.43% vs. 1.1 ± 1.7%, p = 0.78). The arterio-venous ratio (AVR) was higher in the VAD group (0.90 ± 0.06 vs 0.85 ± 0.09, p = 0.01), reflecting wider retinal arteriolar and narrower venular diameters. There was no difference in vascular function between patients with CF-LVAD and pulsatile Bi-VAD. In patients with advanced heart failure, VAD implantation was associated with better endothelial function at the level of large arteries, but not in the microcirculation.

The Effect of 4-Month Treatment with Glycocalyx Dietary Supplement on Endothelial Glycocalyx Integrity and Vascular Function in Patients with Psoriasis.

Psoriasis predisposes to cardiovascular dysfunction. We investigated whether glycocalyx dietary supplement (GDS), which contains glycosaminoglycans and fucoidan, improves endothelial glycocalyx and arterial stiffness in psoriatic patients. Fifty participants with psoriasis under biological agents were randomly assigned to GDS (n = 25) or placebo (n = 25) for 4 months. We measured at baseline and at follow-up: (a) perfused boundary region (PBR) of the sublingual microvessels (range 4 to 25 μm), a marker of endothelium glycocalyx integrity; (b) carotid-femoral pulse wave velocity (PWV-Complior SP-ALAM) and augmentation index (AIx), markers of arterial stiffness and (c) psoriasis area and severity index (PASI) score. Both groups displayed a similar decrease in PASI at four months (p < 0.05), and no significant differences were found between groups (p > 0.05). Compared to the placebo, participants in the GDS showed a greater percentage reduction in PBR4-25 μm (-9.95% vs. -0.87%), PBR 4-9 μm (-6.50% vs. -0.82%), PBR10-19 μm (-5.12% vs. -1.60%), PBR 20-25 μm (-14.9% vs. -0.31%), PWV (-15.27% vs. -4.04%) and AIx (-35.57% vs. -21.85%) (p < 0.05). In the GDS group, the percentage reduction in PBR 4-25 μm was associated with the corresponding decrease in PWV (r = 0.411, p = 0.015) and AΙx (r = 0.481, p = 0.010) at follow-up. Four-month treatment with GDS improves glycocalyx integrity and arterial stiffness in patients with psoriasis. Clinical trial Identifier: NCT05184699.

Effects of short-term dietary nitrate supplementation on exercise and coronary blood flow responses in patients with peripheral artery disease.

Peripheral arterial disease (PAD) is a prevalent vascular disorder characterized by atherosclerotic occlusion of peripheral arteries, resulting in reduced blood flow to the lower extremities and poor walking ability. Older patients with PAD are also at a markedly increased risk of cardiovascular events, including myocardial infarction. Recent evidence indicates that inorganic nitrate supplementation, which is abundant in certain vegetables, augments nitric oxide (NO) bioavailability and may have beneficial effects on walking, blood pressure, and vascular function in patients with PAD. We sought to determine if short-term nitrate supplementation (via beetroot juice) improves peak treadmill time and coronary hyperemic responses to plantar flexion exercise relative to placebo (nitrate-depleted juice) in older patients with PAD. The primary endpoints were peak treadmill time and the peak coronary hyperemic response to plantar flexion exercise. Eleven PAD patients (52-80 yr.; 9 men/2 women; Fontaine stage II) were randomized (double-blind) to either nitrate-rich (Beet-IT, 0.3 g inorganic nitrate twice/day; BRnitrate) or nitrate-depleted (Beet-IT, 0.04 g inorganic nitrate twice/day, BRplacebo) beetroot juice for 4 to 6 days, followed by a washout of 7 to 14 days before crossing over to the other treatment. Patients completed graded plantar flexion exercise with their most symptomatic leg to fatigue, followed by isometric handgrip until volitional fatigue at 40% of maximum on day 4 of supplementation, and a treadmill test to peak exertion 1-2 days later while continuing supplementation. Hemodynamics and exercise tolerance, and coronary blood flow velocity (CBV) responses were measured. Although peak walking time and claudication onset time during treadmill exercise did not differ significantly between BRplacebo and BRnitrate, the diastolic blood pressure response at the peak treadmill walking stage was significantly lower in the BRnitrate condition. Increases in CBV from baseline to peak plantar flexion exercise after BRplacebo and BRnitrate showed a trend for a greater increase in CBV at the peak workload of plantar flexion with BRnitrate (p = 0.06; Cohen's d = 0.56). Overall, these preliminary findings suggest that inorganic nitrate supplementation in PAD patients is safe, well-tolerated, and may improve the coronary hyperemic and blood pressure responses when their calf muscles are most predisposed to ischemia.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT02553733.

Investigating the Relationship Between Clinical Characteristics, Mental Health, and Vascular Function in Minor Ischemic Stroke or Transient Ischemic Attack Patients.

Over the past decade, there has been extensive research exploring the relationship between vascular health and mental well-being, encompassing aspects such as mood and cognition. However, there is a notable gap in research focusing on the mental and vascular conditions of minor ischemic stroke or transient ischemic attack (TIA) patients, particularly within the Thai population. To investigate the clinical characteristics and mental issues related to vascular functions in patients who have experienced a minor ischemic stroke or TIA. This study, approved by the Buriram Hospital Ethics Committee (IRB: BR0033.102.1/8), adhered to the guidelines of the Helsinki Declaration and obtained informed consent from all participants. A prospective cross-sectional study was conducted at Buriram Hospital, a government regional hospital located in Buriram province, Thailand, involving twenty-three participants diagnosed with minor ischemic stroke or TIA. Measurements included clinical characteristics, Hospital Anxiety and Depression Scale-part Anxiety (HADS-A), Hospital Anxiety and Depression Scale-part Depression (HADS-D), mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), flow-mediated dilation (FMD), and brachial-ankle pulse wave velocity (baPWV). Linear regression analysis was employed to investigate the factors associated with vascular function (FMD and baPWV). The factor related to FMD was HADS-D (β = -0.5, 95% CI -0.33 to -0.04). Factors associated with baPWV included age (β = 0.51, 95% CI 5.05 to 39.50) and the duration of minor ischemic stroke or TIA (β = 0.48, 95% CI 25.41 to 290.99). FMD shows a connection with depressive symptoms in patients with minor ischemic stroke or TIA. Therefore, it is important to detect and provide appropriate treatment for depressive symptoms in these patients, as it may lead to improvements in vascular function and better cerebrovascular outcomes.

Relationship of Warfarin and Apixaban with Vascular Function in Patients with Atrial Fibrillation

Introduction: Atrial fibrillation (AF) is associated with endothelial damage/dysfunction. Herein, we tested the hypothesis that brachial artery flow-mediated dilation (FMD) is superior in AF patients taking apixaban compared to warfarin. Methods: AF patients on apixaban (n = 46; 67 [7] years; mean [standard deviation]; 15 women) and warfarin (n = 27; 73 [9] years (p < 0.01); 11 women) were recruited. Duplex Doppler ultrasound imaging was undertaken during baseline (2 min), cuff inflation (5 min), and following cuff deflation (3 min). FMD was defined as peak increase in brachial artery diameter following cuff deflation and analysed as percentage change in diameter, as a ratio of FMD, shear rate area under the curve (SR_AUC; FMD-to-SR_AUC), and using SR_AUC as a covariate (FMD_SR). Results: Baseline artery diameter (4.96 [1.14] vs. 4.89 [0.88] mm), peak diameter (5.12 [1.17] vs. 5.14 [0.93] mm), and FMD_SR (3.89 [3.62] vs. 4.80 [3.60] %) were not different between warfarin and apixaban (p > 0.05; analysis of covariance with age, CHA₂DS₂-VASc, years since AF diagnosis, number of diabetics, alcohol drinkers, and units of alcohol consumed per week as covariates). Stepwise multiple regression identified independent association of fibrillation, hypertension, and increased age with FMD. Conclusion: AF patients on warfarin and apixaban exhibit similar endothelium-dependent vasodilation. Increased blood pressure negatively impacts vasodilator capacity in AF patients.

Relationship between peri-coronary inflammation and coronary vascular function in patients with suspected coronary artery disease.

In this study, we aim to investigate the relationship between the attenuation of peri-coronary adipose tissue (PCAT) in patients with suspected coronary artery disease (CAD) and the assessment of coronary vascular functions using coronary flow reserve (CFR). We included 364 patients who underwent 13N-NH3 positron emission tomography/computed tomography and coronary computed tomography angiography (CCTA). We determined the relationship between fat attenuation index (FAI), PCAT volume, and other qualitative CT-derived anatomic parameters with CFR. We detected a decrease in CFR (<2.5) in 206 (57%) patients. At the patient level, those with reduced CFR showed a significantly higher prevalence of diffused atherosclerosis (41% vs. 23%; P < 0.001) and higher FAI (-75.5 HU vs. -77.1 HU; P = 0.014). In patients without obstructive CAD, FAI was significantly higher in those with reduced CFR (-75.5 HU vs. -77.7 HU, P = 0.026). On the vessel level, 1,092 vessels were analyzed, and 642 (59%) exhibited reduced CFR. The vessels with reduced CFR presented a significantly higher prevalence of obstructive CAD (37% vs. 26%; P < 0.001), diffused atherosclerosis (22% vs. 11%; P < 0.001), low-attenuation plaque (6% vs. 3%; P = 0.030), and positive remodeling (7% vs. 2%; P = 0.001). FAI was higher in vessels with reduced CFR (-80.8 HU vs. -81.8 HU; P = 0.045) than in normal CFR. In the patient-level analysis, obstructive CAD, diffused atherosclerosis, and FAI were independently linked with CFR. FAI was still associated with global CFR after adjusting for traditional risk factors (age, hypertension, diabetes, hyperlipidemia, and smoking). FAI remained independently associated with reduced CFR in patients without obstructive CAD. Coronary perivascular inflammation evaluated by CCTA was independently associated with coronary vascular function. In patients without obstructive CAD, FAI was higher in the presence of reduced CFR. Altogether, FAI can help reveal microcirculatory damage in patients who do not exhibit epicardial artery stenosis.

Serum Fibroblast Growth Factor 23 Levels are Associated with Vascular Smooth Muscle Dysfunction in Type 2 Diabetes.

Increased level of serum fibroblast growth factor 23 (FGF23) is a hallmark of abnormal phosphate metabolism in patients with chronic kidney disease (CKD) and is recently shown to be associated with the risk of cardiovascular disease even in those without CKD. This study investigated the association between serum FGF23 levels and vascular function in patients with type 2 diabetes. This was a cross-sectional study involving 283 Japanese patients with type 2 diabetes. Flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) of the brachial artery were measured via ultrasonography to evaluate vascular endothelial and smooth muscle functions, respectively. Serum intact FGF23 levels were determined via a sandwich enzyme-linked immunosorbent assay. The median values of FMD, NMD, and serum FGF23 were 6.0%, 14.0%, and 27.3 pg/mL, respectively. The serum FGF23 levels were inversely associated with NMD but not with FMD, and the association was independent of atherosclerotic risk factors, estimated glomerular filtration rate (eGFR), and serum phosphate levels. Furthermore, the relationship between serum FGF23 levels and NMD was modified by kidney function, which was pronounced in subjects with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2). Serum FGF23 levels are independently and inversely associated with NMD in patients with type 2 diabetes, particularly in those with normal kidney function. Our results indicate that FGF23 is involved in vascular smooth muscle dysfunction and that increased serum levels of FGF23 may serve as a novel biomarker for vascular smooth muscle dysfunction in patients with type 2 diabetes.

Impact of overnight 1 mg dexamethasone on vascular function in patients with nonfunctioning adrenal adenomas

The purpose of this study was to evaluate the effects of administration of overnight 1 mg dexamethasone on vascular function in patients with nonfunctioning adrenal adenomas (NFA). Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were measured to assess vascular function in 22 patients with NFA who had hypertension and/or diabetes mellitus (DM) and 272 patients without adrenal incidentalomas who had hypertension and/or DM (control patients with hypertension and/or DM). FMD and NID were measured in the morning before and after administration of 1 mg of dexamethasone at 2300 h in 18 patients with NFA. There were no significant differences in FMD and NID between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM (3.4 ± 2.8% vs. 2.9 ± 1.9% and 11.5 ± 5.7% vs. 11.4 ± 4.3%, P = 0.46, and P = 0.99, respectively). There were no significant differences in vascular function between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM even after adjustment for cardiovascular risk factors. Overnight 1 mg dexamethasone increased FMD from 2.4 ± 1.9% to 5.3 ± 3.2% (P < 0.01) and increased NID from 12.1 ± 4.2% to 14.0 ± 2.8% (P < 0.01) in patients with NFA. The overnight 1 mg dexamethasone suppression test does not impair FMD and NID in patients with NFA. Decreases in circulating levels of cortisol may improve vascular function.Clinical Trial Registration: This study was approved by principal authorities and ethical issues in Japan (URL for Clinical Trial: http://www.umin.ac.jp/ctr/index.htm Registration Number for Clinical Trial: UMIN000039512).

Olive extract enriched with hydroxytyrosol improves cardiac and vascular function in patients with stable coronary artery disease: a double-blind, placebo-controlled trial

Abstract Aims We investigated the effect of olive extract enriched with hydroxytyrosol, on vascular and myocardial function markers in patients with stable coronary artery disease (SCAD). Methods In a prospective, cross-over, double-blind, placebo-controlled, clinical trial, 30 patients with stable CAD were randomly assigned to an oral supplement containing olive oil extract enriched with hydroxytyrosol (OOHT) or placebo for one month and then were crossed over to the alternate treatment (placebo or OOHT for one more month). We measured a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), b) flow-mediated dilation (FMD), c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography d) Pulse Wave Velocity (PWV) e) oxidative/nitrosative stress and inflammatory biomarkers and blood lipids at baseline and after one month treatment. Results Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.81±0.35 vs 1.77±0.40 μm p=0.04 3.71±2.12 vs 6.51±2.31%, p&amp;lt;0.001;2.37±0.40 vs 2.45±0.41, p=0.030 and 11.03±1.81 vs 11.78±2.34 m/sec, p=0.002), while there was no effect after placebo (p&amp;gt;0.05). Compared to baseline, treatment with OOHT reduced malondialdehyde (MDA) a marker of lipid peroxidation (2.10±1.37 vs 1.69±0.83 mmol/lt, p=0.045), oxidized LDL, triglycerides, PCSK9 and CRP blood levels (p&amp;lt;0.05) in contrast to placebo. There was a parallel improvement of E’ of the mitral annulus and deceleration time of the E wave of mitral inflow after OOHT (p&amp;lt;0.05) but not after placebo. Conclusions Olive extract enriched with hydroxytyrosol improves endothelial and arterial function likely by reducing oxidative and inflammatory burden leading to improved LV diastolic function after one month of treatment in patients with stable CAD.

SGLT2 Inhibition Improves Vascular Function in Patients with Type 2 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Crossover Trial

SGLT2 Inhibition Improves Vascular Function in Patients with Type 2 Diabetes: A Double-Blind, Randomized, Placebo-Controlled Crossover Trial

Effect of regulated vitamin D increase on vascular markers in patients with chronic kidney disease: A systematic review and meta-analysis of randomized controlled trials

AimThe effect of increased vitamin D levels on vascular function in patients with chronic kidney disease (CKD) is controversial. This meta-analysis aimed to assess the effect of regulated vitamin D increase on vascular markers in patients with CKD. Data synthesisWe searched PubMed, Web of Science, Embase and ClinicalTrials.gov from database inception up until July 21, 2023. We included randomized controlled trials assessing the effects of using vitamin D and its analogues on vascular function in patients with CKD. Fixed-effects and random-effects model analyses were performed using weighted mean difference effects for each trial by heterogeneity (I2) assessment. Primary outcomes encompassed blood flow-mediated dilation (FMD)、pulse wave velocity (PWV) and augmentation index (AIx). FindingsFrom 1964 records we selected 12 trials, 5 (n = 331) on FMD, 8 (n = 626) on PWV and 4 (n = 393) on AIx. Vitamin D and VDRA supplementation failed to significantly improve FMD (WMD 1.68%; 95% CI -0.18 to 3.53; P = 0.08; I2 = 88%)、PWV (WMD -0.41 m/s; 95%CI -0.95 to 0.13; P = 0.14; I2 = 57%)and AIx (WMD -0.53%; 95%CI -1.69 to 0.63; P = 0.37; I2 = 0%). Subgroup analysis revealed that 2 μg paricalcitol significantly improved FMD (WMD 2.09%; 95%CI 1.28 to 2.90; P < 0.00001); I2 = 0%), as did cholecalciferol (WMD 5.49%; 95% CI 4.35 to 6.63; P < 0.00001). ConclusionSupplementation vitamin D and VDRA are associated with improved vascular function as measured by FMD, but not arterial stiffness as measured by PWV and AIx, tentatively suggesting that regulating the increase of vitamin D could not potentially reduce the incidence of cardiovascular disease.

The Effects of Exercise Training on Exercise Capacity and Vascular Function after Transcatheter Aortic Valve Implantation-A Pilot Study.

Transcatheter aortic valve implantation (TAVI) improves event-free survival in patients with severe aortic stenosis, but patients' exercise capacity remains poor after the procedure. Therefore, we sought to compare the effects of a supervised center-based exercise training program and unsupervised exercise routine on exercise capacity and vascular function in patients after TAVI. Patients were randomized to either center-based exercise training (12-24 sessions of combined aerobic and low-weight resistance training twice weekly for 8-12 weeks) or an unsupervised home-based exercise routine (initial appraisal with detailed recommendations and monthly follow-up). Exercise capacity (cardiopulmonary testing) and vascular function (ultrasonographic measurement of flow-mediated vasodilation (FMD) and arterial stiffness) were assessed at the baseline and after the study period. We included 23 patients (mean age of 81 years, 61% women), with higher-than-expected drop-out rates (41%) because of the coronavirus-19 pandemic outbreak. Exercise capacity improved over time, irrespective of the intervention group: 0.09 mL/min/kg increase in peak oxygen uptake (95% CI [0.01-0.16]; p = 0.02), 8.2 Watts increase in workload (95% CI [0.6-15.8]; p = 0.034), and 47 s increase in cumulative exercise time (95% CI [5.0-89.6]; p = 0.029). A between-group difference in change over time (treatment effect) was detected only for FMD (4.49%; 95% CI [2.35; 6.63], p < 0.001), but not for other outcome variables. Both supervised and unsupervised exercise training improve exercise capacity and vascular function in patients after TAVI, with supervised exercise training possibly yielding larger improvements in vascular function, as determined by FMD.

Olive extract enriched with hydroxytyrosol improves cardiac and vascular function in patients with stable coronary artery disease: a double-blind, placebo-controlled trial

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Olive Heart Operational Programme Competitiveness, Entrepreneurship and Innovation 2014–2020 (EPAnEK) Aims We investigated the effect of olive extract enriched with hydroxytyrosol, on vascular and myocardial function markers in patients with stable coronary artery disease (SCAD). Methods In a prospective, cross-over, double-blind, placebo-controlled, clinical trial, 30 patients with stable CAD were randomly assigned to an oral supplement containing olive oil extract enriched with hydroxytyrosol (OOHT) or placebo for one month and then were crossed over to the alternate treatment (placebo or OOHT for one more month). We measured a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), b) flow-mediated dilation (FMD), c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography d) Pulse Wave Velocity (PWV) e) oxidative/nitrosative stress and inflammatory biomarkers and blood lipids at baseline and after one month treatment. Results Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.81±0.35 vs 1.77±0.40 μm p = 0.04 3.71±2.12 vs 6.51±2.31%, p&amp;lt;0.001;2.37±0.40 vs 2.45±0.41, p = 0.030 and 11.03±1.81 vs 11.78±2.34 m/sec, p = 0.002), while there was no effect after placebo (p&amp;gt;0.05). Compared to baseline, treatment with OOHT reduced malondialdehyde (MDA) a marker of lipid peroxidation (2.10±1.37 vs 1.69±0.83 mmol/lt, p = 0.045), oxidized LDL, triglycerides, PCSK9 and CRP blood levels (p&amp;lt;0.05) in contrast to placebo. There was a parallel improvement of E’ of the mitral annulus and deceleration time of the E wave of mitral inflow after OOHT (p&amp;lt;0.05) but not after placebo. Conclusions Olive extract enriched with hydroxytyrosol improves endothelial and arterial function likely by reducing oxidative and inflammatory burden leading to improved LV diastolic function after one month of treatment in patients with stable CAD.

Frequency and Clinical Impact of Family History of Coronary Artery Disease in Patients with Vasospastic Angina.

Family history (FH) of coronary artery disease (CAD) [FH-CAD] is a well-known risk factor for atherosclerotic CAD. However, FH-CAD frequency in patients with vasospastic angina (VSA) remains unknown, and the clinical characteristics and prognosis of VSA patients with FH-CAD are unclear. Therefore, this study compared FH-CAD frequency between patients with atherosclerotic CAD and those with VSA and examined the clinical characteristics and prognosis of VSA patients with FH-CAD. Coronary angiography and spasm provocation tests (SPT) were used to investigate chest pain of coronary artery origin in patients classified into atherosclerotic CAD (362 cases), VSA (221 cases; positive for SPT) and non-VSA (73 cases; negative for SPT) groups, with FH-CAD being defined. In the VSA group, flow-mediated vasodilation (FMD) and nitroglycerin-independent vasodilation (NID) via brachial artery echocardiography and clinical symptoms in the groups with and without FH-CAD were checked, with Kaplan-Meier curves revealing major adverse cardiovascular events (cardiac death and rehospitalisation for cardiovascular disease) between the two groups. The atherosclerotic CAD group had a significantly lower FH-CAD frequency (12%, p = 0.029) than the VSA (19%) and non-VSA groups (19%). FH-CAD was more common in females in the VSA and non-VSA groups than in the atherosclerotic CAD group (p < 0.001). Nonpharmacological treatment for CAD in FH-CAD was more common in the atherosclerotic CAD group (p = 0.017). In the VSA group, FH-CAD tended to be more common in females (p = 0.052). Although no differences in FMD of the brachial artery were observed between the groups, the FH-CAD (+) group had significantly higher NID than the FH-CAD (-) group (p = 0.023). Kaplan-Meier's analysis revealed a similar prognosis between the two groups, and other clinical characteristics did not differ. Patients with VSA have a higher FH-CAD frequency than those with atherosclerotic CAD, especially in females. Although FH-CAD may affect vascular function in patients with VSA, its effect on the severity and prognosis of VSA appears to be minimal. FH-CAD and its confirmation may assist in CAD diagnosis, especially in female patients.

Abstract 690: Circulating Proteomics And Endothelial Cell Phenotype In Patients With Type 2 Diabetes Mellitus (T2DM)

Patients with T2DM display endothelial dysfunction that predicts cardiovascular risk. We have previously demonstrated reduced eNOS activation in endothelial cells (ECs) isolated from patients with T2DM. We sought to identify drivers of EC dysfunction using a combination of proteomic and transcriptomic approaches by measuring: serum O-link cardiovascular panels II and III along with insulin-mediated eNOS phosphorylation and miRNA profiling (NextGen sequencing) in isolated ECs. In 69 patients (37 with T2DM and 32 age- and sex-similar non-T2DM controls) proteomic analysis identified 35 upregulated and 6 downregulated (FDR p&lt;0.05) proteins that included metabolic, vascular and fluid homeostasis, immune and apoptosis related biomarkers. Several biomarkers related to the degree of insulin-mediated eNOS phosphorylation in isolated EC: (renin r= -0.38, p=0.004, chymotrypsin C r= 0.37, p=0.006, paraoxinase 3, r= 0.35, p=0.009, lipoprotein lipase r= 0.34, p=0.01, superoxide dismutase 2 r= 0.31, p=0.02 and adrenomedullin r= -0.27, p=0.049). In a subset of 10 patients (5/group), we confirmed expression of EC-specific miRNA in ECs purified by CD144 microbeads. Comparing patients with T2DM and controls we found 6 upregulated and 7 downregulated miRNAs (FDR P&lt;0.05). Ingenuity Pathway Analysis shows that these miRNAs are involved in the regulation of inflammation, glucose metabolism, stress signaling and cell cycle pathways. Further we found overlap of differentially expressed miRNA with predicted regulation of biomarkers that were altered in T2DM including: miR-4326 and miR-1270 regulate TNFRSF10A and ALCAM, while, miR-4433-5p and miR-342-3p are involved in regulation of superoxide dismutase 2. Our findings demonstrate that an association of circulating biomarkers particularly those that relate to fluid metabolism and oxidative stress with altered endothelial cell signaling in patients with T2DM. Further we have early evidence of altered non-coding miRNA expression in ECs in T2DM that may be related to inflammation and oxidative stress. Ongoing studies are evaluating the functional implications of altered miRNA expression in regulating vascular function in patients with T2DM.

Decreased peripheral vascular function in patients with stage 3 and 4 chronic kidney disease who have elevated symmetric dimethylarginine but not asymmetric dimethylarginine

Cardiovascular disease is a leading cause of death in chronic kidney disease (CKD), yet the mechanisms remain unclear. Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous nitric oxide synthase inhibitors shown to be independent risk markers for cardiovascular disease. Previous research has predominantly focused on ADMA as a primary risk marker of reduced vascular function and increased cardiovascular mortality in end-stage (stage 5) CKD. However, limited research has explored the potential roles of ADMA and SDMA in relation to vascular function in the middle stages (stages 3 and 4) of CKD. Therefore, we tested the hypothesis that patients with stage 3-4 CKD would have elevated circulating ADMA and SDMA, which would correspond to a reduced vascular function compared to controls. We studied 17 patients with stage 3-4 CKD (age: 66 ± 7 years, 5 males, eGFR: 44 ± 16 ml/min/1.73m 2 ) and 8 controls (age: 59 ± 7 years; 3 males, eGFR: 81 ± 14 ml/min/1.73m 2 ). ADMA and SDMA were assessed in whole blood serum using liquid chromatography/tandem mass spectrometry by a commercial laboratory (Quest diagnostics). Macro- and micro-vascular function were assessed as brachial artery flow-mediated dilation (FMD; %) and peak reactive hyperemia blood velocity, respectively, using duplex Doppler ultrasound. Arterial stiffness was assessed as carotid-femoral pulse wave velocity (cfPWV) using arterial tonometry. Data are expressed as mean ± standard deviation. Interestingly, we found that SDMA (control: 103 ± 14, CKD: 143 ± 42 ng/mL, p=0.01) but not ADMA (control: 109 ± 7; CKD: 111 ± 28 ng/mL, p=0.40) was significantly elevated in patients with CKD compared to controls. FMD was significantly reduced in the CKD group (control: 5.04 ± 2.59.; CKD: 3.18 ± 1.98 %, p=0.03), while peak blood velocity was similar between groups (control: 53.47 ± 10.40, CKD: 59.72 ± 23.99 cm/s, p=0.25). There tended to be a negative relationship between SDMA concentrations and FMD (R= -0.31, p=0.07), whereas there was no relationship between ADMA and FMD (R= 0.22, p=0.14). Arterial stiffness was also significantly greater in the patient with CKD compared to controls (control: 6.74 ± 0.91, CKD: 7.95 ± 1.60 m/s, p=0.034). These data suggest that patients with stage 3-4 CKD who have elevated circulating SDMA but not ADMA exhibit an impaired macro-vascular function. Moreover, an augmented cfPWV also suggests increased arterial stiffness in patients with CKD with elevated SDMA. Collectively, these preliminary findings suggest that SDMA, but not ADMA, may play a more predominant role in mediating impaired vascular function in the middle stages of CKD. This project was supported by the National Heart, Lung, and Blood Institute R01 HL-127071. 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 Function Is Preserved in Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy

Heart failure (HF) is associated with endothelial dysfunction. Vascular function per se plays an important role in cardiac function, whether it is a cause or consequence. However, there is no information on vascular function in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). The purpose of this study was to evaluate vascular function in patients with ATTRwt-CM. We measured flow-mediated vasodilation (FMD) as an index of endothelial function and nitroglycerine-induced vasodilation (NID) as an index of vascular smooth muscle function and brachial artery intima-media thickness (bIMT) and brachial-ankle pulse wave velocity (baPWV) as indices of arterial stiffness in 22 patients with ATTRwt-CM and in 22 one-by-one matched control patients using vascular function confounding factors. FMD was significantly greater in patients with ATTRwt-CM than in the controls (5.4 ± 3.4% versus 3.5 ± 2.4%, p = 0.038) and the N-terminal pro-brain natriuretic peptide (NT-proBNP) level was significantly greater in patients with ATTRwt-CM than in the controls (2202 ± 1478 versus 470 ± 677 pg/mL, p < 0.001). There were no significant differences in NID, bIMT or baPWV between the two groups. There was a significant relationship between NT-proBNP and FMD in patients with ATTRwt-CM (r = 0.485, p = 0.022). NT-proBNP showed no significant relationships with NID, bIMT or baPWV. Conclusions: Endothelial function was preserved in patients with ATTRwt-CM. Patients with ATTRwt-CM may have compensatory effects with respect to endothelial function through elevation of BNP.

Effect of olmesartan and amlodipine on serum angiotensin-(1–7) levels and kidney and vascular function in patients with type 2 diabetes and hypertension

BackgroundRecent studies suggest that angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1–7) [Ang-(1–7)] might have beneficial effects on the cardiovascular system. We investigated the effects of olmesartan on the changes in serum ACE2 and Ang-(1–7) levels as well as kidney and vascular function in patients with type 2 diabetes and hypertension.MethodsThis was a prospective, randomized, active comparator-controlled trial. Eighty participants with type 2 diabetes and hypertension were randomized to receive 20 mg of olmesartan (N = 40) or 5 mg of amlodipine (N = 40) once daily. The primary endpoint was changes of serum Ang-(1–7) from baseline to week 24.ResultsBoth olmesartan and amlodipine treatment for 24 weeks decreased systolic and diastolic blood pressures significantly by > 18 mmHg and > 8 mmHg, respectively. Serum Ang-(1–7) levels were more significantly increased by olmesartan treatment (25.8 ± 34.5 pg/mL → 46.2 ± 59.4 pg/mL) than by amlodipine treatment (29.2 ± 38.9 pg/mL → 31.7 ± 26.0 pg/mL), resulting in significant between-group differences (P = 0.01). Serum ACE2 levels showed a similar pattern (6.31 ± 0.42 ng/mL → 6.74 ± 0.39 ng/mL by olmesartan treatment vs. 6.43 ± 0.23 ng/mL → 6.61 ± 0.42 ng/mL by amlodipine treatment; P < 0.05). The reduction in albuminuria was significantly associated with the increases in ACE2 and Ang-(1–7) levels (r = − 0.252 and r = − 0.299, respectively). The change in Ang-(1–7) levels was positively associated with improved microvascular function (r = 0.241, P < 0.05). Multivariate regression analyses showed that increases in serum Ang-(1–7) levels were an independent predictor of a reduction in albuminuria.ConclusionsThese findings suggest that the beneficial effects of olmesartan on albuminuria may be mediated by increased ACE2 and Ang-(1–7) levels. These novel biomarkers may be therapeutic targets for the prevention and treatment of diabetic kidney disease.Trial registration: ClinicalTrials.gov NCT05189015.