Change In Flow-mediated Dilation Research Articles

Acute daily exposure to ambient air pollution impairs endothelium-dependent vasodilator responses in young, healthy individuals.

Exposure to ambient air pollution influences cardiovascular (CV) morbidity and mortality. The differential effects of changing particulate or gaseous air pollution on endothelial function in young healthy individuals remain unclear. The aim of this study was to evaluate the relationships between exposures to different pollutants and vascular function in a group of 39 young (33±11 years old) subjects with low CV risk. Flow-mediated dilatation (FMD) and nitroglycerin-mediated dilatation (NMD) were performed, when air pollution reached highest levels (heating period) and repeated in a subgroup of 18 participants a few months later (just before the heating period starts). Daily mean concentrations of PM2.5 and PM10 were inversely correlated with FMD, and this relationship remained significant after adjusting for factors known to affect vascular dysfunction. Endothelial function did not differ between the two time points studied. However, we observed a strong inverse association between the change in the concentration of particulate matter (deltaPM2.5 and deltaPM10) and the change in FMD (deltaFMD) between the two visits (R= -0.65, p= 0.02; R= -0.64, p= 0.02, respectively). In summary, we provide evidence that the concentration of PM2.5 and PM10, but not SO2, NO, NO2, CO, or O3 is associated with impaired endothelial function in young, healthy individuals.

Transiently impaired endothelial function during thyroid hormone withdrawal in differentiated thyroid cancer patients.

Endothelial dysfunction, which was associated with chronic hypothyroidism, was an early event in atherosclerosis. Whether short-term hypothyroidism following thyroxine withdrawal during radioiodine (RAI) therapy was associated with endothelial dysfunction in patients with differentiated thyroid cancer (DTC) was unclear. Aim of the study was to assess whether short-term hypothyroidism could impair endothelial function and the accompanied metabolic changes in the whole process of RAI therapy. We recruited fifty-one patients who underwent total thyroidectomy surgery and would accept RAI therapy for DTC. We analyzed thyroid function, endothelial function and serum lipids levels of the patients at three time points: the day before thyroxine withdrawal(P1), the day before 131I administration(P2) and 4-6 weeks after RAI therapy(P3). A high-resolution ultrasound named flow-mediated dilation (FMD) was used to measure endothelial function of the patients. We analyzed the changes of FMD, thyroid function and lipids at three time points. FMD(P2) decreased significantly compared to FMD(P1) (P1vsP2, 8.05 ± 1.55vs 7.26 ± 1.50, p<0.001). There was no significant difference between FMD(P3) and FMD(P1) after restoring TSH (thyroid stimulating hormone) suppression therapy (P1 vs P3, 8.05 ± 1.55 vs 7.79 ± 1.38, p=0.146). Among all parameters, the change of low-density lipoprotein (ΔLDL) was the only factor correlated negatively with the change of FMD (ΔFMD) throughout the RAI therapy process (P1-2, r=-0.326, p=0.020; P2-3, r=-0.306, p=0.029). Endothelial function was transiently impaired in DTC patients at short-term hypothyroidism state during the RAI therapy, and immediately returned to the initial state after restoring TSH suppression therapy.

Pulmonary rehabilitation and endothelial function in patients with chronic obstructive pulmonary disease: A prospective cohort study

BackgroundChronic obstructive pulmonary disease (COPD) is associated with subclinical atherosclerosis and endothelial dysfunction, thereby leading to increased cardiovascular risk. In the present study, we evaluated the changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of severe COPD patients undergoing pulmonary rehabilitation. MethodsConsecutive COPD patients referred to our Pulmonary Rehabilitation Unit were screened for inclusion. All study procedures were performed at hospital admission and discharge. ResultsOf 78 patients screened for eligibility, a total of 40 participants (67.5% males, median age 72.5 years) were included. After pulmonary rehabilitation, a significant improvement in functional parameters, exercise capacity, and measures of disability and quality of life were documented. FMD changed from 3.25% (IQR: 2.31–4.26) to 4.95% (IQR: 3.57–6.02), corresponding to a 52.3% increase of its median value (P < 0.001). Significantly lower changes in FMD were documented in COPD patients with hypercholesterolemia as compared to those without (+0.33% ± 1.61 vs. +1.62% ± 1.59, P = 0.037). Changes in FMD (ΔFMD) were positively associated with changes in forced expiratory volume in 1 s (FEV1), when expressed both as absolute values (ΔFEV1) (r = 0.503, P = 0.002) and as percentages of predicted values (ΔFEV1%) (r = 0.608; P < 0.001). In multiple linear regressions, after adjusting for major cardiovascular risk factors, ΔFEV1 (β=0.342; P = 0.049) and ΔFEV1% (β=0.480; P = 0.015) were both confirmed as independent predictors of ΔFMD. ConclusionsResults of our study suggest that endothelial function may improve in COPD after pulmonary rehabilitation. The potential beneficial effect in terms of cardiovascular risk prevention should be evaluated in ad hoc designed studies.

Transcatheter aortic valve implantation improves endothelial and autonomic function

Abstract Funding Acknowledgements Type of funding sources: None. Background Degenerative aortic stenosis is the leading native valve pathology in developed countries. Its degeneration process is affected by aging, common cardiovascular risk factors and an atherosclerotic-like process preceded by endothelial and autonomic dysfunction. With the increasing integration of transcatheter aortic valve implantation (TAVI) in the treatment of aortic stenosis in the elderly, research is being intensively oriented into its beneficial effect on the cardiovascular system. Measurements of vascular function with flow mediated dilatation (FMD) and autonomic cardiac function using heart rate variability parameters represent a validated method for treatment evaluation at different time-points. Purpose The purpose of our study was to assess whether haemodynamic and structural changes after TAVI will have a positive impact on endothelial and autonomic cardiac function on early and late follow-up. Methods 50 patients with severe aortic stenosis destinated to TAVI were prospectively included. Data was collected at baseline (24 hours before the procedure), on early follow-up (48 hours after the procedure) and on late follow-up (6 months after the procedure). While different heart rate variability parameters were obtained using a high-resolution electrocardiogram, FMD was assessed using a standardized ultrasound-based process with induced forearm hyperaemia. Results 43 patients completed the study (mean age 81 (75-85); 60% women). FMD measurements significantly changed from baseline to early follow-up (2.8 ± 1.5 % to 4.7 ± 2.7 %, p &amp;lt; 0.001). Improvement was persistent on late follow up (4.8 ± 2.7 %, p = 0.936). Moreover, heart rate variability parameters remained unchanged on early follow-up and improved 6 months after. Late follow-up statistical significance was reached by HF, a frequency-domain parameter (5231 ± 1783 to 6507 ± 1789 ms2; p = 0.029) and two Poincare diagram parameters: RR ecc (682 to 906 ms2; p &amp;lt; 0.001) and SDRR (9.6 to 23.9 ms; p = 0.001). Significant predictors of FMD change were as following: baseline maximal aortic valve velocity (R = 0.415; p = 0.011), mean aortic gradient (R = 0.373; p = 0.018), indexed stroke volume (R = 0.503; p = 0.006) and NT-proBNP (R = 0.491; p = 0.001). Conclusions Both endothelial and autonomic function improved after TAVI. While FMD seems to change early due to acute haemodynamic changes attributed to aortic valve stenosis resolution, autonomic cardiac functions remain stable and ameliorate late after procedure, likely reflecting left ventricular reverse remodelling.

Improved Endothelial and Autonomic Function after Transcatheter Aortic Valve Implantation.

Degenerative aortic stenosis is an atherosclerotic-like process associated with impaired endothelial and autonomic function. Transcatheter aortic valve implantation (TAVI) has become a treatment of choice for patient with severe degenerative aortic stenosis at high surgical risk. The effect of this procedure on endothelial function measured with flow mediated dilatation (FMD) and autonomic function measured with heart rate variability (HRV) at different time-points of disease management (early and late follow-up) remains unknown. We prospectively included 50 patients with severe aortic stenosis who were deemed suitable for TAVI by the Heart Team. FMD and HRV parameters were collected at baseline ( 24 h pre-TAVI), at early follow-up (up to 48 h post-TAVI) and at late follow-up (3-6 months post-TAVI). 43 patients (mean age 81 (75-85); 60% women) completed the study. FMD significantly improved from 2.8 1.5% before TAVI to 4.7 2.7% early after TAVI (p 0.001) and was later maintained on late follow-up (4.8 2.7%, p = 0.936). Conversely, high-resolution ECG parameters remained preserved at early and improved at late follow-up after TAVI. Significant improvement was detected in a high frequency-domain parameter-HF (from 5231 1783 to 6507 1789 ; p = 0.029) and in two Poincare plot parameters: ratio of the short- and long-term R-R variability in the Poincare plot-SD1/SD2 (from 0.682 to 0.884 ; p = 0.003) and short-term R-R variability in the Poincare plot-SDRR (from 9.6 to 23.9 ms; p = 0.001). Echocardiographic parameters comprising baseline maximal aortic valve velocity (R = 0.415; p = 0.011), mean aortic gradient (R = 0.373; p = 0.018), indexed stroke volume (R = 0.503; p = 0.006), change in aortic valve maximal velocity (R = 0.365; p = 0.031), change in mean aortic gradient (R = 0.394; p = 0.019) and NT-proBNP (R = 0.491; p = 0.001) were found as significant predictors of change in FMD. Endothelial function measured with FMD and autonomic function obtained with HRV parameters significantly improve after TAVI. While endothelial function improves early and is maintained later after TAVI, autonomic function remains stable and improves on late follow-up. This is most likely caused by early hemodynamic changes after resolution of aortic valve obstruction and gradual left ventricular remodeling. www.clinicaltrials.gov, identifier NCT04286893.

Oxidative stress-related impairment of endothelial function in uncomplicated obesity

Purpose: Visceral obesity is associated with vascular oxidative stress and development of hypertension. Therefore, we tested the hypothesis that suppression of vascular oxidative stress in adults with visceral obesity would improve endothelium-dependent dilation. Methods: IV infusion of a water-soluble antioxidant (ascorbic acid) was performed in 15 middle-age obese adults (3 men/12 women) without diabetes or hypertension in a placebo-controlled, double-blinded, crossover study design. Ascorbic acid was infused at 0.06g/kg fat free mass in 100 ml saline at 5 mL/min over 20 min (bolus) followed by a drip infusion at 0.02 g/kg fat-free mass in 30 ml saline at 0.5 mL/min over 60 min. Endothelium-dependent dilation was assessed via brachial artery flow-mediated dilation (FMD) and expressed as % increase in diameter from baseline before forearm occlusion. Results: Android fat distribution in the visceral cavity (VAT%) was 39 ± 10% and body mass index (BMI) was 37 ± 6 kg/m2. IV infusion significantly increased plasma ascorbic acid concentrations (Baseline: 42 ± 2 vs. Bolus: 66 ± 6 vs. End: 62 ± 4 μmol/L, P&lt;0.001). Compared with baseline, bolus infusion of ascorbic acid significantly increased FMD (Baseline: 5.8 ± 2.5 vs. Bolus: 9.0 ± 4.0 vs. End: 8.0 ± 4.2 %, P=0.01), which remained after statistically adjusting for the stimulus (shear rate area under the curve) via analysis of covariance (P=0.04). No significant change in FMD was observed following placebo (saline) during a separate study visit (Baseline: 8.0 ± 4.4 vs. Bolus: 8.3 ± 3.9 vs. End: 8.6 ± 2.9 %, P=0.86). Conclusions: These preliminary findings suggest that acute elevations in plasma ascorbic acid concentrations improve endothelium-dependent dilation in middle-aged adults with visceral obesity. Future studies should target mechanisms by which mediators of oxidative stress in obesity (e.g., hyperlipidemia, hyperinsulinemia) inhibit nitric oxide-mediated vasodilation. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or CTSA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The associations of markers of endothelial dysfunction with hip fracture risk.

Endothelial dysfunction underlies the development of atherosclerotic vascular disease. Vascular disease, in turn, is associated with the risk of osteoporotic fractures, such as hip fractures. Here, we examine whether two measures of endothelial dysfunction are related to hip fracture risk. Participants for this study were 2792 individuals (mean age 78.6years) who had flow-mediated dilation (FMD) measured after ischemia in the forearm and 2255 adults (mean age 73.3years) with measured soluble intercellular adhesion molecule (siCAM) levels, a constitutive endothelial cell membrane protein associated with the initiation of atherosclerosis. Mean follow-up was 9.7 and 11.7years, respectively. There were 375 and 265 incident hip fractures, respectively, in each group. In Cox proportional hazards models, there was no significant association between FMD response and incident hip fracture (HR per 1% higher FMD was 0.98 [0.93, 1.04]; p = 0.44). In exploratory analyses, when data were examined dichotomously, participants in the lowest 80% of FMD (≤ 4.5%) had an adjusted 1.29 (0.98, 1.68; p = 0.067) higher hazard of hip fracture compared to participants in the upper 20% of FMD change. There were no significant associations between siCAM and incident hip fracture whether examined as a continuous or dichotomized variable. Among older adults, two measures of endothelial dysfunction were not significantly associated with hip fracture risk. There was a trend for higher fracture risk with lower FMD.

The effect of levodopa treatment on vascular endothelial function in Parkinson's disease.

There has been increasing awareness that micro-vascular alteration or vascular inflammation has been associated with levodopa-induced dyskinesia in PD. Vascular endothelial function assessed by flow mediated dilation (FMD) is known to reflect early microvascular change. We compare the impact of levodopa or dopamine agonist treatment on the change of FMD in de novo PD patients. This retrospective study used a selected sample from registry. We identified de-novo PD patients who underwent FMD at baseline, and follow-up FMD after 1year (± 2month) of levodopa (n = 18) or dopamine agonist (n = 18) treatment. FMD decreased after levodopa (8.60 ± 0.46 to 7.21 ± 0.4, p = 0.002) but there were no significant changes after DA treatment (8.33 ± 0.38 to 8.22 ± 0.33, p = 0.26). Homocysteine rose (11.52 ± 0.45 to 14.33 ± 0.68, p < 0.05) during levodopa treatment, but dopamine agonist had no effect (10.59 ± 0.38 to 11.38 ± 0.67, p = 0.184). Correlation analysis revealed that the changes in homocysteine level had non-significant correlation with FMD change (r = - 0.30, p = 0.06). FMD change was not associated with age (p = 0.47), disease duration (p = 0.81), baseline motor UPDRS (p = 0.43), motor UPDRS change (p = 0.64), levodopa equivalent dose change (p = 0.65). We found that 1-year levodopa treatment may adversely affect vascular endothelial function in de novo PD. Further studies are needed to clarify the exact pathogenesis and clinical implication of levodopa-induced endothelial dysfunction in PD.

Improving the Effects of Imeglimin on Endothelial Function: A Prospective, Single-Center, Observational Study.

Endothelial dysfunction is a risk factor for cardiovascular disease in patients with diabetes. We hypothesized that imeglimin, a novel oral hypoglycemic agent, would improve endothelial function. In this study, imeglimin was administered to patients with type2 diabetes and HbA1c ≥ 6.5% who were not receiving insulin therapy. A meal tolerance test (592kcal, glucose 75.0g, fat 28.5g) was performed before and 3months after administration, and endothelial function, blood glucose, insulin, glucagon, and triglycerides were evaluated. Endothelial function was assessed by flow-mediated dilation (FMD). Twelve patients (50% male) with a median age of 55.5years old (interquartile range [IQR] 51.3-66.0) were enrolled. Fasting FMD did not differ before or 3months after imeglimin administration (from 6.1 [3.9-8.5] to 6.6 [3.9-9.0], p = 0.092), but 2h postprandial FMD was significantly improved 3months after imeglimin administration (from 2.3 [1.9-3.4] to 2.9 [2.4-4.7], p = 0.013). In terms of the glucose profile, imeglimin administration significantly improved HbA1c (from 7.2 ± 0.6% to 6.9 ± 0.6%, p = 0.007), fasting glucose (from 138 ± 19mg/dL to 128 ± 20mg/dL, p = 0.020), and 2h postprandial glucose (from 251 ± 47mg/dL to 215 ± 68mg/dL, p = 0.035). The change in 2h postprandial FMD between before and 3months after imeglimin administration (Δ2h postprandial FMD) was negatively correlated with Δ2h postprandial glucose (r = - 0.653, p = 0.021) in a univariate correlation coefficient analysis. Both patients with and without decreased postprandial glucose 3months after imeglimin administration had improved postprandial FMD. In this small study, imeglimin administration improved 2h postprandial FMD. Both glycemic control-dependent and -independent mechanisms might contribute to improved endothelial function. This research was registered in the University Hospital Medical Information Network (UMIN, UMIN000046311).

Air pollution exposure and vascular endothelial function: a systematic review and meta-analysis.

Vascular endothelial dysfunction is an early stage to cardiovascular diseases (CVDs), but whether air pollution exposure has an effect on it remains unknown. We conducted a systematic review and meta-analysis to summarize epidemiological evidence between air pollution and endothelial dysfunction. We searched the database of PubMed, EMBASE, the Cochrane Library, and Web of Science up to November 10, 2022. Fixed and random effect models were used to pool the effect change or percent change (% change) and 95% confidence interval (95% CI) of vascular function associated with particulate matter (PM) and gaseous pollutants. I2 statistics, funnel plot, and Egger's test were used to evaluate heterogeneity and publication bias. There were 34 articles included in systematic review, and 25 studies included in meta-analysis. For each 10µg/m3 increment in short-term PM2.5 exposure, augmentation index (AIx) and pulse wave velocity (PWV) increased by 2.73% (95% CI: 1.89%, 3.57%) and 0.56% (95% CI: 0.22%, 0.89%), and flow-mediated dilation (FMD) decreased by 0.17% (95% CI: - 0.33%, - 0.00%). For each 10µg/m3 increment in long-term PM2.5 exposure, FMD decreased by 0.99% (95% CI: - 1.41%, - 0.57%). The associations between remaining pollutants and outcomes were not statistically significant. The effect of short-term PM2.5 exposure on FMD change was stronger in population with younger age, lower female proportion, higher mean body mass indexand higher PM2.5 exposure. Cardiac or vasoactive medication might attenuate this effect. Our study provides evidence that PM2.5 exposure had adverse impact on vascular endothelial function, indicating the importance of air quality improvement for early CVD prevention.

The acute effect of heat exposure on forearm macro- and microvascular function: Impact of measurement timing, heating modality and biological sex.

What is the central question of this study? Do measurement timing, heating modality and biological sex modulate the acute effect of heat exposure on brachial artery flow-mediated dilatation and postocclusion reactive hyperaemia? What is the main finding and its importance? The acute effect of heat exposure on brachial artery flow-mediated dilatation and postocclusion reactive hyperaemia is: (1) transient and short lasting; (2) different between forearm and whole-body heating; (3) unaffected by forearm heating during whole-body heating; and (4) not different but not always equivalent between males and females. These findings provide a useful basis for future studies to investigate the acute effect of heat exposure on vascular function. The aim of this study was to gain a better understanding of the acute effect of heat exposure on brachial artery flow-mediated dilatation (FMD) and postocclusion reactive hyperaemia (PORH) by: characterizing the time course of changes post-heating; comparing forearm and whole-body heating; determining the impact of forearm heating during whole-body heating; and comparing males and females. Twenty adults (11 males and nine females; 28±6years of age) underwent two forearm [10min electric blanket (EB) or 30min hot water immersion (WI)] and two whole-body [60min water-perfused suit with forearm covered (WBH-C) or uncovered (WBH-U)] heating modalities. The FMD and PORH were measured before and after (≤5, 30, 60, 90 and 120min) heating. The FMD increased from baseline 30min after EB, and 30 and 90min after WI. In contrast, FMD decreased from baseline immediately after both WBH modalities. Peak PORH increased immediately after WI and both WBH modalities. Total PORH did not differ after WI, whereas it decreased immediately after both WBH modalities. Covering the forearm during WBH did not alter acute changes in FMD or PORH. Changes in FMD and PORH did not differ statistically between males and females during each heating modality, although the observed differences could not always be considered equivalent. These results demonstrate that the acute effect of heat exposure on brachial artery FMD and PORH is: (1) transient and short lasting; (2) different between forearm heating and WBH; (3) unaffected by direct forearm heating during WBH; and (4) not different but not always equivalent between males and females.

Vascular anomalies in patients with growth hormone-secreting pituitary adenomas: illustrative case report and systematic review of the literature

PurposeEndonasal resection is the first-line treatment for patients harboring growth hormone (GH)-secreting pituitary adenomas. The complexity of the parasellar neurovascular structures makes pre-operative diagnostic imaging essential to understanding the anatomy of this region. We aimed to describe vascular anomalies in acromegalic patients and emphasize their relevance for surgery and preoperative planning.MethodsA systematic review following the PRISMA statement was performed in July 2021.ResultsThirty-three studies were evaluated. Elevated GH and insulin-like growth factor-1 (IGF-1) levels are linked to the occurrence of cardiovascular risk factors. This is attributed to endothelial dysfunction, mainly caused by changes in flow-mediated dilatation (FMD), which is probably the main cause of vascular anomalies in acromegaly. The occurrence of protrusions of the internal carotid artery (ICA) (35–53%), a narrow intercarotid distance, and an asymmetrical course was described. In 13–18% of acromegalic patients, the presence of an intracerebral aneurysm could be reported (incidence in the general population:0.8–1.3%). The selected studies were however performed with a small patient sample (range:1–257).We present a case report of a 57y/o male patient with anomalies of the ICA (“kissing carotid arteries”) harboring a GH-secreting adenoma, which was resected via an endoscopic endonasal approach.ConclusionsThere is an association between acromegaly and endothelial dysfunction, which increases cardiovascular risk factors and vascular anomalies. Preoperative vascular imaging, e.g., CT angiography, should be implemented as a standard to identify patients at risk and estimate surgical morbidity. However, no evidence-based recommendations exist so far, so future studies are necessary.

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&amp;lt;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.

A single, high-fat meal adversely affects postprandial endothelial function: a systematic review and meta-analysis

ABSTRACTBackgroundEndothelial dysfunction is a predictive risk factor for the development of atherosclerosis and is assessed by flow-mediated dilation (FMD). Although it is known that NO-dependent endothelial dysfunction occurs after consuming a high-fat meal, the magnitude of the effect and the factors that affect the response are unquantified.ObjectivesWe conducted a systematic review and meta-analysis exploring the quantitative effects of a single high-fat meal on endothelial function and determined the factors that modify the FMD response.MethodsSix databases were systematically searched for original research published up to January 2022. Eligible studies measured fasting and postprandial FMD following consumption of a high-fat meal. Meta-regression was used to analyze the effect of moderator variables.ResultsThere were 131 studies included, of which 90 were suitable for quantitative meta-analysis. A high-fat meal challenge transiently caused endothelial dysfunction, decreasing postprandial FMD at 2 hours [−1.02 percentage points (pp); 95% CI: −1.34 to −0.70 pp; P < 0.01; I2 = 93.3%], 3 hours [−1.04 pp; 95% CI: −1.48 to −0.59 pp; P < 0.001; I2 = 84.5%], and 4 hours [−1.19 pp; 95% CI: −1.53 to −0.84 pp; P < 0.01; I2 = 94.6%]. Younger, healthy-weight participants exhibited a greater postprandial reduction in the FMD percentage change than older, heavier, at-risk groups after a high-fat meal ( P < 0.05). The percentage of fat in the meals was inversely associated with the magnitude of postprandial changes in FMD at 3 hours (P < 0.01).ConclusionsA single, high-fat meal adversely impacts endothelial function, with the magnitude of the impact on postprandial FMD moderated by the fasting FMD, participant age, BMI, and fat content of the meal. Recommendations are made to standardize the design of future postprandial FMD studies and optimize interpretation of results, as high-fat meals are commonly used in clinical studies as a challenge to assess endothelial function and therapeutics. This trial was registered at PROSPERO as CRD42020187244.

Evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial

BackgroundSodium-glucose cotransporter 2 inhibitors (SGLT2i) improve endothelial dysfunction and reduce cardiovascular events in individuals with type 2 diabetes (T2D). Proprotein convertase subtilisin/kexin 9 (PCSK9i) inhibitors reduce cardiovascular events in high-risk patients. Whether the addition of PCSK9i to SGLT2i treatment adds benefits is not known.ObjectivesTo assess the PCSK9-i effect on the endothelial function of T2D individuals under treatment with SGLT2-i.MethodsIndividuals with T2D were randomized in a 1:1 ratio to a 16-week treatment with either empagliflozin (E) or empagliflozin plus evolocumab (EE). The primary endpoint was post-treatment change from baseline in flow-mediated dilation (FMD) at 1-min. Secondary outcomes included changes in plasma levels of nitric oxide metabolites and isoprostane.ResultsA total of 110 patients were enrolled, the mean age was 58 years, and 71% were men. The median post-treatment change in FMD at 1-min was 2.7% (interquartile range [IQR]: 0.9%) and 0.4% (IQR: 0.9%) in the EE and E groups, respectively (p < 0.001). There was a greater increase in plasma levels of nitrate [5.9 (16.5) vs. 2.6 (11.8); p = 0.001] and nitrite [0.14 (0.72) vs. 0.02 (0.74); p = 0.025] in the EE group than in the E group, respectively. Isoprostane reduction was more pronounced in the EE group when compared to the E group [−1.7 (5.9) vs. −1.1 (5.3); p < 0.001).ConclusionsIn individuals with T2D, the addition of evolocumab on top of empagliflozin improves endothelial function.

Exercise training and vascular function in postmenopausal individuals: a systematic review and meta-analysis.

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality for menopausal individuals. Flow-mediated dilation (FMD), a surrogate marker of CVD, improves with aerobic exercise training in healthy and nonhealthy cohorts. However, systematic evaluation and precise estimate of this effect for menopausal individuals are unknown. We conducted a systematic review with meta-analysis to evaluate the influence of exercise training on FMD in postmenopausal individuals. Studies were identified from systematic search of major electronic databases (PubMed, ScienceDirect, and Cochrane Library) from inception to February 2021. Healthy, postmenopausal individuals were included, following an aerobic exercise intervention assessing FMD. A random-effects meta-analysis was used to calculate a pooled effect size (mean difference [MD]) with 95% confidence interval. Heterogeneity was assessed using I2 statistics. Metaregression was used to assess the association between changes in FMD and physical characteristics (eg, blood pressure, age, baseline FMD) and intervention details (metabolic equivalents and change in maximal oxygen uptake [∆V˙ o2max ]). For variables that significantly correlated, a multiple metaregression model was used to assess the accounted variance in between-study ∆FMD%. Study quality was assessed using the National Heart, Lung, and Blood Institute assessment tool. Nine studies, including 11 interventions (6 controlled interventions and 5 pre-post interventions; N = 182), with age range of 52 ± 4 to 64 ± 7 years underwent quantitative pooling of data. Exercise training significantly improved ∆FMD% (MD, 0.99; 95% confidence interval, 0.46-1.52; P < 0.001). Between-study heterogeneity was large and statistically significant ( I2 = 93.8%, P < 0.001). Post hoc analysis based on study design identified significant heterogeneity in the MD in ∆FMD% between controlled and pre-post study interventions ( P < 0.05). According to multiple metaregression, diastolic and systolic blood pressure and ∆V˙ o2max significantly predicted ∆FMD% ( Q = 15.74, df = 3, P < 0.01, R2 = 0.72). Aerobic exercise training improves FMD for postmenopausal individuals, and this observation was greater among controlled versus pre-post interventions. A higher resting blood pressure and the greatest ∆V˙ o2max yielded the largest improvements in FMD.

Short-Term Effects of Cholecalciferol Supplementation on cFGF23 Levels in Children with Chronic Kidney Disease and Vitamin D Insufficiency.

Data on the effect of vitamin D supplementation on fibroblast growth factor 23 (FGF23), in chronic kidney disease (CKD) are scarce. In a prospective interventional study, the effect of vitamin D supplementation on cFGF23 (C-terminal FGF23) levels in children with CKD stages 2-4 was examined. Forty-one children with CKD and vitamin D insufficiency were administered 600,000 units of cholecalciferol over 3 d; 88% of patients achieved sufficiency at 8 wk. Significant increase in serum cFGF23 and phosphate levels was observed in CKD stage 2 after supplementation, but not in CKD stages 3 and 4. There was no correlation of the change in cFGF23 level with baseline or change in bone health parameters (calcium, phosphate, parathormone or alkaline phosphatase) or with change in flow-mediated dilatation (FMD) of the brachial artery. It is concluded that cholecalciferol supplementation increases serum calcium and reduces PTH, but does not adversely affect FGF23 levels in CKD.

Anti-Inflammatory, Antioxidant, and Anti-Atherosclerotic Effects of Natural Supplements on Patients with FMF-Related AA Amyloidosis: A Non-Randomized 24-Week Open-Label Interventional Study.

We aimed to evaluate the effect of a combination of natural products on parameters related to inflammation, endothelial dysfunction, and oxidative stress in a cohort of familial Mediterranean fever (FMF) patients with Serum Amyloid A amyloidosis, in a non-randomized, 24-week open-label interventional study. Morinda citrifolia (anti-atherosclerotic-AAL), omega-3 (anti-inflammatory-AIC), and extract with Alaskan blueberry (antioxidant-AOL) were given to patients with FMF-related biopsy-proven AA amyloidosis. Patients were >18 years and had proteinuria (>3500 mg/day) but a normal estimated glomerular filtration rate (eGFR). Arterial flow-mediated dilatation (FMD), carotid intima media thickness (CIMT), and serum biomarkers asymmetric dimethylarginine (ADMA), high sensitivity C-reactive protein (hs-CRP), pentraxin (PTX3), malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and glutathione peroxidase (GSH-Px) were studied at baseline and after 24 weeks of treatment. A total of 67 FMF-related amyloidosis patients (52 male (77.6%); median age 36 years (range 21–66)) were enrolled. At the end of a 24-week treatment period with AAL, AIC, and AOL combination therapy, ADMA, MDA, PTX3, hsCRP, cholesterol, and proteinuria were significantly decreased compared to baseline, while CuZn-SOD, GSH-Px, and FMD levels were significantly increased. Changes in inflammatory markers PTX3, and hsCRP were negatively correlated with FMD change, and positively correlated with decreases in proteinuria, ADMA, MDA, cholesterol, and CIMT. Treatment with AAL, AIC and AOL combination for 24 weeks were significantly associated with reduction in inflammatory markers, improved endothelial functions, and oxidative state. Efficient control of these three mechanisms can have long term cardiovascular and renal benefits for patients with AA amyloidosis.

Effect of Daily Avocado Intake for Six Months on Flow-Mediated Dilation: A Sub-Study of the Habitual Diet and Avocado Trial, a Randomized Controlled Study

ObjectivesThe Habitual diet and Avocado Trial (HAT), a multicenter parallel randomized controlled trial, was designed to examine the health effects of consuming 1 avocado per day for 6-months compared to a habitual diet limited in avocados in individuals with abdominal obesity. We assessed the effects of the intervention on endothelial function using flow-mediated dilation (FMD) of the brachial artery. MethodsAll participants were ≥25 years of age with an elevated waist circumference (≥88 cm women; ≥102 cm men). Participants were randomized into either a control group (HD: consumed <2 avocados/month for 6 months) or an experimental group (AVO: consumed 1 avocado/day for 6 months). At the Pennsylvania State University, University Park site (n = 134), FMD was measured at baseline and end of the study. Within-person change scores were calculated by subtracting FMD at baseline from FMD at the end of the study. Linear regression was used to examine between-group differences in change across 6 months. ResultsThe sample was 78% female (BMI 33 ± 5 kg/m2). At baseline, FMD was 7.73 ± 3.37% in the AVO group, and 6.85 ± 2.67% in the HD group. FMD decreased by –0.10 ± 2.94% in the AVO group and increased by 0.52 ± 3.17% in the HD group. There were no significant between-group differences in 6-month change in FMD (0.62%, 95%CI = –0.46–1.70, p = 0.26). The results remained unchanged after adjustment for sex, BMI, and baseline FMD (0.15%, 95%CI = –0.77–1.06, p = 0.75). ConclusionsResults suggest that consumption of 1 avocado per day for 6 months in adults with abdominal obesity is not associated with a significant improvement in endothelial function, compared to adults following their habitual diet. Participants in this study had relatively high FMD at baseline, which may have reduced our ability to observe improvements in endothelial function. Funding SourcesAvocado Nutrition Center and the National Center for Advancing Translational Sciences, National Institutes of Health (1UL1TR002014-01)

META-ANALYSIS ADDRESSING THE EFFECT OF SODIUM-GLUCOSE CO-TRANSPORTER-2 INHIBITORS ON FLOW-MEDIATED DILATION IN PATIENTS WITH TYPE 2 DIABETES MELLITUS

Objective: Endothelial dysfunction seems to play a pivotal role in the pathogenesis of cardiovascular disease and related complications among high-risk patients, such as those suffering from type 2 diabetes mellitus (T2DM). Non-invasive peripheral endothelial function assessment with measurement of brachial artery flow-mediated dilation (FMD) has been demonstrated to predict adverse cardiovascular events. Herein, we sought to determine whether SGLT-2 inhibitors provide a significant effect on endothelial function, as assessed through FMD. Design and method: We searched PubMed, Cochrane Library and grey literature from inception to 10th October 2021 for parallel group randomized controlled trials (RCTs) enrolling adult subjects with T2DM, assigned to a SGLT-2 inhibitor versus placebo or active comparator and addressing their effect on FMD. We set as primary efficacy outcome the change in FMD with SGLT-2 inhibitor versus control. Results: We pooled data from 4 trials in a total of 270 subjects with T2DM. We demonstrated that treatment with SGLT-2 inhibitor versus placebo or active comparator produced a significant increase in FMD by 1.66% (95% CI; 0.56 – 2.76, I2 = 28%, p = 0.003). Notably, all eligible RCTs utilized dapagliflozin. Overall risk of bias was evaluated as low across the selected studies. Conclusions: The present meta-analysis demonstrated a clear benefit on endothelial function with SGLT-2 inhibitors compared to placebo or active comparator. Although the sample size is small, it seems that amelioration of endothelial dysfunction with SGLT-2 inhibitors constitutes another significant mechanism that confers to cardio-protection with this drug class. Larger RCTs will shed further light on this important pathophysiologic link.