Assessment Of Flow-mediated Dilation Research Articles

Phosphatidylserine supplementation as a potential strategy to improve endothelial function in type 2 diabetes

Endothelial dysfunction represents a causal factor in the pathogenesis of cardiovascular disease associated with type 2 diabetes (T2D), including hypertension. Previous work has revealed that endothelial mechanosensing structures are degraded in T2D, resulting in impaired shear stress mechanotransduction and decreased flow-mediated dilation (FMD). One well-known mechanosensor that is susceptible to cleavage is glypican-1, a prominent proteoglycan member of the endothelial glycocalyx. In this regard, recent evidence from a proteomic analysis suggests that glypican-1 is a substrate of the proinflammatory enzyme ADAM17 (a disintegrin and metalloproteinase-17), which is elevated in the vasculature of T2D. Recent work has revealed that exogenous phosphatidylserine (PS) inhibits in vitro ADAM17 sheddase activity, which may aid in retaining the membrane-bound glypican-1. Therefore, we hypothesized that oral administration of PS in diabetic mice (db/db) would enhance shear stress mechanotransduction, as assessed by FMD, and that this would be accompanied by greater presence of glypican-1 on the endothelial surface. We further hypothesized that PS would reduce blood pressure. We tested this hypothesis in ~10-week-old db/db male mice that were randomized to receive a daily peanut butter pellet as vehicle control or the pellet mixed with soy-derived PS (200 mg/kg/day) for 28 days. A third group of untreated age-matched wild-type C57BL/6J male mice served as healthy controls. Excised mesenteric arteries were used for assessment of FMD using pressure myography, while femoral arteries were used for determining presence of glypican-1 content on the endothelial surface using confocal microscopy. Blood pressure was assessed using the tail-cuff method. All reported differences are significant at p<0.05. Compared with wild-types, untreated db/db mice had impaired FMD, reduced presence of endothelial glypican-1, and increased blood pressure. Notably, these effects were not observed in db/db mice treated with PS. These findings suggest that oral PS may be effective at improving indices of endothelial dysfunction in T2D, an effect likely mediated by the retention of endothelial mechanosensor glypican-1 via reduced ADAM17 sheddase activity. No support to disclose. 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.

Effect of Hemodialysis with Medium Cut-Off versus High-Flux Membranes on Endothelial Function of Patients with Chronic Kidney Disease

Introduction: Endothelial dysfunction (ED) is considered a marker of vascular complications, especially in patients with end-stage kidney disease (ESKD). Inflammation and the uremic state contribute to ED in patients undergoing hemodialysis (HD). Recently, the medium cut-off (MCO) dialysis membrane has been proposed to efficiently remove inflammatory cytokines and large, middle-sized uremic toxins, with the potential effect to improve endothelial function. This study aimed to compare the effect of dialysis with MCO or high-flux membranes on the endothelial function of patients on chronic HD. Methods: A prospective, randomized, crossover study in which 32 patients with ESKD were dialyzed for 12 weeks with each membrane, including a 4-week washout period between treatments. Endothelial function was assessed by flow-mediated dilation (FMD) using brachial artery ultrasound at weeks 1, 12, 16, and 28. Results: The population consisted of 59% men, 52.7 ± 13.4 years, 16% non-black, on HD for 8.8 (4.1–15.1) years, and 72% with arteriovenous fistula. Hypertension was the most common etiology of chronic kidney disease, and 34% of patients had previous cardiovascular disease. Patients were grouped, regardless of treatment sequence, into MCO or high-flux groups, since no carryover (p = 0.634) or sequence (p = 0.998) effects were observed in the FMD assessment. The ANOVA model with repeated measures showed no effects of treatment (p = 0.426), time (p = 0.972), or interaction (p = 0.413) in the comparison of FMD between the MCO and high-flux groups. Conclusion: Dialysis performed with MCO, or high-flux membranes, had no influence on endothelial function in patients undergoing HD. However, a trend towards increased FMD was observed with the use of the MCO membrane.

Comparison of CIMT and FMD in the Brachial Artery between Children with Acyanotic Congenital Heart Disease and Healthy Controls: A Case-Control Study.

Congenital heart disease (CHD), a developmental abnormality of the heart and vessels, is encountered in the pediatric age group frequently. Brachial artery flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) are indicators of subclinical cardiovascular disease and are used as surrogate measures of subclinical atherosclerosis. The present study aimed to compare CIMT and FMD between children with acyanotic congenital heart disease (ACHD) and healthy controls. A case-control study on 50 children with ACHD and 43 healthy individuals was done in Isfahan, Iran, between 2021 and 2022. The case group was selected via non-random sampling, and healthy controls were recruited from the relatives of the patients. A checklist, including age, sex, body mass index, and blood pressure, was filled out for all the participants. Then, FMD and CIMT were measured with brachial and carotid artery ultrasonography. Fifty children with ACHD and 43 healthy individuals (controls) under 18 years old participated in this study. Of these, 44 (47.3%) were girls and 49 (52.7%) were boys. The mean FMD was significantly higher in the ACHD group than in the control group (0.084±0.027 vs 0.076±0.042; P=0.021; 95% CI, 007 to 0.122;). CIMT was significantly higher in the ACHD group than in the control group (0.39±0.12 vs 0.34±0.1; P=0.037; 95% CI, 0.009 to 0.102;). However, systolic and diastolic blood pressure did not show differences between the groups. Based on our results, CIMT and FMD assessment may help detect early changes in peripheral vessels associated with atherosclerosis in the future in ACHD. Further studies are needed to confirm our findings.

Insulin pump treatment vs. multiple daily insulin injections in patients with poorly controlled type 2 diabetes mellitus: a comparison of cardiovascular effects

Abstract Background Both hyper- and hypo-glycaemia, as well as large glycaemic variability (GV) are associated with increased cardiovascular events in patients with type 2 diabetes mellitus (T2DM); possible contributing mechanisms of the increased cardiovascular risk include endothelial dysfunction and cardiac sympatho-vagal imbalance. Recent studies suggest that continuous subcutaneous insulin infusion (CSII) improves glycaemic control compared to multiple daily insulin injections (MDI). Purpose In this study, we assessed whether CSII may improve cardiac autonomic and vascular dilation function compared to MDI. Methods We enrolled in a small randomized pilot study consecutive T2DM patients without cardiovascular disease with poor glycaemic control, despite optimized MDI therapy. Patients were randomized to CSII (Group 1) or to continue MDI (Group 2); insulin dose was adjusted to achieve optimal glycaemic target ranges. Patients were studied at baseline and after 6 months by: 1) assessment of flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) of the brachial artery; 2) heart rate variability (HRV) by 24-hour ECG Holter monitoring; 3) a 7-day continuous glucose monitoring (CGM) was performed at baseline and follow-up in 8 and 7 patients of Group 1 and 2, respectively. Results Overall, 21 patients were enrolled, 12 randomized to CSII and 9 to MDI. Daily insulin dose, glycated hemoglobin levels and CGM parameters did not differ significantly between the 2 groups, both at baseline and at follow-up. Both FMD (6.7±2.5 vs 4.6±2.0 %, p=0.51) and NMD (8.9±3.1 vs 7.0±3.0 %, p=0.18), as well as HRV parameters, showed no significant differences between the 2 groups at 6-month follow-up. No relation between GV and both peripheral dilator function and cardiac autonomic function was also detected. Conclusions In this small, randomized pilot study we show that, in T2DM patients, CSII achieves similar medium-term glycaemic control compared to MDI, without any significant adverse effect on the cardiovascular system.

Effect of endodontic treatment on endothelial dysfunction and subclinical atherosclerosis-a prospective intervention study.

The objective of this study is to investigate the effect of endodontic treatment on flow-mediated dilatation (FMD) and carotid intima-media thickness (c-IMT) in patients with apical periodontitis (AP). The study includes 32 young men having AP with a mean age of 25.78 years free from cardiovascular disease (CVD) and its risk factors, including periodontitis. All subjects underwent complete physical and dental examination, echocardiography, and ultrasound assessment of FMD on the brachial artery and c-IMT on the carotid artery at baseline and 12 months after the endodontic treatment. Data were analyzed using paired Student's t-test and Pearson's correlation coefficient (r) test using SPSS 26 version. Endodontic treatment leads to the improvement of FMD significantly from a pooled baseline value of 4.84 ± 1.55% to 7.68 ± 2.08% (p < 0.05). The study also depicts a statistically significant difference between c-IMT (mean = 0.62 ± 0.11 mm) before treatment as compared to 12 months after treatment (mean = 0.59 ± 0.11 mm) (p < 0.05). Endodontic treatment leads to improved FMD and decreased c-IMT suggesting that treating AP can be help revert the early stages of CVD. AP could be a potential etiological factor of future CVD and should be treated as soon as diagnosed.

#2513 EFFECT OF HEMODIALYSIS WITH MEDIUM CUT-OFF VERSUS HIGH-FLUX MEMBRANES ON ENDOTHELIAL FUNCTION OF CHRONIC KIDNEY DISEASE PATIENTS

Abstract Background and Aims Endothelial dysfunction (ED) is considered a marker of vascular complications, especially in patients with chronic kidney disease (CKD). Inflammation and the uremic state contribute to ED in hemodialysis (HD) patients. Recently, the medium cut-off (MCO) HD membrane has been proposed to efficiently remove inflammatory cytokines and higher molecular weight uremic toxins. This study aimed to compare the effect of dialysis with medium cut-off (MCO) or high-flow (HF) membranes on the endothelial function of patients on chronic HD. Method A prospective, randomized, crossover study in which 32 patients with CKD were dialyzed for 12 weeks with each membrane, including a 4-week washout period between treatments. Endothelial function was assessed by flow-mediated dilation (FMD) using brachial artery ultrasound at weeks 1, 12, 16, and 28. Results The population consisted of 59% men, 52.7±13.4 years, 16% non-black, on HD for 8.8(4.1-15.1) years, 72% with arteriovenous fistula). Hypertension was the most common etiology of CKD and 34% of patients had previous cardiovascular disease. Table 1 shows clinical and demographic characteristics of all subjects. The Patients were grouped, regardless of treatment sequence, into MCO or high flow groups, since no drag (p = 0.634) or sequence (p = 0.998) effects were observed in the FMD assessment. The ANOVA model with repeated measures showed no effects of treatment (p = 0.426), time (p = 0.972) or interaction (p = 0.413) in the comparison of FMD, between the MCO and high flow groups. Conclusion Dialysis performed with MCO, or HF membranes did not influence endothelial function in patients undergoing chronic HD.

The impact of statin therapy on in-hospital prognosis and endothelial function of patients at high-to-very high cardiovascular risk admitted for COVID-19.

Statins may protect against adverse outcomes from Coronavirus disease 2019 (COVID-19) through their pleiotropic effects. Endothelial dysfunction seems to be implicated in the pathophysiology of COVID-19, and can be attenuated by statins. This study assessed the role of preadmission statin therapy and its interaction with endothelial function, measured using flow-mediated dilation (FMD) at hospital admission, in predicting in-hospital outcomes among patients with COVID-19 having high-to-very high cardiovascular (CV) risk. We conducted a retrospective cohort study of hospitalized patients with COVID-19 having high-to-very high CV risk, including a subgroup of patients who underwent FMD assessment. Among 342 patients, 119 (35%) were treated with statins at study baseline. Preadmission statin therapy was independently associated with a 75% risk reduction of intensive care unit admission/in-hospital death (adjusted hazard ratio 0.252, 95% confidence interval 0.122-0.521, p < 0.001). In the subgroup of patients with an FMD assessment (245 patients, 40% statin-treated), preadmission statin therapy was independently associated with higher FMD values (β = 0.159, p = 0.013). However, preadmission statin therapy × FMD interaction was not associated with in-hospital outcomes (F = 0.002, pinteraction = 0.960). Preadmission statin therapy is associated with better in-hospital outcomes among patients with COVID-19 having high-to-very high CV risk, independent of the endothelium-protective effects of these drugs.

PS-BPC02-2: CLINICAL IMPACTS OF ENDOTHELIUM-DEPENDENT FLOW-MEDIATED VASODILATION ASSESSMENT ON PRIMARY ALDOSTERONISM

Objective: Primary aldosteronism (PA) is defined as autonomous aldosterone production from the adrenal glands and represents the most common and treatable cause of hypertension. Also, it is well known that the incidence of cardiovascular morbidity is higher among patients with PA than among those with essential hypertension (EH). Histologically, PA is divided into two major subtypes, aldosterone-producing adenoma (APA) and bilateral idiopathic hyperplasia (IHA). However, the nature of vascular function in PA patients remains to be determined. The aim of this study was to determine the vascular function and investigate the implications of vascular function assessments in the patients with PA. Design and Method: All patients were diagnosed with PA according to the guidelines of the Japan Endocrine Society. Flow-mediated dilation (FMD), as an index of endothelial function, and cardio-ankle vascular index (CAVI), as an index of arterial stiffness, were retrospectively compared between 42 patients with APA, 37 patients with IHA, and 42 patients with EH. These values were also compared with background factors, KCNJ5 mutation and clinical outcome in terms of blood pressure reduction after adrenalectomy in the APA group. Results: No differences were found among the three groups (APA, IHA and EH) with regard to age, sex, duration of hypertension, body mass index, blood pressure, renal function and hemoglobin A1c. FMD was significantly lower in the APA group (4.8 ± 2.1%) and IHA group (4.1 ± 1.9%) than in the EH group (5.7 ± 2.1%). CAVI did not differ significantly among APA, IHA and EH groups (7.9 ± 1.3, 7.8 ± 1.0, 7.8 ± 1.1, respectively). Although no significant correlations were seen between FMD and background factors (i.e. age, body mass index, renal function, glucose and lipid metabolic parameters, and hormonal data) in the IHA group, FMD correlated negatively with BMI and plasma aldosterone concentration in the APA group (rs = -0.313, rs = -0.342, respectively). No significant difference in FMD (4.8 ± 1.4%, 4.5 ± 2.1%, respectively) or CAVI (8.1 ± 1.8, 8.0 ± 1.1, respectively) was seen between the KCNJ5-mutant group and the wild-type group. A cut-off FMD of 4.3% was selected for complete clinical success after adrenalectomy, offering 78% sensitivity and 80% specificity. Conclusions: Patients with PA displayed impaired endothelial function. Complete clinical success after adrenalectomy was associated with preserved endothelial function. This study provides a better understanding of FMD assessment in patients with PA.

Flow-Mediated Dilation Can be used as an Indicator for Assessing Severity and Deaths by Covid-19 at the Initial Hours of Hospitalization

Assessment of Flow-Mediated Dilation (FMD) in patients hospitalized for COVID-19 will assist with regard to early identification of markers at the onset of SARS-CoV-2 infection. Therefore, the early evaluation of simple markers, obtained at the bedside before the most serious manifestations are already installed, can help health professionals to act preventively to save lives, direct care in the initial stage of infection, helping in the prognosis and diagnosis. Given the importance and relevance of this technique in this population at this time and the need to better understand the pathophysiology of COVID-19 as well as its damage to the endothelium, we performed an evaluation of FMD in different severity of COVID-19 in recently hospitalized patients. A total of 100 patients were enrolled in the study and were divided into two groups according to the severity of COVID- 19. The results provide new evidence that patients with COVID-19 classified as severe/critical have greater endothelial dysfunction and that FMD may be a simple marker, helping in the prognosis and diagnosis and, consequently, in the prevention of thrombotic events.

High prevalence of lower limb atherosclerosis is linked with the gut-liver axis in patients with primary biliary cholangitis.

Hypercholesterolemia is frequent in people with primary biliary cholangitis (PBC); however, it does not seem to confer an increased risk of cardiovascular disease. We aimed to evaluate the prevalence of peripheral arterial disease in PBC women and its association with the gut-liver axis and systemic inflammation. Thirty patients affected by PBC and hypercholesterolemia were enrolled, with equal-sized groups of women with non-alcoholic fatty liver disease (NAFLD) and healthy controls (CTRL). All patients underwent Doppler ultrasound examination of peripheral arteries, assessment of flow-mediated dilation, quantification of circulating cytokines and vasoactive mediators and characterization of the gut microbiota. PBC patients had a higher prevalence of lower extremity arterial disease (LEAD) defined as atherosclerotic plaques in any of femoral, popliteal and/or tibial arteries compared with both NAFLD and CTRL women (83.3% vs. 53.3% and 50%, respectively; p= .01). Factors associated with LEAD at univariate analysis were VCAM-1 (p= .002), ICAM-1 (p= .003), and TNF-alpha (p= .04) serum levels, but only VCAM-1 (OR 1.1, 95% CI 1.0-1.1; p= .04) and TNF-alpha (OR 1.12, 95% CI 0.99-1.26; p= .04) were confirmed as independent predictors in the multivariate model. Gut microbiota analysis revealed that Acidaminococcus (FDR=0.0008), Bifidobacterium (FDR=0.001) and Oscillospira (FDR=0.03) were differentially expressed among groups. Acidaminococcus, which was increased in PBC, was positively correlated with TNF-alpha serum levels. Down-regulation of metabolic pathways linked to fatty acid and butyrate metabolism, glyoxylate metabolism and branched-chain amino acids degradation was found in the functional gut metagenome of PBC women. LEAD is common in patients affected by PBC and is associated with inflammatory markers and alterations in the gut-liver axis.

Peculiarities of hemostasis in patients with COVID-19

Analysis of the dynamics of different stages of clot formation and its lysis in patients with different COVID-19 severity. We prospectively included 58 patients with COVID-19 (39 patients with moderate disease severity and 18 patients with severe disease) and 47 healthy volunteers as a control group. All participants underwent the assessment of flow-mediated dilation (FMD) of brachial artery, impedance aggregometry, rotational thromboelastometry and thrombodynamics. Von Willebrand factor antigen (vWF:Ag) quantification was also performed in patients with COVID-19. Measurements were repeated on the 3rd and 9th day of hospitalization. Compared to the control group, patients with COVID-19 showed reduced values of platelet aggregation and greater values of the clot growth rate, as well as its size and density. On the first day of hospitalization, we found no differences in the activity of plasma hemostasis and endogenous fibrinolysis between subgroups of patients. With the progression of the disease, the growth rate and size of the clot were higher in the severe subgroup, even despite higher doses of anticoagulants in this subgroup. An increase in platelet aggregation was noted during the progression of the disease, especially in the severe subgroup. There were no differences in the results of the FMD test by subgroups of patients. The vWF:Ag level was significantly higher in the severe subgroup. Thus, plasma hemostasis followed by secondary platelet activation correlates with the severity of COVID-19. Patients with moderate to severe coronavirus infection have predominantly local rather than generalized endothelial dysfunction.

Endothelial Function in Postmenopausal Women: The Possible Role of Heat Shock Protein 60 and Serum Androgens

Background: Heat shock protein 60 (HSP60), a potentially homeostatic antigen, is involved in physiological and non-physiological conditions. Experimental data support the role of HSP60 in placental and mitochondrial steroidogenesis. Furthermore, HSP60 is translocated into the endothelial-cell plasma membrane and the extracellular space under stress conditions, promoting the atherosclerotic process. Therefore, we investigated the association between HSP60 and endothelial function in postmenopausal women, considering the possible atherogenic effect of androgenic hormones.Methods: This study included 123 healthy postmenopausal women. Exclusion criteria were treated hypertension or dyslipidaemia, menopause hormone therapy during the last 6 months, and previously diagnosed peripheral vascular disease or cardiovascular disease. Fasting venous blood samples were obtained for biochemical and hormonal assessment and evaluation of HSP60. Sonographic assessment of flow-mediated dilation (FMD) occurred immediately after that in one session.Results: Univariate analysis showed that women with FMD values below median 5.12% had lower logHSP60 values (low vs. high FMD, HSP60 values: 2.01 ± 1.16 ng/ml vs. 3.22 ± 1.17 ng/ml, p-value = 0.031). Multivariable analysis showed that logHSP60 was associated with FMD (b-coefficient = 0.171, p-value = 0.046), adjusting for traditional cardiovascular risk factors (TRFs) and insulin levels. Further adjustment for testosterone and DHEAS rendered the result non-significant. In the multivariable analysis, FMD was associated with insulin (b-coefficient = −0.166, p-value = 0.034), testosterone (b-coefficient = −0.165, p-value = 0.034), DHEAS (b-coefficient = −0.187, p-value = 0.017), adjusting for TRFs.Discussion: The results of this study indicate that the association between androgens and endothelial function is possibly mediated by HSP60 molecules, in women with low insulin resistance and androgenicity. Further prospective studies are needed to explore the significance of our findings.

Endothelial Dysfunction in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis.

Individuals with nonalcoholic fatty liver disease (NAFLD) are characterized by increased cardiovascular risk. Endothelial dysfunction, a mechanism implicated in those processes, may constitute the missing link in this interaction. Therefore, this systematic review and meta-analysis aims to evaluate the association of endothelial dysfunction, assessed by flow-mediated dilation (FMD) of the brachial artery, with NAFLD. We conducted a systematic literature search for studies assessing the difference in FMD between patients with NAFLD and controls. Exclusion criteria consisted of preclinical studies, studies in children/adolescents, no FMD assessment, and the absence of an NAFLD/control group. The database search identified 96 studies. Following the application of the exclusion criteria, 22 studies were included in the meta-analysis (NAFLD: 2164 subjects; control: 3322 subjects). Compared with controls, patients with NAFLD had significantly lower FMD% values (SMD: −1.37, 95% CI −1.91 to −0.83, p < 0.001, I2: 98%). Results remained unaffected after exclusion of any single study. Subgroup analysis revealed significantly decreased FMD in NAFLD subjects diagnosed with liver ultrasound or liver biopsy compared with method combination or other methods, while no differences were observed according to the chosen cuff inflation threshold, the presence of a significant difference in obesity measures between the groups, or the type of the control group (age- and sex-matched vs. other). Funnel plot asymmetry was not observed. Finally, compared with patients with pure steatosis, individuals with nonalcoholic steatohepatitis had significantly lower FMD (SMD: −0.81, 95% CI −1.51 to −0.31, p = 0.003, I2: 81%). In conclusion, FMD of the brachial artery, indicative of endothelial dysfunction, was significantly reduced in subjects with nonalcoholic fatty liver disease. Patients with nonalcoholic steatohepatitis might be facing a more pronounced endothelial impairment.

Theoretical and Experimental Study on Assessment of Flow-Mediated Dilatation Using the Cuff Method in Brachial Arteries

Endothelial dysfunction has been shown to be an important risk factor in the pathogenesis of atherosclerosis, hypertension, and heart failure. The flow-mediated vasodilation (FMD) of the peripheral arteries is an endothelium-dependent function, which is assessed by measuring the diameter change in the brachial artery before and after ischemic stress. Brachial-artery ultrasound scanning (BAUS) is the gold standard for assessing the FMD in clinical practice. However, ultrasonography requires an operator or physician with a professional training to perform accurate measurement of the diameter of the brachial artery. Thus, some studies have used the cuff method to measure the FMD in percentage, the value of which is significantly larger than that using BAUS. The goal of this study was to explore this phenomenon. We explain the interaction between the volume changes (oscillation magnitudes in volume due to cardiac pulsations) of the artery and cuff bladder under different transmural pressures when a sphygmomanometer is wrapped around an upper arm. The compliance of the cuff bladder would be of a fixed value when the cuff pressure is low. The cuff-volume change could be replaced with a cuff-pressure change (oscillation magnitude in cuff pressure due to cardiac pulsation). With the cuff method, the FMDc could be assessed with pressure changes. Then, an inequality formula regarding FMD values by both BAUS (FMDu) and the cuff method (FMDc) was derived; FMDc &gt; 2*FMDu + FMDu2. In order to experimentally verify this inequality formula, fifty-one subjects, including thirty-eight healthy adults and thirteen patients with hypertension, participated in this study. The systolic and diastolic diameters of their brachial arteries and cuff-pressure changes due to cardiac pulsations were separately measured by BAUS and a pressure sensor before and after an ischemic stress. The results showed that FMDu and FMDc were 8.1 ± 4.3% and 121.6 ± 48.6% in the healthy group and 4.5 ± 1.1% and 55.2 ± 22.8% in the patient group, respectively. Thus, the experimental findings comply with the theoretically derived inequality formula.

Impact of a single bout of resistance exercise on serum Klotho in healthy young men.

BackgroundIt has been shown that Klotho protects vascular endothelial function. Given that a single bout of resistance‐exercise‐induced hypertensive stimulus causes endothelial dysfunction, we postulated that acute resistance exercise would reduce serum Klotho levels. In this respect, the reduction in serum Klotho levels would be associated with the response of flow‐mediated dilation (FMD). Therefore, the purpose of this study was to investigate the impact of acute resistance exercise on the Klotho response in serum. In addition, we examined the relationship between the serum Klotho and FMD responses following acute resistance exercise.MethodsTwelve untrained men participated in this study (20.4 ± 0.3 years). Following baseline measurements (blood pressure, blood collection, FMD), subjects performed leg extensions, which consisted of 10 repetitions for five sets at 70% of one‐repetition maximum. After the exercise, measurement of blood pressure, blood collection, and FMD assessment were repeated for 60 min. We analyzed Klotho and endothelin‐1 (ET‐1) concentrations in blood serum.ResultsAs expected, the exercise significantly elevated blood pressure and led to decreased FMD (p < 0.05). However, Klotho concentrations were significantly increased following exercise (p < 0.05). No correlation was observed in Klotho and FMD responses following acute resistance exercise. However, there was a significant positive correlation between Klotho and ET‐1 in response to resistance exercise (p < 0.05).ConclusionIn conclusion, the present study reveals that serum Klotho significantly increased following a single bout of resistance exercise. However, the increase in Klotho may not associate with the acute reduction in endothelial function.

Effects of autonomic nervous system activation on endothelial function in response to acute exercise in hypertensive individuals: study protocol for a randomized double-blind study

BackgroundArterial hypertension has a direct association with endothelial dysfunction and major cardiovascular events. There is evidence showing the benefits of aerobic exercise on flow-mediated dilation (FMD) in hypertensive individuals but little is known about the effect of autonomic nervous system (ANS) activation on FMD of the brachial artery in response to different types of exercise in this specific population. This study aims to examine the effects of ANS activation on FMD of the brachial artery in response to exercise in hypertensive individuals following a session of different types of exercise including aerobic exercise (AE), resistance exercise (RE), or combined exercise (CE).MethodsThirty-nine hypertensive volunteers aged 35 to 55 years will be randomly assigned to two exercise sessions: AE (40 min on a cycle ergometer at 60% of HR reserve), RE (4 lower limb sets with 12 repetitions at 60% 1-RM for 40 min), or CE (RE for 20 min + AE for 20 min). Each exercise group will be randomized to receive either an α1-adrenergic blocker (doxazosin 0.05 mg/kg−1) or placebo. Ultrasound measurement of FMD is performed 10 min before and 10, 40, and 70 min after exercise. ANS activation is monitored using a Finometer and measurements are taken during 10 min before each FMD assessment. Arterial stiffness is assessed by pulse wave velocity (PWV) analysis using a Complior device.DiscussionWe expect to demonstrate the effect of ANS activation on FMD of the brachial artery in hypertensive individuals in response to different types of exercise. This study may give some insight on how to improve exercise prescription for hypertension management.Trial registrationhttps://clinicaltrials.gov and ID "NCT04371757". Registered on May 1, 2020.

Flow-mediated dilation analysis coupled with nitric oxide transport to enhance the assessment of endothelial function.

Flow-mediated dilation (FMD), mainly mediated by nitric oxide (NO), aims to assess the shear-induced endothelial function, which is widely quantified by the relative change in arterial diameter after dilation (FMD%). However, FMD% is affected by individual differences in blood pressure, blood flow, and arterial diameter. To reduce these differences and enhance the assessment of FMD to endothelial function, we continuously measured not only the brachial artery diameter and blood flow with ultrasound but also blood pressure with noninvasive monitor during standard FMD test. We further constructed an analytical model of FMD coupled with NO transport, blood flow, and arterial deformation. Combining the time-averaged and peak values of arterial diameter, blood flow, and pressure, and the modeling, we assumed the artery was completely healthy and calculated an ideally expected FMD% (eFMD%). Then, we expressed the fractional flow-mediated dilation (FFMD%) for the ratio of measured FMD% (mFMD%) to eFMD%. Furthermore, using the continuous waveforms of arterial diameter, blood flow, and pressure, the endothelial characteristic parameter (ϵ) was calculated, which describes the function of the endothelium to produce NO and ranges from 1 to 0 representing the endothelial function from healthiness to complete loss. We found that the mFMD% and eFMD% between the young age (n = 5, 21.2 ± 1.8 yr) and middle age group (n = 5, 34.0 ± 2.1 yr) have no significant difference (P = 0.222, P = 0.385). In contrast, the FFMD% (P = 0.008) and ϵ (P = 0.007) both show significant differences. Therefore, the fractional flow-mediated dilation (FFMD%) and the endothelial characteristic parameter (ϵ) may have the potential for specifically diagnosing the endothelial function.NEW & NOTEWORTHY FMD% is affected by various factors, which limits its ability to assess the endothelial function. We developed an analytical model of FMD process coupled with nitric oxide based on the mathematical modeling and physiological measurements. Two model-derived indicators (FFMD% and ϵ) were introduced based on the modeling. Our results indicated that FFMD% and ϵ may have the potential to distinguish the endothelial function between the young- and middle age groups.

Effects of Orlistat/Phentermine versus Phentermine on Vascular Endothelial Cell Function in Obese and Overweight Adults: A Randomized, Double-Blinded, Placebo-Controlled Trial.

BackgroundIn clinical practice, concomitant treatment of orlistat with phentermine is commonly used off-label. However, clinical trials have not been performed to evaluate whether their combination improves metabolic parameters and cardiovascular risk factors other than weight loss. Therefore, we aimed to compare the efficacy of concomitant administration of orlistat and phentermine versus phentermine alone on the endothelial cell function in overweight and obese adults with back pain.MethodsWe conducted a 12-week, double-blinded, placebo-controlled clinical trial involving 114 patients with a body mass index of ≥30 (obese) or ≥27 (overweight) with weight-related comorbidities. We randomly assigned patients in a 1:1 ratio to receive orlistat (120mg) three times daily and phentermine (37.5mg) once daily, or a placebo three times daily and phentermine (37.5mg) once daily. Primary endpoint was changes in endothelium-dependent vasodilatation measured using ultrasound assessment of flow-mediated dilatation (FMD). Differences within groups after intervention were compared using the paired t-test or Wilcoxon signed-rank test. Differences in changes between the groups were calculated using an analysis of covariance after adjusting for each baseline value.ResultsMean weight loss during the 12-week study period was 6.1kg in the orlistat/phentermine group and in the placebo/phentermine group. Adjusted mean changes in total and non-high-density lipoprotein cholesterol were significantly greater in the orlistat/phentermine group than in the placebo/phentermine group. Adjusted mean changes in endothelium-dependent FMD were significantly greater in the orlistat/phentermine group than in the placebo/phentermine group (4.97±0.98% vs 2.05±0.99%, respectively; p=0.038). Changes in endothelium-independent nitroglycerin-mediated dilatation were not significantly different between the groups.ConclusionOrlistat/phentermine significantly improved the vascular endothelial cell function compared with phentermine alone. Orlistat might have beneficial effects on the decrease of the risk of cardiovascular disease, especially in overweight and obese patients with comorbidities.Trial RegistrationClinicalTrails.gov number, NCT03675191.

Improving the Assessment of Flow-Mediated Dilation Through Detection of Peak Time in Healthy Subjects and Subjects With Type 2 Diabetes

The assessment of flow-mediated dilation (FMD) is widely used to quantify endothelial function. Historically, FMD was determined at 60 seconds post-cuff deflation. We investigated whether FMD would be more accurate if determined at maximum dilatory peak (MDP) than at 60 seconds in healthy subjects and subjects with type 2 diabetes mellitus (T2DM). We studied 95 healthy and 72 subjects with T2DM and assessed FMD at MDP, 60 and 90 seconds. Twenty-four healthy and 12 subjects with T2DM underwent a repeat FMD after 28 days. In healthy subjects, FMD at MDP was higher than at 60 and 90 seconds, with mean difference MDP versus 60 seconds 1.14% (95% CI: 0.6-1.7); P < .0001 and MDP versus 90 seconds 1.9% (95% CI: 1.3-2.5) with similar results in T2DM, that is, 1.0% (95% CI: 0.1-1.9) and 2.3% (95% CI: 1.3-3.2), respectively. Intraindividual variability was lowest with MDP compared with 60 and 90 seconds, that is, 15.0 versus 23.2% and 40.0%, respectively, resulting in a more than 2-fold reduction in necessary sample size. In healthy subjects and subjects with T2DM, assessment of FMD using MDP results in a more accurate and precise assessment leading to a substantial reduction in sample size.

Effect of testosterone on lipid metabolism and endothelium in men with type 2 diabetes mellitus and hypogonadism

Abstract Background To date, knowledge about the effects of testosterone (T) on the cardiovascular system of men remains controversial and requires additional research. Especially the putative impact of T replacement therapy (TRT) on lipid metabolism and endothelial dysfunction as a starting mechanism for the development of cardiovascular pathology in men with type 2 diabetes mellitus (T2DM) presenting with T deficiency has to be elucidated. The aim of this work was to evaluate the effect of T replacement therapy on lipid metabolism and function of endothelium in men with T2DM and hypogonadism. Methods The study included 95 men (mean age 55,3±2,4 years) with T2DM and late onset hypogonadism, established according to EAU 2015 criteria. Parameters of carbohydrate and lipid metabolism, as well as ultrasound assessment of flow-mediated dilatation of the brachial artery (FMD-BA) and intima-media thickness (IMT) of brachial arteries were performed at baseline and after 9 months. Patients were randomized into 2 groups: 1 - 45 men receiving TRT, using 1% transdermal T-gel and 2 (control group) - 50 men, who were not assigned to TRT. Statistical analysis was carried out using the Wilcoxon - test for repeated measurements (STATISTICA 10 software package). Results During the treatment period no serious adverse events were registered. The study revealed a significant decrease in HbA1c (p&amp;lt;0.001), total cholesterol (p=0.009), triglycerides (p=0.004) and LDL (p=0.01) levels as well as an increase in HDL level (p=0.001) in the 1st group vs baseline and compared to the 2nd one. There was a decrease in IMT (from 1.0 [0.8; 1.1] to 0.7 [0.6; 0.9] mm, p=0.002) in the 1st group compared to the 2nd (p&amp;lt;0.001). The endothelium-dependent FMD-BA increased 1.5 - fold in men applying T-Gel vs baseline as well as compared to the control group at the time point of follow- up (p&amp;lt;0.001). At the same time TRT leaded to acceleration of the time until maximal vasodilation – it became twice faster (from 120 [90; 120] to 60 [60; 90] sec, p&amp;lt;0.001) compared to baseline and the 2nd group (p&amp;lt;0.001). Linear blood flow velocity increased markedly in the 1st group compared to the 2nd at the time point of follow-up (p=0.03). Conclusion TRT in men with T2DM and T deficiency leads to an improvement in carbohydrate and lipid metabolism together with a significant decrease in IMT and enhancement of endothelium vasomotor function, seems to facilitate a reduction in cardiovascular risk. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Russian Science Foundation