Do incretins improve endothelial function?

An impaired endothelial function has been recognized in the early stage of atherosclerosis, and is a major factor affecting the future development of cardiovascular events. Type 2 diabetes mellitus (T2DM) is widely prevalent, and is one of the most important risk factors for cardiovascular disease. T2DM is associated with increases in both morbidity and mortality, particularly from cardiovascular disease. New therapies based on the incretin hormone and its actions are now becoming widely used, and appear to offer advantages over conventional therapies by keeping the body weight steady and limiting hypoglycemia, while also achieving attractive glycemic control. However, there is little data available about the effects of incretins on the cardiovascular system. This review will focus on the effects of incretin therapies, including glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase (DPP)-4 inhibitors, on the endothelial function, and will discuss the potential mechanisms underlying these effects

Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive hyperemia in patients with essential hypertension: relationship between treatment periods and resistance artery endothelial function

AbstractOBJECTIVESThe purpose of this study was to evaluate the effects of the angiotensin-converting enzyme (ACE) inhibitor imidapril and the calcium antagonist amlodipine on endothelial function before and after 2, 4, 8, 12, 24 and 48 weeks of treatment.BACKGROUNDThere are limited data on whether and how long endothelial function is improved after initiation of ACE inhibitor treatment and how the grade of endothelial function further progresses after improvement of endothelial dysfunction in patients with essential hypertension.METHODSThe forearm blood flow (FBF) was measured in 25 patients with essential hypertension and in 25 normotensive subjects by using strain-gauge plethysmography during reactive hyperemia (RH) (280 mm Hg for 5 min) and after sublingual administration of nitroglycerin (NTG, 0.3 mg).RESULTSThe FBF of patients with essential hypertension during RH was significantly less than that of normotensive subjects. The increase in FBF after sublingual NTG was similar in both groups. Both imidapril (n = 13) and amlodipine (n = 12) significantly reduced systolic blood pressure and diastolic after eight weeks of treatment from the pretreatment values. Forearm vascular resistance was significantly decreased after two weeks of treatment. Imidapril significantly augmented RH after 12 weeks of treatment from the pretreatment values (31.6 ± 5.7 to 38.2 ± 6.0 ml/min per 100 ml tissue, p < 0.05), whereas amlodipine did not alter RH for each treatment period. The ability of imidapril to improve RH was maintained throughout the 48-week treatment period. There was no significant difference in RH at 12, 24 and 48 weeks. The increase in FBF after sublingual administration of NTG was similar in all treatment periods for the two groups. The infusion of NG-monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the enhancement of RH in hypertensive patients treated with imidapril.CONCLUSIONSThese findings suggest that the ACE inhibitor imidapril augments RH after 12 weeks of treatment in patients with essential hypertension and that this ACE inhibitor-induced augmentation of RH may be due to an increase in NO

A single consumption of curry improved postprandial endothelial function in healthy male subjects: a randomized, controlled crossover trial

BACKGROUND: Curry, one of the most popular foods in Japan, contains spices that are rich in potentially antioxidative compounds, such as curcumin and eugenol. Oxidative stress is thought to impair endothelial function associated with atherosclerosis, a leading cause of cardiovascular events. The aim of this study was to determine whether a single consumption of curry meal would improve endothelial function in healthy men. METHODS: Fourteen healthy male subjects (BMI 23.7 ± 2.7 kg/m(2); age 45 ± 9 years) were given a single serving of curry meal or spice-free control meal (180 g of curry or control and 200 g of cooked rice; approximately 500 kcal in total) in a randomized, controlled crossover design. Before and 1 hr after the consumption, fasting and postprandial flow-mediated vasodilation (FMD) responses and other parameters were measured. RESULTS: The consumption of the control meal decreased FMD from 5.8 ± 2.4% to 5.1 ± 2.3% (P = 0.039). On the other hand, the consumption of the curry meal increased FMD from 5.2 ± 2.5% to 6.6 ± 2.0% (P = 0.001), and the postprandial FMD after the curry meal was higher than that after the control meal (P = 0.002). Presence of spices in the curry did not alter significantly the systemic and forearm hemodynamics, or any biochemical parameters including oxidative stress markers measured. CONCLUSIONS: These findings suggest that the consumption of curry ameliorates postprandial endothelial function in healthy male subjects and may be beneficial for improving cardiovascular health. TRIAL REGISTRATION: UMIN Clinical Trials Registry 000012012

Estimation of Arterial Viscosity Based on an Oscillometric Method and Its Application in Evaluating the Vascular Endothelial Function

This paper proposes an algorithm for estimating the arterial viscosity using cuff pressures and pulse waves measured by an automatic oscillometric sphygmomanometer. A change in the arterial viscosity during the enclosed-zone flow-mediated dilation test is calculated as an index for evaluating the vascular endothelial function %η. In all, 43 individuals participated in this study. After the index %η was calculated, the accuracy of the index %η in distinguishing healthy subjects and subjects at a high risk of arteriosclerosis was tested via a receiving operating characteristic (ROC) analysis. The calculated %η for the healthy participants and those at a high risk of arteriosclerosis was 13.4 ± 55.1% and −32.7 ± 34.0% (mean ± S.D.), respectively. The area under the ROC curve was 0.77. Thus, it was concluded that the proposed method can be used to evaluate the vascular endothelial function.This research was partly supported by the Transportation Technology Development Promotion Competitive Funding Program from Ministry of Land, Infrastructure, Transport and Tourism, and the Center of Innovation Program from Japan Science and Technology Agency

Low body mass index is a risk factor forimpaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress

AbstractObjectivesThe purpose of this study was to evaluate the relationship between body mass index (BMI), including low BMIs, and endothelial function.BackgroundEpidemiologic study has demonstrated that not only obesity but also a low BMI may be a risk factor for cardiovascular disease.MethodsThe forearm blood flow (FBF) response to acetylcholine (ACh) and isosorbide dinitrate (ISDN) was measured in 87 healthy young men (15 low BMI, 51 normal, 14 obese, and 7 extremely obese).ResultsPlasma concentrations of 8-hydroxy-2′-deoxyguanosine and serum concentrations of malondialdehyde-modified low-density lipoprotein were higher in low BMI, obese, and extremely obese subjects than in normal subjects and were similar among the low BMI, obese, and extremely obese groups. The FBF response to ACh was greater in the normal group than in the other groups (p < 0.001), and was lower in the extremely obese group as compared with the other groups (p < 0.001). The ACh-stimulated vasodilation was similar between the low BMI group and the obese group. The ISDN-stimulated vasodilation was similar in all four groups. There were no significant differences in ACh-stimulated vasodilation between the four groups after the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine infusion. Co-infusion of vitamin C augmented the FBF response to ACh in low BMI, obese, and extremely obese groups—but not in normal BMI group.ConclusionsThese findings suggest that not only obesity but also a low BMI may be a risk factor for impaired endothelium-dependent vasodilation through the increased oxidative stress, leading to the reduced bioavailability of NO

Long‑term effect of sitagliptin on endothelial function in type 2 diabetes : a sub‑analysis of the PROLOGUE study

Background: As a sub-analysis of the PROLOGUE study, we evaluated the long-term effect of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on endothelial function in the conduit brachial artery in patients with type 2 diabetes. Methods: In the PROLOGUE study, patients were randomly assigned to either add-on sitagliptin treatment (sitagliptin group) or continued conventional antihyperglycemic treatment (conventional group). Among the 463 participants in the PROLOGUE study, FMD was measured in 17 patients in the sitagliptin group and 18 patients in the conventional group at the beginning and after 12 and 24 months of treatment. Results: HbA1c levels were significantly decreased after 12 and 24 months of treatment compared to baseline values in both groups (7.0 ± 0.4 vs. 6.6 ± 0.3 and 6.6 ± 0.4 % in the sitagliptin group; 7.0 ± 0.6 vs. 6.6 ± 0.7 and 6.6 ± 0.7 % in the conventional group; P < 0.05, respectively). There was no significant difference between FMD values at baseline and after 12 and 24 months in the sitagliptin group (4.3 ± 2.6 vs. 4.4 ± 2.1 and 4.4 ± 2.3 %, P = 1.0, respectively). Although FMD had a tendency to increase from 4.3 ± 2.4 % at baseline to 5.2 ± 1.9 % after 12 months and 5.1 ± 2.2 % after 24 months in the conventional group, there was no significant difference between FMD values at baseline and after 12 and 24 months (P = 0.36 and 0.33, respectively). Conclusions: Add-on sitagliptin to conventional antihyperglycemic drugs in patients with type 2 diabetes did not alter endothelial function in the conduit brachial artery measured by FMD during a 2-year study period. Sitagliptin may be used without concern for an adverse effect on endothelial function in patients with type 2 diabetes

Assessment of Lower-limb Vascular Endothelial Function Based on Enclosed Zone Flow-mediated Dilation

This paper proposes a novel non-invasive method for assessing the vascular endothelial function of lower-limb arteries based on the dilation rate of air-cuff plethysmograms measured using the oscillometric approach. The principle of evaluating vascular endothelial function involves flow-mediated dilation. In the study conducted, blood flow in the dorsal pedis artery was first monitored while lower-limb cuff pressure was applied using the proposed system. The results showed blood flow was interrupted when the level of pressure was at least 50 mmHg higher than the subject’s lower-limb systolic arterial pressure and that blood flow velocity increased after cuff release. Next, values of the proposed index, %ezFMDL, for assessing the vascular endothelial function of lower-limb arteries were determined from 327 adult subjects: 87 healthy subjects, 150 subjects at high risk of arteriosclerosis and 90 patients with cardiovascular disease (CAD). The mean values and standard deviations calculated using %ezFMDL were 30.5 ± 12.0% for the healthy subjects, 23.6 ± 12.7% for subjects at high risk of arteriosclerosis and 14.5 ± 15.4% for patients with CAD. The %ezFMDL values for the subjects at high risk of arteriosclerosis and the patients with CAD were significantly lower than those for the healthy subjects (p < 0.01). The proposed method may have potential for clinical application.This work was supported by JSPS KAKENHI Grant Number 16K21076

Rationale and design of a multicenter randomized study for evaluating vascular function under uric acid control using the xanthine oxidase inhibitor, febuxostat : the PRIZE study

Background: Xanthine oxidase inhibitors are anti-hyperuricemic drugs that decrease serum uric acid levels by inhibiting its synthesis. Xanthine oxidase is also recognized as a pivotal enzyme in the production of oxidative stress. Excess oxidative stress induces endothelial dysfunction and inflammatory reactions in vascular systems, leading to atherosclerosis. Many experimental studies have suggested that xanthine oxidase inhibitors have anti-atherosclerotic effects by decreasing in vitro and in vivo oxidative stress. However, there is only limited evidence on the clinical implications of xanthine oxidase inhibitors on atherosclerotic cardiovascular disease in patients with hyperuricemia. We designed the PRIZE study to evaluate the effects of febuxostat on a surrogate marker of cardiovascular disease risk, ultrasonography-based intima-media thickness of the carotid artery in patients with hyperuricemia. Methods: The study is a multicenter, prospective, randomized, open-label and blinded-endpoint evaluation (PROBE) design. A total of 500 patients with asymptomatic hyperuricemia (uric acid >7.0 mg/dL) and carotid intima-media thickness ≥1.1 mm will be randomized centrally to receive either febuxostat (10–60 mg/day) or non-pharmacological treatment. Randomization is carried out using the dynamic allocation method stratified according to age (<65, ≥65 year), gender, presence or absence of diabetes mellitus, serum uric acid (<8.0, ≥8.0 mg/dL), and carotid intima-media thickness (<1.3, ≥1.3 mm). In addition to administering the study drug, we will also direct lifestyle modification in all participants, including advice on control of body weight, sleep, exercise and healthy diet. Carotid intima-media thickness will be evaluated using ultrasonography performed by skilled technicians at a central laboratory. Follow-up will be continued for 24 months. The primary endpoint is percentage change in mean intima-media thickness of the common carotid artery 24 months after baseline, measured by carotid ultrasound imaging. Conclusions: PRIZE will be the first study to provide important data on the effects of febuxostat on atherosclerosis in patients with asymptomatic hyperuricemia

Febuxostat and carotid atherosclerosis in asymptomatic hyperuricemia

Background An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. Methods and findings The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10–60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat − control], −0.007 mm [95% confidence interval (CI) −0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, −0.016 mm [95% CI −0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI −0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI −0.5% to 3.3%] in the control group (n = 193); mean between-group difference, −0.2% [95% CI −2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI −0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, −2.62 mg/dL [95% CI −2.86 mg/dL to −2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia. Conclusions In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population

Longitudinal association among endothelial function, arterial stiffness and subclinical organ damage in hypertension

Objectives: To examine the longitudinal mutual association between endothelial dysfunction and arterial stiffness, and also to determine which of the two variables was more closely associated with the progression of subclinical organ damage. Methods: The brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), estimated glomerular filtration rate, microalbuminuria and flow-mediated vasodilatation of the brachial artery (FMD) were measured three times at 1.5-year intervals in 674 Japanese patients receiving antihypertensive treatment. Results: The change of the baPWV during the study period was larger in the subjects with baseline FMD values in the lowest tertile as compared to those with baseline FMD values in the highest tertile. The change of the CIMT was smaller in the subjects with baseline baPWV values in the lowest tertile than in those with baseline baPWV values in the highest tertile. After the adjustment, the FMD value at the baseline was inversely associated with the baPWV at the end of the study period (beta = − 0.07, p = 0.01), although, the reverse association was not significant. The baPWV, but not the FMD value, at the baseline was associated with the CIMT (beta = 0.06, p = 0.04) measured at the end of the study period. Conclusions: In hypertension, endothelial dysfunction was associated with the progression of arterial stiffness, although the reverse association was not confirmed. The increased arterial stiffness rather than endothelial dysfunction may be more closely associated with the progression of atherosclerotic vascular damage, and the endothelial dysfunction-arterial stiffness-atherosclerosis continuum may be important in hypertension