Venous endothelial function in heart failure: comparison with healthy controls and effect of clinical compensation

BACKGROUND: Endothelial function has been extensively evaluated at the arterial bed in several cardiovascular scenarios. Venous endothelial dysfunction, however, has not been thoroughly explored particularly in heart failure (HF). AIMS: To characterize venous endothelial function in severe HF. METHODS AND RESULTS: Venous endothelial function was evaluated by the dorsal hand vein technique using a tripod holding a linear variable differential transformer. Dorsal hand veins were pre-constricted with phenylephrine and dose-response curves were constructed after acetylcholine and sodium nitroprusside administration. Maximum vasodilator response to acetylcholine, a marker of endothelium-dependent venodilation, was significantly lower (47+/-53% versus 102+/-54%, respectively, p=0.0004) in HF (n=27) patients compared to healthy controls (n=20). No difference in the endothelium-independent venodilator response was observed (p=0.87). Maximum vasodilator response to acetylcholine was also significantly lower on admission compared to the response immediately before hospital discharge in patients with acute decompensated HF (p<0.01). Improvement in venous endothelial function paralleled weight loss (mean difference of -3.8 kg, p<0.01) and improvement in the 6-minute walk test (mean difference of 107 m, p<0.01). There was no significant change in angiotensin-converting enzyme inhibitor or beta-blocker use during hospital stay. CONCLUSIONS: HF patients experience marked endothelium-dependent venous dysfunction with partial recovery during in-hospital management.     

Effect of local and remote ischemic preconditioning on endothelial function in young people and healthy or hypertensive elderly people

To verify whether age affects remote preconditioning, we compared healthy young people (mean age = 28.0 years, SD: 7.2), healthy elderly people (age = 69.2 years, SD: 5.0), and hypertensive elderly people (group 3, age = 72.8 years, SD: 3.9). Each group included 10 participants. The flow-mediated-dilation (FMD) was measured after local (same arm) and remote (leg) ischemic preconditioning.Healthy elderly people had the greatest increase of FMD after ischemic preconditioning compared to baseline (173% after local and 181% after remote preconditioning) and young participants the smallest increase (77% after local and 69% after remote preconditioning) while hypertensive elderly had an intermediate increase (P for comparison across groups: 0.347 for local and 0.064 for remote preconditioning). However, absolute values of FMD after preconditioning were much lower in elderly hypertensive than in healthy young adults.Remote preconditioning increases endothelial reactivity in healthy and hypertensive elderly. The potential clinical relevance of this finding deserves consideration.     

White coat phenomenon, anxiety and endothelial function in healthy normotensive elderly subjects

Objective. The white coat phenomenon (WCP) is a blood pressure (BP) elevation specifically observed in the clinical setting. Though WCP has been suggested to associate with emotional responses such as anxiety or with cardiovascular complications, its pathogenesis and clinical significance are unclear. We studied the possible association between WCP and anxiety or vascular function in normotensive elderly subjects without major cardiovascular risk factors. Methods. As a parameter of anxiety, the State and Trait Anxiety Inventory (STAI) was used. WCP was evaluated by calculating the difference between the clinic BP and mean daytime ambulatory BP. As parameters of vascular function, brachial artery endothelium-dependent flow-mediated dilation (FMD) and the endothelium-independent dilation response to sublingual glyceryl trinitrate (GTN) were measured using high-resolution ultrasound. Results. Using confounding factors as covariates, no association was observed between WCP and the STAI-trait or STAI-state score. There was a significant negative association between WCP and the percent change of FMD but no association between WCP and the percent change of GTN. Conclusion. WCP in the healthy normotensive elderly subjects may reflect a decrease in endothelial function, i.e. initial stage atherosclerosis, rather than anxiety.     

血管内皮功能与肥胖高血压发生的相关性随访研究

目的探讨血管内皮功能障碍与肥胖高血压发生的关联性。方法对2000年石家庄市部分社区居民健康检查筛查出的体重指数≥25kg／m^2的单纯肥胖者583例（男376例，女207例）进行内皮依赖性血管舒张（EDD）功能以及体重指数（BMI）、腰围（WC）、腰臀比（WHR）、血压、血脂、空腹血糖（FPG）和胰岛素（Fins）、胰岛素抵抗指数（HOMA—IR）测定。并在7年后对上述人群进行随访，共随访到524例，男356例，女168例。结果7年内共发生高血压者203人，占随访对象的38．74％。初访时伴有内皮功能障碍的297例中发生高血压者158例，占53．20％，初访时内皮功能正常者134例，发生高血压者45例，占33．58％，前者显著高于后者（P〈0．01）。按照随访时有无高血压分组后比较，肥胖高血压组初访时WC、WHR、甘油三酯（TG）、Fins和HOMA—IR均显著高于肥胖非高血压组（P〈0．05或P〈0．01）。肥胖高血压组EDD显著低于肥胖非高血压组（P〈0．01）。Logistic分析显示，EDD、HOMA—IR与肥胖高血压发生密切相关。结论血管内皮功能障碍可能是导致肥胖高血压发生的重要原因，与胰岛素抵抗共同参与肥胖高血压的发病机制。     

The impact of early compared to late morning hours on brachial endothelial function and long-term cardiovascular events in healthy subjects with no apparent coronary heart disease

Background

Adverse cardiovascular events (CVE) tend to peak during early morning post-waking hours. Our objective was to explore a possible correlation between early and late morning hours and flow-mediated dilation (FMD), and whether early morning FMD reduction contributes to a circadian pattern of cardiac and vascular vulnerability.

Methods

Brachial FMD was prospectively assessed in 268 consecutive healthy subjects, 169 (63%) men, mean age 53 ± 11 years, without any concomitant medications. Following an overnight fast, FMD and endothelium-independent nitroglycerin-mediated vasodilation were assessed using high-resolution ultrasound. All subjects were followed up by phone every 6 months for combined CVE, which included all-cause mortality, myocardial infarction, hospitalization for heart failure or angina pectoris, stroke, coronary artery bypass grafting and percutaneous coronary interventions.

Results

The cohort was divided into Group A with FMD performed immediately post-waking, between 6:00 and 10:00 am [n = 151 (56%) subjects], and Group B after 10:00 am [n = 117 (46%) subjects]. Although both groups were comparable regarding baseline brachial artery diameter and the prevalence of risk factors, FMD was significantly lower in Group A compared with Group B subjects (10.4 ± 3.4% vs. 13.5 ± 3.5%, p = 0.007, respectively). In a mean follow-up of 45 ± 21 months, the composite CVEs were significantly more common in subjects with ≤(n = 128) vs. >(n = 140) the median FMD of 11.3% [18/128 (14.1%) vs. 1/140 (0.7%), p = 0.007, respectively]. Furthermore, FMD independently predicted long-term adverse CVE.

Conclusions

FMD is blunted in early compared to late morning post-waking hours, and independently predicts long-term adverse CVE in healthy subjects with no apparent heart disease.     

Insulin resistance and acute coronary syndrome in the young Japanese population have a strong association

There are few data regarding acute coronary syndrome (ACS) in young Japanese patients. We examined the risk factors for ACS in young Japanese patients, especially impaired glucose metabolism. From a database of 789 consecutive patients admitted to our hospital with ACS between 2000 and 2005, we compared risk factors of patients divided into two age categories: ≤45 years (group Y, n = 41) and ≥46 years (group O, n = 748). All patients in group Y were male. Overt diabetes, hypertension, and a family history of ischemic heart disease were not so important to group Y. Higher triglyceride (160.5 ± 86.0 vs 133.9 ± 75.2 mg/dl, P = 0.0296) and lower high-density lipoprotein cholesterol (43.9 ± 12.1 vs 48.7 ± 13.5 mg/dl, P = 0.027) concentrations were present in group Y. We obtained data concerning insulin resistance in 326 of 789 patients. Although the incidence of impaired glucose tolerance was similar between the groups (31% vs 31%, not significant), a higher homeostasis model assessment insulin resistance index (2.26 ± 2.03), indicating insulin resistance, was present in group Y. Insulin resistance might be correlated with the development of ACS in the young adult Japanese population.     

Renal function and cardiovascular mortality in elderly men: the role of inflammatory, procoagulant, and endothelial biomarkers.

AIMS: To assess the extent to which inflammatory, procoagulant, and endothelial biomarkers modify the relationship between diminished renal function and cardiovascular mortality. METHODS AND RESULTS: Prospective study of 4029 men aged 60-79 years followed up for a mean period of 6 years, during which 304 cardiovascular deaths occurred. Predicted estimated glomerular filtration rate (eGFR) was used as a measure of renal function. Reduced eGFR was associated with increased prevalence of established cardiovascular risk factors [cardiovascular disease, diabetes, hypertension, left ventricular (LV) hypertrophy, and dyslipidaemia] and higher levels of inflammatory markers [interleukin 6 (IL-6), C-reactive protein], endothelial markers [von Willebrand factor (vWF) and tissue plasminogen activator], activated coagulation markers (fibrin D-dimer), and blood viscosity. Cardiovascular mortality risk increased with decreasing levels of eGFR, particularly among men with eGFR <60 mL/min per 1.73 m(2) even after adjustment for established risk factors (adjusted RR 1.49, 95% CI 1.10, 2.03; <60 vs. > or =70 mL/min per 1.73 m(2)). The association was attenuated after further adjustment for vWF, D-dimer, and IL-6 (adjusted RR 1.34, 95% CI 0.98-1.82). CONCLUSION: Mild-to-moderate renal insufficiency is associated with significantly increased cardiovascular mortality in elderly men, which is partly explained by the increased prevalence of established risk factors, markers of coagulation, endothelium, and inflammation.     

普罗布考对急性心肌梗死介入术后炎性反应和血管内皮功能的影响

目的 观察普罗布考对急性心肌梗死（AMI）患者经皮冠状动脉介入治疗（PCI）后炎性因子和血管内皮功能的影响.方法 78例AMI患者均行冠状动脉造影及PCI治疗,术后分为对照组40例和普罗布考组38例.两组均常规使用硝酸酯类和他汀类药物,普罗布考组在常规用药基础上加服普罗布考500 mg/次,每日2次.记录所有患者出院后6个月内心血管事件,检测血脂、炎症相关生物标志物和血管内皮功能指标.结果 出院后6个月内普罗布考组心血管事件发生率显著低于对照组（P〈0.05）;6个月后普罗布考组血脂、血清白介素-6（IL-6）、高敏C反应蛋白（hs-CRP）、血内皮素-1（ET-1）及氧化低密度脂蛋白（ox-LDL）比对照组显著降低（P〈0.01或P〈0.05）;普罗布考组血一氧化氮（N0）及内皮依赖性血管舒张功能（FMD）比治疗前显著升高（P〈0.05）.对照组血NO、ET-1、ox-LDL及FMD治疗前后差异无统计学意义（P〉0.05）.普罗布考组未发现严重的不良反应.结论 普罗布考可减轻AMI患者PCI术后炎性反应,改善血管内皮功能,且不良反应少.     

A reduction of 3 g/day from a usual 9 g/day salt diet improves endothelial function and decreases endothelin-1 in a randomised cross_over study in normotensive overweight and obese subjects

Background and aim

It is unclear if a modest reduction in dietary salt intake has beneficial effects on vascular function. The aim was to compare the effects of 9 g salt/day with 6 g salt/day intake on measures of vascular function and explore mechanisms of effect in overweight and obese adults.

Methods

Twenty-five overweight/obese subjects (BMI 27–40 kg/m²) completed a randomised cross-over study of 6 weeks each on a reduced salt (RS) (6 g/day) and usual salt diet (US) (9 g/day). Flow-mediated-dilatation (FMD), 24 h blood pressure (BP), augmentation index (AIx), pulse wave velocity (PWV), plasma and urinary nitrate/nitrite, asymmetric dimethylarginine (ADMA), renin, aldosterone and endothelin-1 and vascular adhesion molecules were measured after 2 days and 6 weeks. Adherence to the diets was determined from two 24 h urine collections.

Results

Urinary sodium excretion was 155 ± 58 mmol/24 h US vs 113 ± 45 mmol/24 h RS (p = 0.002). Following the RS diet there was a significant improvement in FMD from 3.5 ± 2.8% to 5.6 ± 2.8% (P < 0.001) and decrease in serum endothelin-1 from 1.45 ± 0.38 pg/ml to 1.25 ± 0.39 pg/ml (P < 0.05). Endothelium-independent vasodilatation was also significantly different between treatments (P < 0.05). AIx, PWV, serum ADMA and plasma and urinary nitrate/nitrite concentrations were not different between treatments. Change in FMD was related to the urinary sodium: creatinine ratio (r = −0.47, P < 0.05) and was independent of blood pressure. Aldosterone and renin were unchanged.

Conclusions

A small reduction in dietary salt intake of 3 g/day improves endothelial function in normotensive overweight and obese subjects. This response may be mediated by serum endothelin-1. This small reduction in salt had no effect on aldosterone and renin concentrations.This trial was registered with the Australian and New Zealand Clinical Trials Registry Unique Identifier: ACTRN12609000321246 http://www.anzctr.org.au/ACTRN12609000321246.aspx     

Noninvasive assessment of the effect of atorvastatin on coronary microvasculature and endothelial function in patients with dyslipidemia

INTRODUCTION AND OBJECTIVES: The effect of statins has been monitored mainly in peripheral arteries. It is now possible to study coronary microcirculation by analyzing coronary reserve with transthoracic echocardiography. The aim of this study was to use this noninvasive technique to evaluate the effect of atorvastatin on peripheral endothelial function and on the coronary microvasculature in patients with dyslipidemia. PATIENTS AND METHOD: We included 21 patients with dyslipidemia but no clinical antecedents of atherosclerosis. Mean (SD) age was 64.9 (11) years, and women made up 61.9% of the group. All patients were treated with 20 mg atorvastatin during 3 months. Lipid profile, carotid intima-media thickness, endothelium-dependent vasodilation and coronary flow reserve were determined at baseline and at the end of treatment. All studies were performed with echocardiographic techniques. RESULTS: Together with improvements in the lipid profile, we found a 43% increase in endothelium-dependent vasodilation (4.3 [4.4] to 6.2 [3.8]; P=.07) and a 25% increase in coronary flow reserve (2.5 [0.6] vs 3.1 [0.8]; P=.002). The increase in endothelium-dependent vasodilatation correlated with age (r=-0.60; P=.004), intima-media thickness (r=-0.47; P=.029), low-density lipoprotein level before treatment (r=-0.43; P=.05), and baseline endothelium-dependent vasodilatation (r=-0.63; P=.002). The increase in coronary flow reserve correlated with low-density lipoprotein level after treatment (r=-0.51; P=.04). CONCLUSIONS: Short-term treatment with atorvastatin improved the lipid profile, coronary microvascular function and endothelium-dependent vasodilation in the peripheral circulation. The noninvasive assessment of coronary reserve is feasible with transthoracic echocardiography.     

Effects of magnesium supplements on blood pressure,endothelial function and metabolic parameters in healthy young men with a family history of metabolic syndrome

Background and aimsMagnesium plays an important role in the modulation of vascular tone and endothelial function and can regulate glucose and lipid metabolism. Patients with hypertension, metabolic syndrome (MetS) and diabetes mellitus (T2DM) have low body magnesium content; indeed, magnesium supplementation has been shown to have a positive effect on blood pressure (BP) and gluco-metabolic parameters. The aim of our study was to evaluate the effect of magnesium supplements on hemodynamic and metabolic parameters in healthy men with a positive family history of MetS or T2DM.Methods and resultsIn a randomized, double-blind, placebo-controlled 8-week crossover trial with a 4 week wash-out period, oral supplements of 8.1 mmol of magnesium-pidolate or placebo were administered twice a day to 14 healthy normomagnesemic participants, aged 23–33 years. The primary endpoint was office BP, measured with a semiautomatic oscillometric device. Secondary endpoints included characteristics of the MetS, namely endothelial function, arterial stiffness and inflammation. Plasma and urinary magnesium were measured in all participants while free intracellular magnesium was measured only in a subsample.There was no significant difference in either systolic and diastolic BP in participants post-magnesium supplementation and post-placebo treatment when compared to baseline BP measurements. Further, the metabolic, inflammatory and hemodynamic parameters did not vary significantly during the study.ConclusionsOur study showed no beneficial effect of magnesium supplements on BP, vascular function and glycolipid profile in young men with a family history of MetS/T2DM (trial registration at clinicaltrial.gov ID: NCT01181830; 12th of Aug 2010).     

Improvement of endothelial function in parallel with the amelioration of dry cough and dyspnea due to interstitial pneumonia by intravenous cyclophosphamide pulse therapy in patients with systemic sclerosis: a preliminary report of two cases

Abstract

Intravenous cyclophosphamide pulse therapy (IVCY) exerts its efficacy against interstitial lung disease (ILD) associated with systemic sclerosis (SSc) by restoring vascular injuries as well as aberrant immune activation. We recently experienced two patients with SSc-ILD in whom the values of brachial flow-mediated dilation (FMD) reflected the efficacy of IVCY. We herein report the details of these cases and discuss the potential of FMD to predict and evaluate the effect of IVCY on SSc-ILD.     

Gender differences in the associations among fish intake,lifestyle, and non-HDL-C level in Japanese subjects over the age of 50 years: Anti-atherosclerotic effect of fish consumption

Background and aimsHigher fish consumption may lead to the suppression of atherogenesis. The present study was aimed at investigating the gender differences in association with the frequency of fish intake, lifestyle behaviors and serum non-high-density lipoprotein cholesterol (non-HDL-C) levels.Methods and resultsThis cross-sectional study was conducted in a cohort of 4320 (2479 males, 1570 females) healthy Japanese subjects over 50 years of age registered at the Health Planning Center of Nihon University Hospital between April 2018 and March 2019. The average weekly frequency of fish intake was 2.58 ± 1.39 days in males and 2.42 ± 1.36 days in females. In males, the serum non-HDL-C level decreased significantly as the weekly frequency of fish intake (0–1 days, 2–3 days, 4–5 days, or 6–7 days) increased (p < 0.0001). Multiple stepwise regression analysis identified the weekly frequency of fish intake (β = ?0.056, p = 0.004) and habitual aerobic exercise (β = ?0.063, p = 0.001) as independent determinants of the serum non-HDL-C level. On the other hand, no such associations were observed in females. However, the proportion of subjects engaging in habitual aerobic exercise increased as the frequency of fish intake increased even among females.ConclusionsA higher frequency of fish intake may be associated with healthier lifestyle behaviors and lower non-HDL-C levels in males, but not in females. There appear to be gender differences in the relationships between the intake of fish and lifestyle behaviors on lipid metabolism.Clinical trial registrationumin (http://www.umin.ac.jp/) Study ID: UMIN000035899.     

Endothelial function, insulin action and cardiovascular risk factors in young healthy adult offspring of parents with Type 2 diabetes: effect of vitamin E in a randomized double-blind, controlled clinical trial.

BACKGROUND AND AIMS: Endothelial dysfunction, insulin resistance and oxidative stress are believed to be central and associated mechanisms in atherogenesis. We aimed to determine the effect of the antioxidant vitamin E on endothelial function, insulin action and cardiovascular risk markers in young healthy adult offspring of parents with Type 2 diabetes. METHODS: Healthy, glucose-tolerant adults (18-38 years), 14 (12 male/2 female) with at least one parent with Type 2 diabetes, and 14 (12 male/2 female) subjects with no family history of diabetes (controls) were studied. Insulin action was assessed by euglycaemic hyperinsulinaemic clamp (1 mU/kg/min). Endothelial function was assessed by forearm blood flow (FBF) responses to intra-brachial artery infusions of acetylcholine (ACh) (endothelium-dependent vasodilation), sodium nitroprusside (SNP) (endothelium-independent vasodilation) and N(G)-monomethyl L-arginine (LNMMA) (nitric oxide synthase inhibition). Thirteen offspring (18-38 years, 11 male/2 female, BMI < 30 kg/m2) completed a randomized, double-blind, crossover trial (12 weeks vitamin E 800 IU/day or placebo, 6-week washout). RESULTS: Exogenous glucose infusion rates to maintain euglycaemia were positively associated with response to acetylcholine in offspring (r = 0.61, P < 0.05), and were linked with triglycerides. Vitamin E had no effect on endothelial function, insulin action or cardiovascular risk markers in healthy adult offspring of parents with Type 2 diabetes. CONCLUSIONS: Our results support a positive association between insulin action and endothelial-dependent vasodilation in young healthy adult offspring of parents with Type 2 diabetes, but indicate no effect of vitamin E on these parameters.