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An experimental study showed that potassium inhibits the formation of reactive oxygen species by vascular cells. The purpose of this study was to investigate the association between serum potassium levels and vascular function.We measured flow-mediated vasodilation (FMD) as an index of endothelial function in 3045 subjects (1964 men; mean age, 62.3±13.8 years) and nitroglycerine-induced vasodilation (NID) as an index of vascular smooth muscle function in 1578 subjects (1001 men; mean age, 61.8±16.3 years).In the 3045 subjects, there was a significant positive correlation between FMD and serum potassium levels (r=0.09, P＜0.001). Multivariate analysis revealed that serum potassium levels were significantly associated with FMD (β=0.109, P＜0.001). When subjects were divided into two groups based on treatment with drugs that could alter serum potassium levels, the association between serum potassium levels and FMD was significant both in subjects with (β=0.096, P＜0.001) and subjects without (β=0.123, P＜0.001) treatment with drugs that could alter serum potassium levels. In the 1578 subjects, there was a significant positive correlation between NID and serum potassium levels (r=0.11, P＜0.001). Multivariate analysis revealed that serum potassium levels were significantly associated with NID (β=0.098, P＜0.001). The association between serum potassium levels and NID was significant both in subjects with (β=0.121, P=0.001) and subjects without (β=0.083, P=0.03) treatment with drugs that could alter serum potassium levels.Serum potassium levels of 4.5-＜5.0 mmol/L are associated with better vascular function regardless of the presence or absence of treatment with drugs that could alter serum potassium levels.

Aims: Volume elastic modulus (V E ), an index of arterial elasticity, and arterial diameter of the brachial artery can be automatically measured by a newly developed oscillometric device. We investigated the associations of V E with flow-mediated vasodilation (FMD), an index of endothelium-dependent vasodilation, nitroglycerine-induced vasodilation (NID), an index of endothelium-independent vasodilation, and intima-media thickness (IMT) of the brachial artery and association of oscillometrically measured brachial artery diameter with ultrasonographically measured brachial artery diameter in patients with cardiovascular risk factors. Methods: Oscillometric measurements of V E and brachial artery diameter and ultrasound measurements of brachial artery diameter, FMD, NID, and IMT of the brachial artery were performed in 50 patients with cardiovascular risk factors. Results: The mean values were 2.1±0.4 mmHg/% for V E , 0.31±0.05 mm for brachial IMT, 4.48±0.70 mm for oscillometric brachial artery diameter, and 4.30±0.55 mm for ultrasound brachial artery diameter. V E significantly correlated with brachial IMT (r=0.51, P ＜0.001), whereas there was no significant correlation of V E with FMD (r=-0.08, P =0.58) or NID (r=0.07, P =0.61). Multivariate analysis revealed that V E was significantly associated with brachial IMT (β=0.33, P =0.04). Oscillometric brachial artery diameter significantly correlated with ultrasound brachial artery diameter (r=0.79, P ＜0.001). The Bland-Altman plot showed good agreement between oscillometric brachial artery diameter and ultrasound brachial artery diameter (mean difference, -0.17 mm; limits of agreement, -1.03 mm to 0.69 mm). Conclusions: In patients with cardiovascular risk factors, V E may represent atherosclerotic structural alterations of the vascular wall but not vascular function. The accuracy of oscillometric measurement of brachial artery diameter is acceptable.

The estimated morbidity rate of chronic kidney disease is 8% to 16% worldwide, and many patients with chronic kidney disease eventually develop renal failure. Thus, the development of new therapeutic strategies for preventing renal failure is crucial. In this study, we assessed the effects of daily low-intensity pulsed ultrasound (LIPUS) therapy on experimental hypertensive nephropathy and diabetic nephropathy. Unilateral nephrectomy and subcutaneous infusion of angiotensin II via osmotic mini-pumps were used to induce hypertensive nephropathy in mice. Immunohistochemistry revealed that daily LIPUS treatment ameliorated renal fibrosis and infiltration of inflammatory cells induced by angiotensin II. A similar therapeutic effect was also observed in mice with angiotensin II-induced hypertensive nephropathy in which splenectomy was performed. In addition, LIPUS treatment significantly decreased systolic blood pressure after 21 days. Subsequently, db/db mice with unilateral nephrectomy developed proteinuria; daily LIPUS treatment significantly reduced proteinuria after 42 days. In addition, immunohistochemistry revealed that renal fibrosis was significantly ameliorated by LIPUS treatment. Finally, LIPUS stimulation suppressed TGF-β1 (transforming growth factor-β1)-induced phosphorylation of Smad2 and Smad3 in HK-2 (human proximal tubular cell line) cells. LIPUS treatment may be a useful therapy for preventing the progression of renal fibrosis in patients with chronic kidney disease.

The percentage of people aged 80 years or older in Japan has been increasing. The purpose of this study was to investigate the association between vascular functions and aging in the elderly population and to clarify the characteristics of vascular functions in subjects aged 80 years or older. We measured flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), and brachial-ankle pulse wave velocity (baPWV) in 737 subjects aged 60 years or older who visited the outpatient clinic at Hiroshima University Hospital. FMD and NID were significantly lower in subjects aged 80 years or older than in subjects aged 60–69 years or in subjects aged 70–79 years (1.9 ± 2.0% vs. 2.9 ± 2.6% and 2.7 ± 2.6%, P = 0.008 and P = 0.03, respectively and 8.6 ± 5.1% vs. 12.1 ± 5.6% and 11.2 ± 5.5%, P

The usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, is not fully known for the management of treated hypertensive patients with a history of coronary artery disease (CAD) who have blood pressure less than 130/80 mmHg, a recommended blood pressure target in the updated major hypertension guidelines. We analyzed data for 447 treated hypertensive patients with CAD enrolled in FMD-J Study A for assessment of the predictive value of baPWV for future cardiovascular events. The primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow-up period of 47.6 months, the primary outcome occurred in 64 patients. Blood pressure less than 130/80 mmHg was significantly associated with a lower risk of the composite outcome independent of other cardiovascular risk factors in treated hypertensive patients with CAD (hazard ratio, 0.59; 95% confidence interval (CI), 0.35-0.99; P = 0.04). In treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, baPWV above the cutoff value of 1731 cm/s, derived from receiver-operator characteristic curve analysis for the composite outcome was significantly associated with a higher risk of the composite outcome independent of conventional risk factors (hazard ratio, 2.83; 95% CI, 1.02-7.91; P = 0.04). baPWV was an independent predictor of cardiovascular events in treated hypertensive patients with CAD who had blood pressure less than 130/80 mmHg, for whom measurement of baPWV is recommended for cardiovascular risk assessment.

Background Upstroke time is the transit time from the nadir to peak of the waveform of pulse volume recording. The purpose of this study was to determine whether upstroke time at the ankle is a useful vascular marker for detecting patients with advanced atherosclerosis in combination with ankle‐brachial index (ABI). Methods and Results We measured upstroke time and ABI in 2313 subjects (mean age, 61.2±15.3 years). The prevalence of coronary artery disease (CAD) was significantly higher in patients with prolonged upstroke time (≥180 ms) than in subjects with normal upstroke time (P P =0.02). In 1954 subjects with normal ABI (1.00 ≤ ABI ≤ 1.40), the prevalence of CAD was significantly higher in patients with prolonged upstroke time than in subjects with normal upstroke time (29.5% versus 10.6%; P P =0.001), whereas there was no significant association between upstroke time and CAD in subjects with low ABI (P =0.44). Conclusions Upstroke time may be a useful vascular marker for detecting patients with CAD, especially in subjects with normal ABI who are usually considered not to have advanced atherosclerosis by ABI measurement alone. More attention should be paid to upstroke time for detecting patients with advanced atherosclerosis. Registration URL: https://www.umin.ac.jp ; Unique identifier: UMIN000039512.

An elevation of serum low-density lipoprotein cholesterol (LDL-C) levels has been associated with endothelial dysfunction in statin na&iuml, ve subjects. However, there is no information on endothelial function in subjects with extremely low levels of LDL-C. The purpose of the present study was to determine the relationship of LDL-C levels, especially low levels of LDL-C, with endothelial function. Endothelial function assessed by flow-mediated vasodilation (FMD) measurement and LDL-C levels were evaluated in 7120 subjects without lipid-lowering therapy. We divided the subjects into five groups by LDL-C levels: &lt, 70 mg/dL, 70&ndash, 99 mg/dL, 100&ndash, 119 md/dL, 120&ndash, 139 mg/dL, and &ge, 140 mg/dL. FMD values were significantly smaller in subjects with LDL-C levels of &ge, 140 mg/dL than in those with LDL-C levels of 70&ndash, 99 mg/dL and 100&ndash, 119 mg/dL (p &lt, 0.001 and p = 0.004, respectively). The FMD values in the LDL-C of &lt, 70 mg/dL group were not significantly different from those in the other groups. To evaluate the relationship of extremely low LDL-C levels with endothelial function, we divided the subjects with LDL-C of &lt, 70 mg/dL into those with LDL-C levels of &lt, 50 mg/dL and 50&ndash, 69 mg/dL. FMD values were similar in the LDL-C &lt, 50 mg/dL group and &ge, 50 mg/dL group in the propensity score-matched population (p = 0.570). A significant benefit was not found in subjects with low LDL-C levels from the aspect of endothelial function.

ObjectivesThe purpose of this study was to evaluate the relationship between high-density lipoprotein cholesterol (HDL-C) levels and endothelial function in women.DesignCross-sectional study.Setting22 university hospitals and affiliated clinics in Japan.Participants1719 Japanese women aged 17–90 years who were not receiving lipid-lowering therapy.MeasuresWe evaluated flow-mediated vasodilation (FMD) and serum levels of HDL-C. All participants were divided into four groups by HDL-C level: low HDL-C (ResultsUnivariate regression analysis revealed a significant relationship between FMD and HDL-C (r=0.12, pConclusionsEndothelial function increased in relation to HDL-C levels. However, there was no association of HDL-C levels with endothelial function after adjustment of traditional cardiovascular risk factors in women.Trial registration numberUMIN000012950; Results.

Background Diagnostic criteria of flow‐mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin‐induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no‐risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow‐Mediated Dilation Japan study and the Flow‐Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver‐operator characteristic curve analysis of FMD to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no‐risk group was 7.1%. Receiver‐operator characteristic curve analysis of NID to discriminate subjects in the no‐risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no‐risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409

Although reactive hyperemia-peripheral arterial tonometry (RH-PAT) is widely used for assessment of endothelial function, RH index (RHI) cannot be measured in some cases when pulse wave amplitude (PWA) is very low. Decrease in PWA is mainly caused by proper palmar digital artery (PPDA) stenosis. The purpose of this study was to evaluate the relationship between PWA measured by RH-PAT and stenosis of the PPDA measured by digital subtraction angiography and to evaluate the limitation of assessment of endothelial function measured by RHI in patients with PPDA stenosis.We measured baseline PWA in 51 fingers including the first to third fingers of both hands in 10 patients who had PPDA stenosis and in 66 fingers that were the first fingers of both hands in 33 subjects who had no PPDA stenosis. Severe stenosis was defined as over 75% by lower percent diameter stenosis between two PPDAs in a finger.PWA was significantly correlated with stenosis of the digital artery (r=-0.55; P0.0001). A PWV value of 300mV was the optimal cut-off value for severe stenosis (sensitivity, 84.0%; specificity, 88.5%). Log RHI was significantly lower in patients with PPDA stenosis than in subjects without PPDA stenosis (0.33±0.27 versus 0.73±0.27, P=0.007).RH-PAT may be useful for assessment of not only endothelial function but also PPDA stenosis. RHI may be underestimated in patients with PPDA stenosis. We should pay attention to low baseline PWA when measuring RHI.URL for clinical trial: http://UMIN; registration number for clinical trial: UMIN000003409.

Nitroglycerine-induced vasodilation (NID) is usually assessed as a control test for flow-mediated vasodilation (FMD). However, NID per se is impaired in patients with high cardiovascular risk. The purpose of this study was to investigate the associations of chronic kidney disease (CKD) with NID and FMD.We measured NID and FMD in a total of 1567 adult subjects without end-stage renal disease (ESRD), 28% of whom had CKD as judged by measurements of estimated glomerular filtration rate (995 men and 572 women; mean age, 59.0±16.9years; age range, 18 to 92years).NID was significantly smaller in patients with CKD than in those without CKD (10.8±6.0% vs. 12.7±5.7%, P0.001). The prevalence of vascular smooth muscle dysfunction, defined as NID of less than the division point for the lowest quartile, was significantly higher in patients with CKD than in those without CKD (37.5% vs. 21.5%, P0.001). Multivariate analysis revealed that CKD was independently associated with vascular smooth muscle dysfunction (OR: 1.36, 95% CI: 1.02 to 1.81, P=0.04). FMD was significantly smaller in patients with CKD than in those without CKD (3.1±2.8% vs. 4.0±3.0%, P0.001). The prevalence of endothelial dysfunction, defined as FMD of less than the division point for the lowest quartile, was significantly higher in patients with CKD than in those without CKD (31.7% vs. 23.1%, P=0.002). However, CKD was not independently associated with endothelial dysfunction in an age- and sex-adjusted model (OR: 0.95, 95% CI: 0.71 to 1.26, P=0.72).Non-ESRD CKD is independently associated with vascular smooth muscle dysfunction but not with endothelial dysfunction.

Baseline brachial artery (BBA) diameter has been reported to be a potential confounding factor of flow-mediated vasodilation (FMD). The purpose of this study was to evaluate the relationships between BBA diameter and cardiovascular risk factors and compare the diagnostic accuracy of BBA diameter in subjects without cardiovascular risk factors and patients with cardiovascular disease (CVD) with that of FMD.We measured BBA diameter and FMD in 5695 male subjects. In addition, we retrospectively investigated the incidence of cardiovascular events using another population sample consisting of 440 male subjects, to compare the accuracy of BBA diameter with that of FMD in predicting cardiovascular events.BBA diameter and FMD significantly correlated with age, body mass index, systolic blood pressure, diastolic blood pressure, triglycerides, high-density lipoprotein cholesterol, and glucose as well as Framingham risk score. The prevalence of cardiovascular risk factors and CVD increased with the increase in BBA diameter and FMD. Area under the curve (AUC) value of the receiver operating characteristic (ROC) curve for BBA diameter to diagnose subjects without cardiovascular risk factors (0.59 vs. 0.62, p = 0.001) or patients with CVD (0.58 vs. 0.64, p 0.001) was significantly lower than that for FMD. In the retrospective study, the AUC value of the ROC curve for BBA diameter to predict first major cardiovascular events was significantly lower than that of FMD (0.50 vs. 0.62, p = 0.03).In men, BBA diameter was inferior to FMD for assessment of cardiovascular risk.

Purpose The purpose of this study was to evaluate acute effects of coffee with a high content of chlorogenic acids and different hydroxyhydroquinone contents on postprandial endothelial dysfunction. Methods This was a single-blind, randomized, placebo-controlled, crossover-within-subject clinical trial. A total of 37 patients with borderline or stage 1 hypertension were randomized to two study groups. The participants consumed a test meal with a single intake of the test coffee. Subjects in the Study 1 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or coffee with a high content of chlorogenic acids and a high content of hydroxyhydroquinone with crossover. Subjects in the Study 2 group were randomized to single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone or placebo coffee with crossover. Endothelial function assessed by flow-mediated vasodilation and plasma concentration of 8-isoprostanes were measured at baseline and at 1 and 2 h after coffee intake. Results Compared with baseline values, single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone, but not coffee with a high content of chlorogenic acids and high content of hydroxyhydroquinone or placebo coffee, significantly improved postprandial flow-mediated vasodilation and decreased circulating 8-isoprostane levels. Conclusions These findings suggest that a single intake of coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone is effective for improving postprandial endothelial dysfunction. Clinical Trial Registration URL for Clinical Trial: https://upload.umin.ac.jp; Registration Number for Clinical Trial: UMIN000013283.

Hypertension is associated with endothelial dysfunction. Blood pressure significantly correlates with endothelial function in antihypertensive drug-naive subjects. The purpose of this study was to determine whether treatment status affects the relationship between blood pressure and endothelial function. We measured flow-mediated vasodilation (FMD) in 2297 subjects, including 1822 antihypertensive drug-naive subjects and 475 treated hypertensive patients. FMD significantly decreased in relation to increase in systolic blood pressure (8.2±3.1% in subjects with systolic blood pressure of P P =0.77). Propensity score matching analysis revealed that the prevalence of endothelial dysfunction defined as FMD of less than the division point for the lowest tertile, and the middle tertile of FMD was significantly higher in treated hypertensive patients than in untreated subjects in all systolic blood pressure categories. Endothelial function assessed by FMD was impaired regardless of the level of blood pressure achieved by antihypertensive drug treatment in hypertensive patients.

We investigated (1) the relationship between low-density lipoprotein cholesterol (LDL-C) and vascular function in patients receiving and those not receiving statin therapy and (2) optimal level of LDL-C for maintenance of vascular function. Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were inversely correlated with LDL-C in the 957 statin naïve subjects but not in the 392 subjects receiving statin therapy. In statin naïve subjects, non-high LDL-C (≤100 mg/dL) was independently associated with a decrease in adjusted odds ratio of the low tertile of FMD (OR: 0.62, 95% CI: 0.45–0.85; P = 0.003) and NID (OR: 0.69, 95% CI: 0.50–0.96; P = 0.03). Adjusted odds ratio of the low tertile of FMD was significantly lower in the low LDL-C group (≤70 mg/dL) (OR: 0.47, 95% CI, 0.27–0.81; P = 0.006) and in the moderate LDL-C group (70.1–100 mg/dL) (OR: 0.66, 95% CI, 0.48–0.94; P = 0.02) than in the high LDL-C group (>100 mg/dL). There was no significant difference in FMD between the low LDL-C group and moderate LDL-C group. There were significant relationships of FMD and NID with LDL-C levels in statin naïve subjects. In a general population, LDL-C of ≤100 mg/dL may be the optimal target level for maintenance of endothelial function.

Heavy drinking should be a predictor of endothelial dysfunction. However, there is little information on the effects of light to moderate alcohol consumption on endothelial function. The purpose of this study was to estimate the effects of dose-dependent alcohol consumption on endothelial function.We measured flow-mediated vasodilation (FMD) in 2734 men aged 21-81years who provided information on alcohol intake at 3 general hospitals. The subjects were divided into 5 groups; non-drinkers (0g/week), light drinkers (0 to 140g/week), moderate drinkers (140 to 280g/week), heavy drinkers (280 to 420g/week), and excessive heavy drinkers (420g/week).FMD showed a gradual decrease in accordance with alcohol consumption in the entire study population (non-drinkers, 6.6±3.4%; light drinkers, 6.2±3.0%; moderate drinkers, 6.0±3.0%; heavy drinkers, 5.5±2.9%; excessive heavy drinkers, 5.3±3.0%; P0.001). There was a significant difference in FMD between the light alcohol drinker group and the non-drinker group (P=0.015). After adjustment for other risk factors, the odds of having FMD in the lowest quartile was found to be significantly increased in the 4 drinker groups than in the non-drinker group: light (OR, 1.38; 95% CI, 1.10 to 1.75), moderate (OR, 1.36; 95% CI, 1.01 to 1.82), heavy (OR, 2.05; 95% CI, 1.46 to 2.87), excessive (OR, 2.04; 95% CI, 1.43 to 2.89).These findings suggest that FMD is impaired in relation to alcohol consumption and that FMD is significantly smaller even in light alcohol drinkers than in non-drinkers. Alcohol intake per se may be harmful for vascular function.

OBJECTIVE Primary aldosteronism is one of the most common cause of secondary hypertension. It is well known that the incidence of cardiovascular events is higher in patients with primary aldosteronism than in patients with essential hypertension. In a previous study, we showed that aldosterone-producing adenoma is associated with vascular function and structure. The aim of this study was to evaluate the effects of eplerenone on vascular function in the macrovasculature and microvasculature, arterial stiffness and Rho-associated kinase (ROCK) activity in patients with idiopathic hyperaldosteronism (IHA). METHODS Vascular function, including reactive hyperemia index (RHI), flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), arterial stiffness including brachial-ankle pulse wave velocity (baPWV) and brachial intima-media thickness (IMT) and ROCK activity in peripheral leukocytes were measured before and after 12 weeks of treatment with eplerenone in 50 patients with IHA. RESULTS After 12 weeks, eplerenone decreased the aldosterone renin ratio but did not alter SBP and DBP. Eplerenone treatment increased log RHI from 0.56 ± 0.25 to 0.69 ± 0.25 (P

It is not clear whether a high level of high-density lipoprotein cholesterol (HDL-C) is associated with lower risk of atherosclerosis. It is likely that HDL-C is a double-edged sword for atherosclerosis.The purpose of this study was to evaluate the relationship between HDL-C levels and endothelial function in men.This was a cross-sectional study. We evaluated flow-mediated vasodilation (FMD) and serum levels of HDL-C in 5842 men aged 18 to 92 years who were not receiving lipid-lowering therapy. All participants were divided into four groups by HDL-C level: low HDL-C (40 mg/dL), moderate HDL-C (40-59 mg/dL), high HDL-C (60-79 md/dL), and extremely high HDL-C (≥80 mg/dL). We were not able to evaluate the amount of alcohol intake because there was limited information on the amount of alcohol drinking in our database.FMD values were significantly smaller in the low group and the extremely high group than in the high group (P = .001 and P = .016, respectively). There was no significant difference in FMD between the low group and the extremely high group. Multiple logistic regression analysis revealed that extremely high HDL-C, but not low HDL-C, was independently associated with the lowest quartile of FMD (odds ratio: 1.39, 95% confidence interval: 1.09-1.77; P = .009).An extremely high level of HDL-C in men (8.1% of this population) was associated with a significant reduction in FMD.

Nitroglycerine-induced vasodilation, an index of endothelium-independent vasodilation, is measured for the assessment of vascular smooth muscle cell function or alterations of vascular structure. Both coronary and brachial artery responses to nitroglycerine have been demonstrated to be independent prognostic markers of cardiovascular events. The purpose of this study was to evaluate the nitroglycerine-induced vasodilation in coronary and brachial arteries in the same patients.We measured nitroglycerine-induced vasodilation in coronary and brachial arteries in 30 subjects with suspected coronary artery disease who underwent coronary angiography (19 men and 11 women; mean age, 69.0±8.8years; age range, 42-85years).The mean values of nitroglycerine-induced vasodilation in the brachial artery, left anterior descending coronary artery, and left circumflex coronary artery were 12.6±5.2%, 11.6±10.3%, and 11.9±11.0%, respectively. Nitroglycerine-induced vasodilation in the brachial artery correlated significantly with that in the left anterior descending coronary artery (r=0.43, P=0.02) and that in the left circumflex coronary artery (r=0.49, P=0.006). There was also a significant correlation between nitroglycerine-induced vasodilation in the left anterior descending coronary artery and that in the left circumflex coronary artery (r=0.72, P0.001). These findings suggest that vascular smooth muscle cell dysfunction is a systemic disorder and thus impairment of endothelium-independent vasodilation in peripheral arteries and that in coronary arteries are simultaneously present. Nitroglycerine-induced vasodilation in the brachial artery could be used as a surrogate for that in a coronary artery and as a prognostic marker for cardiovascular events.

Aim: Both vascular function and structure are independent predictors of cardiovascular events. The purpose of this study was to evaluate vascular function and structure of a leg artery in patients with peripheral artery disease (PAD). Methods: We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation (NID) as indices of vascular function and intima-media thickness (IMT) as an index of vascular structure of the popliteal artery in 100 subjects, including 20 patients with Buerger disease and 30 patients with atherosclerotic PAD, 20 age- and sex-matched subjects without Buerger disease (control group) and 30 age- and sex-matched patients without atherosclerotic PAD (control group). Results: IMT was significantly larger in the Buerger group than in the control group (Buerger, 0.63 ± 0.20 mm; control, 0.50 ± 0.07 mm; P = 0.01), whereas there were no significant differences in FMD and NID between the two groups. IMT was significantly larger in the atherosclerotic PAD group than in the control group (atherosclerotic PAD, 0.80 ± 0.22 mm; control, 0.65 ± 0.14 mm; P < 0.01), and FMD and NID were significantly smaller in the atherosclerotic PAD group than in the control group (FMD: atherosclerotic PAD, 3.9% ± 1.1%; control, 5.0% ± 1.8%; P < 0.01; and NID: atherosclerotic PAD, 6.1% ± 2.0%; control, 8.4% ± 2.1%; P < 0.01). Conclusion: These findings suggest that vascular function is preserved in patients with Buerger disease and that both vascular function and vascular structure are impaired in patients with atherosclerotic PAD.

Hypertension is associated with vascular failure, such as increased arterial stiffness, endothelial dysfunction, and vascular smooth muscle dysfunction. The purpose of this study was to investigate the relationship between out-of-office blood pressure and vascular function in patients receiving antihypertensive drugs. We assessed out-of-office blood pressure, including daytime and night-time blood pressure, by home blood pressure monitoring and performed vascular function tests, including brachial-ankle pulse wave velocity (baPWV), flow-mediated vasodilation (FMD), and nitroglycerine-induced vasodilation (NID), in 169 patients receiving antihypertensive drugs, of whom 86 (50.9%) had normotension, 23 (13.6%) had isolated nocturnal hypertension (night-time systolic blood pressure ≥120 mm Hg), 26 (15.4%) had isolated daytime hypertension (daytime systolic blood pressure ≥135 mm Hg), and 34 (20.1%) had sustained hypertension (daytime and nocturnal hypertension). baPWV was significantly higher in patients with sustained hypertension than in those without sustained hypertension (1585 ± 257 cm/s in normotension; 1687 ± 267 cm/s in isolated nocturnal hypertension; 1688 ± 313 cm/s in isolated daytime hypertension; and 1923 ± 399 cm/s in sustained hypertension; P

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation ( FMD ) and brachial–ankle pulse wave velocity (ba PWV ) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and ba PWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P =0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P =0.01) primary outcomes. ba PWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P =0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P =0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and ba PWV , stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and ba PWV were significant predictors of cardiovascular events. The combination of FMD and ba PWV provided further cardiovascular risk stratification. Clinical Trial Registration URL : www.umin.ac.jp . Unique identifier: UMIN 000012950.

Measurement of flow-mediated vasodilation (FMD) is an established method for assessing endothelial function. Measurement of FMD is useful for showing the relationship between atherosclerosis and endothelial function, mechanisms of endothelial dysfunction, and clinical implications including effects of interventions and cardiovascular events. To shorten and simplify the measurement of FMD, we have developed a novel technique named short time FMD (stFMD). We investigated the validity of stFMD for assessment of endothelial function compared with conventional FMD.We evaluated stFMD and conventional FMD in 82 subjects including patients with atherosclerotic risk factors and cardiovascular disease (66 men and 16 women, 57 ± 16 years). Both stFMD and conventional FMD were significantly correlated with age, systolic blood pressure, diastolic blood pressure and baseline brachial artery diameter. In addition, stFMD was significantly correlated with conventional FMD (r = 0.76, P 0.001). Bland-Altman plot analysis showed good agreement b etween stFMD and conventional FMD. Moreover, stFMD in the at risk group and that in the cardiovascular disease group were significantly lower than that in the no risk group (4.6 ± 2.3% and 4.4 ± 2.2% vs. 7.3 ± 1.9%, P 0.001, respectively). Optimal cutoff value of stFMD for diagnosing atherosclerosis was 7.0% (sensitivity of 71.0% and specificity of 85.0%).These findings suggest that measurement of stFMD, a novel and simple method, is useful for assessing endothelial function. Measurement of stFMD may be suitable for screening of atherosclerosis when repeated measurements of vascular function are required and when performing a clinical trial using a large population.URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000025458.

Lower urinary tract symptoms (LUTS) is not only common symptoms in elderly men and women but also risk of future cardiovascular events. The purpose of this study was to evaluate the relationships of vascular function and structure with LUTS in men and women.We investigated flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) as vascular function, brachial-ankle pulse wave velocity (baPWV) as vascular structure, and LUTS assessed by International Prostate Symptom Score (IPSS) in 287 men and 147 women.IPSS was significantly correlated with traditional cardiovascular risk factors, Framingham risk score, FMD, NID and baPWV. Moderate to severe LUTS was associated with the prevalence of coronary heart disease in men but not in women. In men, FMD and NID were significantly lower in the moderate to severe LUTS group than in the none to mild LUTS group (2.1 ± 2.0% vs. 4.0 ± 3.0% and 9.3 ± 6.1% vs. 12.8 ± 6.6%, P 0.001, respectively). baPWV was significantly higher in the moderate to severe LUTS group than in the none to mild LUTS group (1722 ± 386 cm/s vs. 1509 ± 309 cm/s, P 0.001). In multivariate analysis, FMD was independently associated with a decrease in the odds ratio of moderate to severe LUTS in men (OR: 0.83, 95% CI, 0.72-0.95; P = 0.008) but not in women. NID and baPWV were not independently associated with moderate to severe LUTS either in men or women.These findings suggest that endothelial dysfunction is associated with LUTS in men. LUTS in men may be useful for a predictor of cardiovascular events.URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409.

Background Flow‐mediated vasodilation ( FMD ) of the brachial artery has been used for the assessment of endothelial function. Considering the mechanism underlying the vasodilatory response of the brachial artery to reactive hyperemia, hyperemic shear stress ( HSS ), a stimulus for FMD ; nitroglycerine‐induced vasodilation ( NID ), an index of endothelium‐independent vasodilation; and baseline brachial artery diameter ( BAD ) are also involved in vasodilatory response. The purpose of this study was to investigate the interrelationships among FMD , HSS , NID , baseline BAD , and cardiovascular risk factors. Methods and Results We measured FMD , HSS , NID , and baseline BAD simultaneously in 1033 participants (633 men and 400 women; mean age: 58.6±17.0 years). Framingham risk score was negatively correlated with FMD , HSS, and NID and was positively correlated with baseline BAD . HSS and NID were positively correlated with FMD , and baseline BAD was negatively correlated with FMD . In participants with normal NID , FMD was correlated with HSS , NID , and baseline BAD , all of which were independent variables of FMD in multivariate analysis. In participants with impaired NID , FMD was correlated with NID and baseline BAD , both of which were independent variables of FMD in multivariate analysis, but there was no association between FMD and HSS . Conclusions NID and baseline BAD were independent variables of FMD regardless of the status of endothelium‐independent vasodilation, whereas there was a significant association between FMD and HSS in participants with normal NID but not in those with impaired NID . The influence of HSS on FMD seems to be dependent on the status of endothelium‐independent vasodilation.

Rho-associated kinases play an important role in a variety of cellular functions. Although Rho-associated kinase activity has been shown to be an independent predictor for future cardiovascular events in a general population, there is no information on Rho-associated kinase activity in patients with acute coronary syndrome. We evaluated leukocyte Rho-associated kinase activity by Western blot analysis in 73 patients with acute coronary syndrome and 73 age- and gender-matched control subjects. Rho-associated kinase activity within 2 hours of acute coronary syndrome onset was higher in patients with acute coronary syndrome than in the control subjects (0.95±0.55 versus 0.69±0.31; P P =0.03 and P =0.03, respectively) and then gradually decreased to 0.83±0.52 after 7 days, 0.78±0.42 after 14 days, and 0.72±0.30 after 6 months ( P =0.22, P =0.29, and P =0.12, respectively). During a median follow-up period of 50.8 months, 31 first major cardiovascular events (death from cardiovascular causes, myocardial infarction, ischemic stroke, and coronary revascularization) occurred. After adjustment for age, sex, cardiovascular risk factors, and concomitant treatment with statins, increased Rho-associated kinase activity was associated with increasing risk of first major cardiovascular events (hazard ratio, 4.56; 95% confidence interval, 1.98–11.34; P

The purpose of this study was to evaluate vascular function and activity of Rho-associated kinases (ROCKs) in patients with primary aldosteronism. Vascular function, including flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation, and ROCK activity in peripheral leukocytes were evaluated in 21 patients with aldosterone-producing adenoma (APA), 23 patients with idiopathic hyperaldosteronism (IHA), and 40 age-, sex-, and blood pressure–matched patients with essential hypertension (EHT). FMD was significantly lower in the APA group than in the IHA and EHT groups (3.2±2.0% versus 4.6±2.3% and 4.4±2.2%; P P r =−0.31; P r =−0.35; P r =−0.34; P r =−0.24; P =0.04), plasma aldosterone concentration ( r =0.33; P r =0.46; P

BACKGROUND Osteoporosis and cardiovascular disease are major public health problems. A number of clinical studies have shown a link between osteoporosis and cardiovascular disease, but there is no information on the associations of risk of osteoporotic fracture with vascular function and vascular structure.Methods and Results:The risk of major osteoporotic fracture was calculated using the World Health Organization fracture risk assessment tool (FRAX); vascular function was assessed using flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID), and vascular structure was assessed on brachial artery intima-media thickness (IMT) in 414 subjects (241 men and 173 women) who underwent health examinations. On univariate regression, FRAX was negatively correlated with FMD (total, r=-0.16, P

The presence of an earlobe crease (ELC) may be a simple sign to predict atherosclerosis. We evaluated the relation between ELC and vascular function. We measured flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) and observed bilateral earlobes in 400 consecutive subjects. At first, the subjects were divided into 3 groups: non-ELC group, unilateral ELC group, and bilateral ELC group. FMD and NID were significantly lower in the unilateral and bilateral ELC groups than those in the non-ELC group. After adjustment of cardiovascular risk factors, bilateral ELC, but not unilateral ELC, was associated with lower FMD and lower NID. We also investigated whether an increase in the number of ELCs worsens endothelial function, whether the difference in ELC structure (cross stripes and/or ramification) affects endothelial function, and whether endothelial function is impaired in subjects with superficial wrinkles depending on age. The number of ELCs, shape of the ELC, and superficial wrinkles were not associated with endothelial dysfunction. In conclusion, these findings suggest that the presence of bilateral ELCs is associated with vascular dysfunction.

OBJECTIVE Advanced glycation end products (AGEs) and their specific receptor, the receptor for AGEs (RAGE), play an important role in atherosclerosis. Recently, a soluble form of RAGE (sRAGE) has been identified in human serum. However, the role of sRAGE in cardiovascular disease is still controversial. There is no information on the association between simultaneous measurements of AGEs and sRAGE and vascular function. In this study, we evaluated the associations between serum levels of AGEs and sRAGE, ratio of AGEs to sRAGE, and vascular function. RESEARCH DESIGN AND METHODS We measured serum levels of AGEs and sRAGE and assessed vascular function by measurement of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in 110 subjects who underwent health examinations. Multivariate regression analyses were performed to identify factors associated with vascular function. RESULTS Univariate regression analysis revealed that FMD correlated with age, BMI, systolic blood pressure, diastolic blood pressure, heart rate, triglycerides, HDL cholesterol, glucose, smoking pack-years, nitroglycerine-induced vasodilation, serum levels of AGEs and sRAGE, and ratio of AGEs to sRAGE. Multivariate analysis revealed that the ratio of AGEs to sRAGE remained an independent predictor of FMD, while serum level of AGEs alone or sRAGE alone was not associated with FMD. CONCLUSIONS These findings suggest that sRAGE may have a counterregulatory mechanism that is activated to counteract the vasotoxic effect of the AGE–RAGE axis. The ratio of AGEs to sRAGE may be a new chemical biomarker of endothelial function.

Background A new device for automatic measurement of flow‐mediated vasodilation ( FMD ) using an oscillometric method has been developed to solve technical problems of conventional FMD measurement. This device measures enclosed zone FMD (ez FMD ). The purpose of this study was to evaluate the prognostic value of endothelial function assessed by ez FMD for future cardiovascular events. Methods and Results We measured ez FMD in 272 participants who underwent health‐screening examinations. First, we investigated cross‐sectional associations between ez FMD and cardiovascular risk factors, and then we assessed the associations between ez FMD and first major cardiovascular events (death from cardiovascular causes, stroke, and coronary revascularization). Univariate regression analysis revealed that ez FMD was significantly correlated with age, triglycerides, glucose, smoking pack‐years, estimated glomerular filtration rate, high‐sensitivity C‐reactive protein, and Framingham risk score. During a median follow‐up period of 36.1 months (interquartile range 18.8–40.1 months), 12 participants died (6 from cardiovascular causes), 3 had stroke, 8 had coronary revascularization, and 10 were hospitalized for heart failure. There was no episode of acute coronary syndrome during the study period. Participants were divided into tertiles (low, intermediate, and high) based on ez FMD . Kaplan–Meier curves for first major cardiovascular events among the 3 groups were significantly different ( P =0.004). After adjustment for cardiovascular risk factors, the low group was significantly associated with an increased risk of first major cardiovascular events compared with the high group (hazard ratio 6.47; 95% CI 1.09–125.55; P =0.038). Conclusions These findings suggest that endothelial function assessed by ez FMD may be useful as a surrogate marker of future cardiovascular events. Clinical Trial Registration URL : https://upload.umin.ac.jp . Unique identifier: UMIN 000004902.

Endothelial dysfunction and abnormal vascular structure may be involved in the pathogenesis of chronic heart failure (HF). The purpose of this study was to evaluate simultaneously vascular function and vascular structure in patients with heart failure with preserved ejection fraction (HFpEF).We measured flow-mediated vasodilatation (FMD) and nitroglycerine-induced vasodilation as indices of vascular function and intima-media thickness (IMT) as an index of vascular structure of the brachial artery in 41 patients with HFpEF (23 men and 18 women; mean age, 66±12yr) and 165 patients without HF (95 men and 70 women; mean age, 54±16yr).FMD was significantly smaller in patients with HFpEF than in patients without HF (2.9±2.1% versus 4.6±2.7%, P=0.0002). Nitroglycerine-induced vasodilation was significantly smaller in patients with HFpEF than in patients without HF (9.3±4.1% versus 12.9±4.9%, P0.0001). Brachial artery IMT was significantly larger in patients with HFpEF than in patients without HF (0.35±0.06mm versus 0.31±0.07mm, P=0.0002). After adjustment for age, sex, hypertension, dyslipidemia, and diabetes mellitus, the associations remained significant between HFpEF and FMD (odds ratio, 0.79; 95% confidence interval, 0.66-0.92; P=0.0032), nitroglycerine-induced vasodilation (odds ratio, 0.88; 95% confidence interval, 0.80-0.96; P=0.0039), and brachial artery IMT (odds ratio, 1.08; 95% confidence interval, 1.01-1.17; P=0.033).These findings suggest that both endothelial dysfunction and abnormal vascular structure may contribute to the pathogenesis and maintenance of HFpEF. Endothelial function and vascular structure may be potential therapeutic targets for HFpEF.

Background Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors. It is thought that PEDF plays a protective role against atherosclerosis. Clinical studies have shown that serum levels of PEDF are increased in subjects with cardiovascular risk factors. The role of PEDF in cardiovascular disease is still controversial. The purpose of this study was to evaluate the associations between serum levels of PEDF and vascular function and structure. Methods We measured serum levels of PEDF, assessed vascular function by measurements of flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation in the brachial artery, and measured brachial artery intima-media thickness (IMT) in 150 subjects who underwent health examinations. Results and conclusions Univariate regression analysis revealed that serum level of PEDF was significantly correlated with body mass index, high-density lipoprotein cholesterol, glucose, FMD, nitroglycerine-induced vasodilation, and brachial artery IMT. Multivariate analysis revealed that serum levels of PEDF remained an independent predictor of nitroglycerine-induced vasodilation (β=−0.20, P=0.02) and brachial artery IMT (β=0.14, P=0.03) after adjustment of cardiovascular risk factors, while serum level of PEDF was not associated with FMD (β=−0.02, P=0.79). These findings suggest that PEDF may be a factor directly associated with atherosclerosis. The serum level of PEDF may be a new biochemical marker of atherosclerosis.

It is established that low-density lipoprotein cholesterol is an independent risk factor for cardiovascular events. Recently, circulating triglycerides level has been focused on as a risk factor for cardiovascular events. In this study, we evaluated the associations between triglycerides and endothelial function in a general population.We analyzed data for 4887 subjects who were enrolled in the FMD-Japan registry. We investigated cross-sectional associations between serum triglyceride levels and endothelial function assessed by measurement of flow-mediated vasodilation (FMD).Serum triglyceride levels were correlated with FMD (r = -0.12, p 0.001). Subjects were divided into six groups based on serum triglyceride levels. FMD was significantly decreased with an increase in serum triglyceride levels (≤0.71 mmol/L, 7.0 ± 3.5%; 0.72-0.94 mmol/L, 6.3 ± 3.5%; 0.95-1.19 mmol/L, 6.0 ± 3.1%; 1.20-1.48 mmol/L, 5.8 ± 3.2%; 1.49-2.02 mmol/L, 5.7 ± 3.1%; ≥2.03 mmol/L, 5.5 ± 3.0%; p for trend0.001). After adjustment for age, sex, and cardiovascular risk factors, including high-density lipoprotein cholesterol, serum triglyceride levels of more than 1.20 mmol/L were independently associated with the low quartile of FMD (1.20-1.48 mmol/L, odds ratio (OR) 1.41, 95% confidence interval (CI) 1.09 to 1.82; 1.49-2.02 mmol/L, OR 1.31, 95% CI 1.00 to 1.70; ≥2.03 mmol/L, OR 1.48, 95% CI 1.13 to 1.95) using serum triglyceride levels of less than 0.71 mmol/L group as the reference.These findings suggest that triglycerides are an independent predictor of endothelial function. Lowering circulating triglyceride levels may improve endothelial function, leading to a decrease in cardiovascular events.URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409.

Measurement of nitroglycerine-induced vasodilation has been performed to differentiate endothelium-dependent vasodilation from endothelium-independent vasodilation as a control test for flow-mediated vasodilation (FMD). Recently, nitroglycerine-induced vasodilation per se has been reported to be a useful marker of the grade of atherosclerosis. The present study aimed to evaluate the prognostic value of FMD combined with nitroglycerine-induced vasodilation for future cardiovascular events. We measured FMD and nitroglycerine-induced vasodilation in 402 subjects, including patients with cardiovascular diseases. During a median follow-up period of 32.3 months, 38 first major cardiovascular events (death from cardiovascular causes, acute myocardial infarction, stroke, and coronary revascularization) occurred. Receiver-operator characteristic curve analysis revealed that FMD alone and nitroglycerine-induced vasodilation alone can predict cardiovascular events with areas under the curve of 0.671 (cutoff 3.3%) and 0.692 (cutoff 11.6%), respectively. FMD combined with nitroglycerine-induced vasodilation predicts cardiovascular events with an area under the curve of 0.701. After adjustment for age, sex, and cardiovascular risk factors, above cutoff FMD (≥3.3%) and below cutoff nitroglycerine-induced vasodilation (P =0.006) and below cutoff FMD (P Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: UMIN000001167.