Serum Potassium Levels of 4.5 to Less Than 5.0 mmol/L Are Associated with Better Vascular Function.

AIM: 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. METHODS: 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). RESULTS: 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 (ß=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 (ß=0.096, P＜0.001) and subjects without (ß=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 (ß=0.098, P＜0.001). The association between serum potassium levels and NID was significant both in subjects with (ß=0.121, P=0.001) and subjects without (ß=0.083, P=0.03) treatment with drugs that could alter serum potassium levels. CONCLUSIONS: 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.

Smoking status and endothelial function in Japanese men.

It is established that smoking is a major risk factor of atherosclerosis. Endothelial dysfunction occurs in the initial step in the pathogenesis of atherosclerosis and plays a critical role in the development of atherosclerosis. The purpose of this study was to evaluate the association between smoking status and endothelial function in detail in men. We measured flow-mediated vasodilation (FMD) in 2209 Japanese men including 1181 men who had never smoked and 1028 current smokers. All of the participants were divided into five groups by smoking pack-years: never smoker group (= 0), light smoker group (> 0 to 10), moderate smoker group (> 10 to 20), heavy smoker group (> 20 to 30) and excessive smoker group (> 30). FMD significantly decreased in relation to pack-years (6.6 ± 3.4% in the never smoker group, 6.8 ± 3.0% in the light smoker group, 6.5 ± 2.9% in the moderate smoker group, 5.9 ± 2.9% in the heavy smoker group, and 4.9 ± 2.7% in the excessive smoker group; P < 0.001). After adjustment for age (≥ 65 years), body mass index, systolic blood pressure, low-density lipoprotein cholesterol, glucose, and year of recruitment, FMD was significantly smaller in the excessive smoker group than in the never smoker group as a reference group (OR 1.95, 95% CI 1.42 to 2.67; P < 0.001). These findings suggest that FMD decreases with an increase in the number of cigarettes smoked and that excessive smoking is associated with endothelial dysfunction. Cigarette smoking is harmful to vascular function in men who are heavy smokers.

Volume Elastic Modulus, Vascular Function, and Vascular Structure in Patients with Cardiovascular Risk Factors.

AIMS: Volume elastic modulus (VE), 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 VE 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 VE 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 VE, 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. VE significantly correlated with brachial IMT (r=0.51, P＜0.001), whereas there was no significant correlation of VE with FMD (r=-0.08, P=0.58) or NID (r=0.07, P=0.61). Multivariate analysis revealed that VE was significantly associated with brachial IMT (ß=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, VE may represent atherosclerotic structural alterations of the vascular wall but not vascular function. The accuracy of oscillometric measurement of brachial artery diameter is acceptable.

Low Levels of Low-Density Lipoprotein Cholesterol and Endothelial Function in Subjects without Lipid-Lowering Therapy.

An elevation of serum low-density lipoprotein cholesterol (LDL-C) levels has been associated with endothelial dysfunction in statin naïve 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: <70 mg/dL, 70-99 mg/dL, 100-119 md/dL, 120-139 mg/dL, and ≥140 mg/dL. FMD values were significantly smaller in subjects with LDL-C levels of ≥140 mg/dL than in those with LDL-C levels of 70-99 mg/dL and 100-119 mg/dL (p < 0.001 and p = 0.004, respectively). The FMD values in the LDL-C of <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 <70 mg/dL into those with LDL-C levels of <50 mg/dL and 50-69 mg/dL. FMD values were similar in the LDL-C <50 mg/dL group and ≥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.

Upstroke Time Is a Useful Vascular Marker for Detecting Patients With Coronary Artery Disease Among Subjects With Normal Ankle-Brachial Index.

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 (<180 ms) (29.6% versus 11.8%; P<0.001), with a significant association between prolonged upstroke time and an increased risk of CAD (odds ratio [OR], 1.61; 95% CI, 1.07-2.44; 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<0.001), with a significant association between prolonged upstroke time and CAD (OR, 2.33; 95% CI, 1.41-3.87; P=0.001), whereas there was no significant association between upstroke time and CAD in subjects with low ABI (<1.00) (OR, 1.24; 95% CI, 0.72-2.16; 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.

Daily Low-intensity Pulsed Ultrasound Ameliorates Renal Fibrosis and Inflammation in Experimental Hypertensive and Diabetic Nephropathy.

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-ß1 (transforming growth factor-ß1)-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.

Relationship between high-density lipoprotein cholesterol levels and endothelial function in women: a cross-sectional study.

OBJECTIVES: The purpose of this study was to evaluate the relationship between high-density lipoprotein cholesterol (HDL-C) levels and endothelial function in women. DESIGN: Cross-sectional study. SETTING: 22 university hospitals and affiliated clinics in Japan. PARTICIPANTS: 1719 Japanese women aged 17-90 years who were not receiving lipid-lowering therapy. MEASURES: We 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 (<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). RESULTS: Univariate regression analysis revealed a significant relationship between FMD and HDL-C (r=0.12, p<0.001). FMD values were significantly smaller in the low HDL-C group (5.2%±3.8%) and moderate HDL-C group (5.2%±3.8%) than in the extremely high HDL-C group (6.7%±3.4%) (p=0.024 and p=0.003, respectively), while there was no significant difference in FMD between the high HDL-C group and the extremely high HDL-C group. Multiple logistic regression analysis did not show a significant association between HDL-C levels and FMD. CONCLUSIONS: Endothelial 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 NUMBER: UMIN000012950; Results.

Vascular function is further impaired in subjects aged 80 years or older.

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 < 0.001 and P < 0.001, respectively). baPWV was significantly higher in subjects aged 80 years or older than in subjects aged 60-69 years or in subjects aged 70-79 years (1978 ± 452 cm/s vs. 1724 ± 319 cm/s and 1811 ± 318 cm/s, P < 0.001 and P < 0.001, respectively). Age over 80 years was significantly associated with lower FMD (OR, 2.02; 95% CI, 1.19-3.42; P = 0.01), lower NID (OR, 3.62; 95% CI, 2.13-6.17; P < 0.001), and higher baPWV (OR, 3.48; 95% CI, 1.99-6.08; P < 0.001) after adjustment for other cardiovascular risk factors. Vascular functions, including endothelial function, vascular smooth muscle function, and arterial stiffness, were shown to be further impaired in subjects aged 80 years or older, suggesting that vascular functions continue to be impaired throughout life with aging.

Increased arterial stiffness and cardiovascular risk prediction in controlled hypertensive patients with coronary artery disease: post hoc analysis of FMD-J (Flow-mediated Dilation Japan) Study A.

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.

Diagnostic Criteria of Flow-Mediated Vasodilation for Normal Endothelial Function and Nitroglycerin-Induced Vasodilation for Normal Vascular Smooth Muscle Function of the Brachial Artery.

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.

Association of extremely high levels of high-density lipoprotein cholesterol with endothelial dysfunction in men.

BACKGROUND: 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. OBJECTIVE: The purpose of this study was to evaluate the relationship between HDL-C levels and endothelial function in men. METHODS: 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. RESULTS: 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). CONCLUSIONS: An extremely high level of HDL-C in men (8.1% of this population) was associated with a significant reduction in FMD.

Relationships Between Calcium Channel Blockers and Vascular Function Tests.

BACKGROUND: Differences between the effects of calcium channel blockers (CCBs) and other antihypertensive drugs on vascular function have not been fully investigated. The purpose of this study was to determine the confounding effect of CCBs on vascular function tests. METHODS: We measured flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), and brachial-ankle pulse wave velocity (baPWV) in 1,134 subjects who underwent health-screening examinations or who visited the outpatient clinic at Hiroshima University Hospital. RESULTS: FMD and NID were significantly lower (4.3 ± 3.2% vs. 2.3 ± 2.4% and 14.1 ± 5.8% vs. 10.6 ± 5.3%, P < 0.001, respectively) and baPWV was significantly higher (1,604 ± 412 cm/s vs. 1,715 ± 343 cm/s, P < 0.001) in subjects receiving CCB treatment than in subjects without CCB treatment. Multivariate analyses revealed that CCB treatment was significantly associated with lower FMD (ß = -0.151, P < 0.001) and lower NID (ß = -0.120, P < 0.001) but not with baPWV (ß = 0.017, P = 0.42). Propensity score matching analyses revealed that FMD and NID were significantly lower and baseline brachial artery diameter was significantly larger in subjects receiving CCB monotherapy than in subjects without antihypertensive medication or subjects receiving non-CCB antihypertensive monotherapy. CONCLUSIONS: CCB treatment was significantly associated with lower FMD and lower NID, which might be, at least in part, due to larger baseline brachia artery diameter, whereas there was no significant association between CCB treatment and baPWV. FMD and NID may be of no use as prognostic markers of cardiovascular events in individuals who have been receiving CCB treatment. PUBLIC TRIALS REGISTRY NUMBER: Trial Number UMIN000003409.

Relationship between home blood pressure and vascular function in patients receiving antihypertensive drug treatment.

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 < 0.001). baPWV above the cutoff value of 1858 cm/s, derived from receiver operating characteristic curve analysis to diagnose patients with sustained hypertension, was significantly associated with sustained hypertension after adjustment of other confounding factors (odds ratio, 5.01; 95% confidence interval, 1.94-13.41; P < 0.001). In contrast, there was no significant association of home blood pressure status with FMD or NID in these patients. In patients receiving antihypertensive drugs, baPWV was significantly associated with sustained hypertension, whereas FMD and NID were impaired regardless of the home blood pressure status.

Coffee with a high content of chlorogenic acids and low content of hydroxyhydroquinone improves postprandial endothelial dysfunction in patients with borderline and stage 1 hypertension.

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.

Eplerenone improves endothelial function and arterial stiffness and inhibits Rho-associated kinase activity in patients with idiopathic hyperaldosteronism: a pilot study.

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 ±â€Š0.25 to 0.69 ±â€Š0.25 (P < 0.01) and NID from 12.8 ±â€Š5.8 to 14.9 ±â€Š6.9% (P = 0.02) and it decreased baPWV from 1540 ±â€Š263 to 1505 ±â€Š281 (P = 0.04) and ROCK activity from 1.20 ±â€Š0.54 to 0.89 ±â€Š0.42 (P < 0.01), whereas there was no significant change in FMD (increase from 4.6 ±â€Š3.4 to 4.6 ±â€Š3.6%, P = 0.99) or brachial IMT (decrease from 0.28 ±â€Š0.07 to 0.28 ±â€Š0.04 mm, P = 0.14). CONCLUSION: Eplerenone improves microvascular endothelial function, vascular smooth muscle function, arterial stiffness and ROCK activity in patients with IHA. CLINICAL TRIAL REGISTRATION INFORMATION: URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409.

Endothelial Dysfunction, Increased Arterial Stiffness, and Cardiovascular Risk Prediction in Patients With Coronary Artery Disease: FMD-J (Flow-Mediated Dilation Japan) Study A.

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 (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV 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. baPWV 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 baPWV, 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 baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification. CLINICAL TRIAL REGISTRATION: URL: www.umin.ac.jp. Unique identifier: UMIN000012950.

New assessment of endothelial function measured by short time flow-mediated vasodilation: Comparison with conventional flow-mediated vasodilation measurement.

BACKGROUND: 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. METHODS AND RESULTS: We evaluated stFMD and conventional FMD in 82 subjects including patients with atherosclerotic risk factors and cardiovascular disease (66 men and 16 women, 57 ±â€¯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 ±â€¯2.3% and 4.4 ±â€¯2.2% vs. 7.3 ±â€¯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%). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION INFORMATION: URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000025458.

Reactive hyperemia-peripheral arterial tonometry is useful for assessment of not only endothelial function but also stenosis of the digital artery.

BACKGROUND: 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. METHODS: 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. RESULTS: PWA was significantly correlated with stenosis of the digital artery (r=-0.55; P<0.0001). 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). CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION INFORMATION: URL for clinical trial: http://UMIN; registration number for clinical trial: UMIN000003409.

Endothelial dysfunction, abnormal vascular structure and lower urinary tract symptoms in men and women.

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ±â€¯2.0% vs. 4.0 ±â€¯3.0% and 9.3 ±â€¯6.1% vs. 12.8 ±â€¯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 ±â€¯386 cm/s vs. 1509 ±â€¯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. CONCLUSIONS: These findings suggest that endothelial dysfunction is associated with LUTS in men. LUTS in men may be useful for a predictor of cardiovascular events. CLINICAL TRIAL REGISTRATION INFORMATION: URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409.

Chronic kidney disease is associated with vascular smooth muscle dysfunction but not with endothelial dysfunction.

BACKGROUNDS: 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. METHODS: 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). RESULTS: NID was significantly smaller in patients with CKD than in those without CKD (10.8±6.0% vs. 12.7±5.7%, P<0.001). 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%, P<0.001). 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%, P<0.001). 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). CONCLUSIONS: Non-ESRD CKD is independently associated with vascular smooth muscle dysfunction but not with endothelial dysfunction.