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We evaluated the relationship of daily coffee intake with endothelial function assessed by flow-mediated vasodilation and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation in patients with hypertension. A total of 462 patients with hypertension were enrolled in this cross-sectional study. First, we divided the subjects into two groups based on information on daily coffee intake: no coffee group and coffee group. The median coffee intake was two cups per day in the coffee group. There were significant differences in both flow-mediated vasodilation (2.6 ± 2.8% in the no coffee group vs. 3.3 ± 2.9% in the coffee group, p = 0.04) and nitroglycerine-induced vasodilation (9.6 ± 5.5% in the no coffee group vs. 11.3 ± 5.4% in the coffee group, p = 0.02) between the two groups. After adjustment for confounding factors, the odds ratio for endothelial dysfunction (OR: 0.55, 95% CI: 0.32-0.95) and the odds ratio for vascular smooth muscle dysfunction (OR: 0.50, 95% CI: 0.28-0.89) were significantly lower in the coffee group than in the no coffee group. Next, we assessed the relationship of the amount of daily coffee intake with vascular function. Cubic spline curves revealed that patients with hypertension who drank half a cup to 2.5 cups of coffee per day had lower odds ratios for endothelial dysfunction assessed by flow-mediated vasodilation and vascular smooth muscle dysfunction assessed by nitroglycerine-induced vasodilation. Appropriate daily coffee intake might have beneficial effects on endothelial function and vascular smooth muscle function in patients with hypertension.

It is well known that white blood cell (WBC) count is an independent predictor of cardiovascular events. However, associations of WBC count and WBC subtypes with endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID) are unclear. The aim of this study was to determine the relationships of WBC count and WBC subtypes with vascular function assessed by FMD and NID. A total of 1351 subjects in whom FMD and NID had been measured were recruited from Hiroshima University Vascular Registry. Mean values were 3.7 ± 2.8% for FMD and 11.8 ± 5.9% for NID. WBC was not correlated with FMD or NID. NID was significantly correlated with lymphocytes in univariate analysis but not with other hematologic parameters. In multiple linear regression analyses, NID was not correlated with lymphocytes. In all subgroups including subgroups of age, gender, body mass index, hypertension, dyslipidemia, diabetes mellitus, smoking and tertile of WBC count, WBC count was not correlated with FMD or NID. WBC count and WBC subtypes were not associated with endothelial function assessed by FMD or vascular smooth muscle function assessed by NID. WBC count and vascular function assessed by FMD and NID may reflect different aspects of atherosclerosis.Clinical Trial Registration Information: URL for Clinical Trial: http://www.umin.ac.jp Registration Number for Clinical Trial: UMIN000039512., (© 2022. The Author(s).)

Hypertension is associated with an impairment of endothelial function. However, it is unclear whether isolated diastolic hypertension is associated with endothelial dysfunction. The purpose of this study was to investigate the association of endothelial function with isolated diastolic hypertension diagnosed by using two major hypertension guidelines: systolic blood pressure (BP) < 130 mmHg and diastolic BP ≥ 80 mmHg according to the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline and systolic BP < 140 mmHg and diastolic BP ≥ 90 mmHg according to the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) hypertension guideline. We measured the flow-mediated vasodilation (FMD) of the brachial artery in subjects without systolic hypertension who were not treated with antihypertensive drugs. Of 3727 subjects (2813 men; mean age: 41.3 ± 10.9 years), 749 (20.1%) had isolated diastolic hypertension according to the 2017 ACC/AHA definition. Multiple logistic regression analysis revealed that isolated diastolic hypertension was not associated with endothelial dysfunction, defined as FMD < 7.0% (OR, 1.15; 95% CI, 0.98-1.35; P = 0.09). Of 4747 subjects (3727 men; mean age: 45.1 ± 10.8 years), 314 subjects (6.6%) had isolated diastolic hypertension according to the ESC/ESH definition. Multiple logistic regression analysis revealed that isolated diastolic hypertension was not associated with endothelial dysfunction after adjusting for age and sex (OR, 1.04; 95% CI, 0.82-1.32; P = 0.76). Isolated diastolic hypertension was not associated with endothelial dysfunction in individuals who were not treated with antihypertensive drugs regardless of the major hypertension guideline definition used., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

We evaluated the relationship between daily stair climbing activity and vascular function as assessed by flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID). This study was a cross-sectional study. A total of 374 patients with hypertension were enrolled. The subjects were divided into three groups based on their daily stair climbing habit: no stairs group, climbing stairs to the 2nd-floor group, and climbing stairs to the ≥3rd-floor group. There was a significant difference in FMD between the ≥3rd-floor group and the other two groups (3.3 ± 2.5% vs. 2.3 ± 2.7% and 2.4 ± 2.7%, p = 0.02, respectively). FMD values were similar in the no stairs group and the 2nd-floor group (p = 0.96). There was a significant difference in NID between the no stairs group and the other two groups (7.4 ± 4.2% vs. 10.9 ± 5.3% and 11.3 ± 5.1%, p < 0.001, respectively). NID values were similar in the second-floor group and the ≥3rd-floor group (p = 0.86). These findings suggest that both endothelial function and vascular smooth muscle function are impaired in individuals who do not climb stairs and that endothelial function but not vascular smooth muscle function is impaired in individuals who climb stairs to the second floor compared with individuals who climb stairs to the ≥3rd floor. Stair climbing activity, a simple method for assessing daily physical activity, may reflect vascular function in patients with hypertension., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

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.

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.

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 (β = -0.151, P < 0.001) and lower NID (β = -0.120, P < 0.001) but not with baPWV (β = 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., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors on blood pressure in patients with diabetes mellitus (DM) are controversial. There is no information on the effect of DPP-4 inhibitors on blood pressure and arterial stiffness in hypertensive patients with DM. We evaluated the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM)., Methods: Blood pressure and brachial-ankle pulse wave velocity (baPWV) were measured before and after 3, 6, and 12 months of treatment with alogliptin in 22 hypertensive patients with T2DM., Results: After 3, 6, and 12 months, alogliptin treatment decreased hemoglobin A1c from 7.0 ± 0.97% to 6.4 ± 0.61%, 6.3 ± 0.58%, and 6.3 ± 0.75% (P < 0.01, respectively), glucose from 8.6 ± 4.39 mmol/l to 7.05 ± 2.16, 7.05 ± 2.28, and 6.44 ± 1.50 mmol/l (P < 0.01, respectively), systolic blood pressure from 137 ± 18 mm Hg to 127 ± 13, 125 ± 15, and 120 ± 17 mm Hg (P < 0.01, respectively), diastolic blood pressure from 79 ± 13 mm Hg to 74 ± 8, 74 ± 10, and 70 ± 8 mm Hg (P < 0.01, respectively) and baPWV from 1,947 ± 349 cm/second to 1,774 ± 259, 1,856 ± 361, and 1,756 ± 286 cm/second (P < 0.01, respectively). A baseline baPWV value of 1,643 cm/second was the optimal cut-off value for patients who had reduced blood pressure after treatment with alogliptin (sensitivity of 83.3% and specificity of 75.0%)., Conclusions: Alogliptin was associated with improvements not only in glucose metabolism but also in blood pressure and arterial stiffness in hypertensive patients with T2DM. The cut-off value of baPWV may enable identification of responders of decrease in blood pressure by alogliptin in hypertensive patients with T2DM., Clinical Trials Registration: Registration Number for Clinical Trial: UMIN000007722., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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 < 0.01) and NID from 12.8 ± 5.8 to 14.9 ± 6.9% (P = 0.02) and it decreased baPWV from 1540 ± 263 to 1505 ± 281 (P = 0.04) and ROCK activity from 1.20 ± 0.54 to 0.89 ± 0.42 (P < 0.01), whereas there was no significant change in FMD (increase from 4.6 ± 3.4 to 4.6 ± 3.6%, P = 0.99) or brachial IMT (decrease from 0.28 ± 0.07 to 0.28 ± 0.04 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.

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 <120 mm Hg, 7.5±2.8% for 120-129 mm Hg, 7.1±2.8% for 130-139 mm Hg, and 6.7±2.6% for ≥140 mm Hg; P <0.001). Systolic blood pressure was independently associated with FMD in untreated subjects. In contrast, there was no significant relationship between systolic blood pressure and FMD in treated hypertensive patients (4.6±3.1% in treated hypertensives with systolic blood pressure of <120 mm Hg, 4.8±2.7% for 120-129 mm Hg, 4.9±2.8% for 130-139 mm Hg, and 4.5±2.3% for ≥140 mm Hg; 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., (© 2017 American Heart Association, Inc.)

Nitroglycerine-induced vasodilation (NID) is usually measured as a control test for flow-mediated vasodilation (FMD). However, NID per se is also associated with atherosclerosis. The purpose of this study was to determine the relationships among NID, FMD and blood pressure, and to evaluate the effects of antihypertensive therapy on NID in patients with hypertension. We measured NID and FMD simultaneously in 94 subjects, including 35 normotensive subjects, 26 patients with stage 1 hypertension (⩾140/90 mm Hg) and 33 patients with stage 2 hypertension (⩾160/100 mm Hg), and we evaluated the effect of antihypertensive therapy for 4 weeks on vascular function in 14 patients with hypertension. NID was smaller in patients with stage 2 hypertension than in patients with stage 1 hypertension and normotensive subjects (10.5±3.9% vs. 13.8±5.0% and 16.2±5.7%; P<0.05, respectively), whereas there was no significant difference in NID between normotensive subjects and patients with stage 1 hypertension. FMD was smaller in patients with stage 2 and stage 1 hypertension than in normotensive subjects (3.1±2.7% and 4.1±1.5% vs. 6.4±2.7%; P<0.05, respectively), whereas there was no significant difference in FMD between patients with stage 1 hypertension and those with stage 2 hypertension. After 4 weeks of antihypertensive therapy, NID was enhanced from 11.9±3.4% to 14.0±3.7% (P=0.03) in patients with hypertension. There was a significant relationship between the decrease in diastolic blood pressure and the increase in NID (r=-0.35, P=0.04). Both NID and FMD were impaired in patients with stage 2 hypertension. Four-week antihypertensive therapy improved NID in patients with hypertension.

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<0.05, respectively), whereas there was no significant difference in FMD between the IHA and EHT groups. There was no significant difference in nitroglycerine-induced vasodilation in the 3 groups. ROCK activity was higher in the APA group than in the IHA and EHT groups (1.29±0.57 versus 1.00±0.46 and 0.81±0.36l; P<0.05, respectively), whereas there was no significant difference in ROCK activity between the IHA and EHT groups. FMD correlated with age (r=-0.31; P<0.01), plasma aldosterone concentration (r=-0.35; P<0.01), and aldosterone:renin ratio (r=-0.34; P<0.01). ROCK activity correlated with age (r=-0.24; P=0.04), plasma aldosterone concentration (r=0.33; P<0.01), and aldosterone:renin ratio (r=0.46; P<0.01). After adrenalectomy, FMD and ROCK activity were restored in patients with APA. APA was associated with both endothelial dysfunction and increased ROCK activity compared with those in IHA and EHT. APA may have a higher risk of future cardiovascular events., (© 2015 American Heart Association, Inc.)

Cardiovascular diseases are associated with chronic activation of Rho-associated kinase. Rho-associated kinase activity is significantly correlated with endothelial function and Framingham risk score. However, there is no information on the prognostic value of Rho-associated kinase activity. We evaluated Rho-associated kinase activity in peripheral leukocytes by Western blot analysis in 633 subjects who underwent health-screening examination at Hiroshima University Hospital. We assessed the associations between Rho-associated kinase activity and first major cardiovascular events (death from cardiovascular causes, myocardial infarction, and stroke), death from cardiovascular causes, acute myocardial infarction, stroke, revascularization (percutaneous coronary intervention, coronary artery bypass grafting), and hospitalization for heart failure. During a median period of 42.0 months (interquartile range, 24.4-56.6 months) of follow-up, 29 subjects died (10 from cardiovascular causes), 2 myocardial infarction, 20 revascularization, 15 stroke, and 17 hospitalization for heart failure. After adjustment for age, sex, cardiovascular risk factors, and other relevant variables, Rho-associated kinase activity remained a strong independent indicator of first major cardiovascular events (hazard ratio, 2.19; 95% confidence interval, 1.35-3.70; P=0.002), death from cardiovascular disease (hazard ratio, 2.57; 95% confidence interval, 1.18-6.60; P=0.002), stroke (hazard ratio, 2.14; 95% confidence interval, 1.24-3.86; P=0.006), and revascularization (hazard ratio, 2.68; 95% confidence interval, 1.60-4.66; P<0.001). Leukocyte Rho-associated kinase activity may be a new biomarker of cardiovascular events. These findings suggest that inhibition of Rho-associated kinase activity may be a therapeutic target for prevention of cardiovascular events.

The purpose of this study was to evaluate the effects of administration of overnight 1 mg dexamethasone on vascular function in patients with nonfunctioning adrenal adenomas (NFA). Flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) were measured to assess vascular function in 22 patients with NFA who had hypertension and/or diabetes mellitus (DM) and 272 patients without adrenal incidentalomas who had hypertension and/or DM (control patients with hypertension and/or DM). FMD and NID were measured in the morning before and after administration of 1 mg of dexamethasone at 2300 h in 18 patients with NFA. There were no significant differences in FMD and NID between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM (3.4 ± 2.8% vs. 2.9 ± 1.9% and 11.5 ± 5.7% vs. 11.4 ± 4.3%, P = 0.46, and P = 0.99, respectively). There were no significant differences in vascular function between control patients with hypertension and/or DM and patients with NFA who had hypertension and/or DM even after adjustment for cardiovascular risk factors. Overnight 1 mg dexamethasone increased FMD from 2.4 ± 1.9% to 5.3 ± 3.2% (P < 0.01) and increased NID from 12.1 ± 4.2% to 14.0 ± 2.8% (P < 0.01) in patients with NFA. The overnight 1 mg dexamethasone suppression test does not impair FMD and NID in patients with NFA. Decreases in circulating levels of cortisol may improve vascular function. Clinical Trial Registration: This study was approved by principal authorities and ethical issues in Japan (URL for Clinical Trial: http://www.umin.ac.jp/ctr/index.htm Registration Number for Clinical Trial: UMIN000039512). [ABSTRACT FROM AUTHOR]