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Various therapeutic strategies for angiogenesis are performed to improve symptoms in patients with critical limb ischemia (CLI). Pre-clinical studies have shown that low-intensity pulsed ultrasound (LIPUS) exposure induces angiogenesis. LIPUS may be a new stratergy for treatment of CLI. The purpose of this pilot trial was to evaluate outcomes in patients with CLI who were treated with LIPUS. Fourteen patients with CLI, who were not candidates for angioplasty or surgical revascularization, were enrolled in this study. Historical control data were obtained from the Hiroshima University PAD database. The primary endpoints were major amputation and death. The outcomes were compared in 16 lower limbs of the 14 patients with CLI who were treated with LIPUS and in 14 lower limbs of 14 patients with CLI as historical controls. All patients were followed for after 5 years after treatment with LIPUS. The mean duration of LIPUS exposure in the LIPUS group was 381± 283 days. During the 5-year follow-up periods, there were 3 major amputations and 7 deaths in the LIPUS group and there were 14 major amputations and 7 deaths in the historical control group. The overall amputation-free survival rate was significantly higher in patients who were treated with LIPUS than in historical controls. There was no significant difference between overall mortality-free survival rates in the LIPUS group and historical control group. LIPUS is a noninvasive option for therapeutic angiogenesis with the potential to reduce the incidence of major amputations in patients with CLI. [ABSTRACT FROM AUTHOR]

The article offers a study on the effects of alogliptin on blood pressure and arterial stiffness in hypertensive patients with type 2 diabetes mellitus (T2DM). Topics discussed include 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; and concludes that alogliptin was associated with improvements not only in glucose metabolism.

The article offers relationships between calcium channel blockers and vascular function tests. Topics discussed include measurement of flow-mediated vasodilation (FMD), nitroglycerine induced vasodilation (NIID), and brachial–ankle pulse wave velocity; and concluded that 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.

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. [ABSTRACT FROM AUTHOR]

The association of body weight with cardiovascular events is still controversial. We evaluated the relationship between body mass index (BMI) and endothelial function. We measured flow-mediated vasodilation (FMD) and BMI in 7682 men. All participants were divided into four groups by BMI: underweight (<18.5 kg/m2), normal weight (18.5 to 24.9 kg/m2), overweight (25.0 to 29.9 kg/m2), and obesity (≥30.0 kg/m2). Multiple logistic regression analysis revealed that overweight (OR: 1.30, 95% CI: 1.14–1.47; P < 0.001) and obesity (OR: 1.40, 95% CI: 1.09–1.80; P = 0.009) were associated with an increased risk of a low quartile of FMD. In 5571 younger adults (<60 years), overweight (OR: 1.34, 95% CI: 1.16–1.55; P < 0.001) and obesity (OR: 1.37, 95% CI: 1.04–1.81; P = 0.03) were associated with an increased risk of a low quartile of FMD, and underweight (OR: 0.56, 95% CI: 0.35–0.89; P = 0.01) was associated with a reduced risk of a low quartile of FMD. In 2111 older adults (≥60 years), underweight (OR: 2.16, 95% CI: 1.22–3.80; P = 0.008) was associated with an increased risk of a low quartile of FMD, and overweight and obesity were not associated with a risk of a low quartile of FMD. In Asian men, endothelial function was impaired in the overweight and obesity groups compared with that in the normal weight group. The risk for endothelial dysfunction was higher in obese younger adults than in obese older adults. The association of BMI with endothelial function may be different in young and elderly men. Clinical Trial Registration Information: http://www.umin.ac.jp (University Hospital Medical Information Network Clinical Trials Registry) (UMIN000012952). • The risk for endothelial dysfunction was higher in obese younger adults than in obese older adults. • Obesity paradox was seen in the endothelial function in the elderly. • Endothelial function was better in underweight younger adults than in the normal weight group. • Endothelial function was impaired in underweight older adults compared with that in normal weight group. • The association of BMI with endothelial function may be different by age. [ABSTRACT FROM AUTHOR]

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 (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., 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.

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.

Objective: The aim of this study was to determine the relationship of haemoglobin A1c (HbA1c) level with flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation (NID) in patients with type 2 diabetes., Design: Cross-sectional study., Setting: 22 university hospitals and affiliated clinics in Japan., Participants: 1215 patients with type 2 diabetes including 349 patients not taking antidiabetic drugs., Measures: We evaluated FMD and HbA1c level. All patients were divided into four groups based on HbA1c level: <6.5%, 6.5%-6.9%, 7.0%-7.9% and ≥8.0%., Results: An inverted U-shaped pattern of association between HbA1c level and FMD was observed at the peak of HbA1c of about 7%. FMD was significantly smaller in the HbA1c <6.5% group than in the HbA1c 6.5%-6.9% group and HbA1c 7.0%-7.9% group (p<0.001 and p<0.001), and FMD values were similar in the HbA1c <6.5% group and HbA1c ≥8.0% group. There were no significant differences in NID values among the four groups. After adjustments for confounding factors, FMD was significantly smaller in the HbA1c <6.5% group than in the HbA1c 6.5%-6.9% and HbA1c 7.0%-7.9% group (p=0.002 and p=0.04). In patients not taking antidiabetic drugs, FMD was also significantly smaller in the HbA1c <6.5% group than in the HbA1c 6.5%-6.9% group and HbA1c 7.0%-7.9% group (p<0.001 and p=0.02), and there were no significant differences in NID values among the four groups., Conclusions: These findings suggest that there is an inverted U-shaped pattern of association between FMD and HbA1c and that a low HbA1c level of <6.5% is associated with endothelial dysfunction., Trial Registration Number: UMIN000012950, UMIN000012951, UMIN000012952 and UMIN000003409., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

Context: It remains unclear whether adrenalectomy has more beneficial effects than treatment with a mineralocorticoid receptor antagonist on vascular function in patients with aldosterone-producing adenoma (APA)., Objective: The aim of this study was to compare the effects of adrenalectomy and treatment with eplerenone on vascular function in patients with APA., Design, Setting, and Patients: Flow-mediated vasodilation (FMD), as an index of endothelium-dependent vasodilation, and nitroglycerine-induced vasodilation (NID), as an index of endothelium-independent vasodilation, were measured to assess vascular function before and after a 3-month treatment with eplerenone and at 3 months after adrenalectomy in 23 patients with APA., Results: Flow-mediated vasodilation and NID after adrenalectomy were significantly higher than those before treatment with eplerenone (5.4 ± 2.6% vs 2.7 ± 1.9% and 14.8 ± 4.7% vs 9.6 ± 4.6%, P < 0.01, respectively) and those after treatment with eplerenone (5.4 ± 2.6% vs 3.1 ± 2.3% and 14.8 ± 4.7% vs 11.0 ± 5.3%, P < 0.01 and P = 0.03, respectively), while treatment with eplerenone did not alter FMD and NID compared with those before treatment with eplerenone. After adrenalectomy, the increase in FMD and NID were significantly correlated with a decrease in plasma aldosterone concentration and a decrease in the aldosterone-renin ratio. There were no significant relationships between FMD and changes in other parameters or between NID and changes in other parameters., Conclusions: Adrenalectomy, but not treatment with eplerenone, improved vascular function in patients with APA. Adrenalectomy may be more effective than treatment with eplerenone for reducing the incidence of future cardiovascular events in patients with APA. Clinical Trial Information: URL for the clinical trial: http://UMIN; Registration Number for the clinical trial: UMIN000003409., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Diabetes mellitus is associated with endothelial dysfunction. However, there is little information on the relationships of fasting blood glucose (FBG), including high normal blood glucose and impaired fasting glucose (IFG) with endothelial function. The purpose of this study was to evaluate the relationship between FBG level and flow-mediated vasodilation (FMD) using a large sample size., Research Design and Methods: This study was a cross-sectional study. We measured FMD in 7265 subjects at 31 general hospitals. The subjects were divided into four groups based on FBG levels: <100, 100-109, 110-125, and ≥126 mg/dL or known diabetes. The subjects were also divided into six groups based on FBG levels: <90, 90-94, 95-99, 100-109, 110-125, and ≥126 mg/dL or known diabetes., Results: FMD decreased in relation to increase in FBG level. There was a significant difference in FMD between the FBG of <100 mg/dL group and the other three groups (6.7±3.1% vs 5.9±2.8%, 5.7±3.1%, and 5.1±2.6%, respectively; p<0.001). After adjustment for confounding factors, the odds of having the lowest quartile of FMD were significantly higher in the FBG of 95-99, 100-104, 105-109, 110-125, and ≥126 mg/dL or known diabetes groups than in the FBG of the <90 mg/dL group., Conclusions: These findings suggest that FBG of 100-109 mg/dL and FBG of 110-125 mg/dL are similarly associated with endothelial dysfunction and that a pre-IFG state (FBG of 95-99 mg/dL) is also a risk for endothelial dysfunction compared with FBG of <90 mg/dL., Trial Registration Number: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with severe Buerger disease, also known as thromboangiitis obliterans (TAO), are at risk of major limb amputation. It has been shown that autologous bone marrow mononuclear cell (BM-MNC) implantation improves the condition of critical limb ischemia in TAO patients. This study was conducted to further clarify the long-term (>10 years) results of autologous BM-MNC implantation in patients with TAO.Methods and Results:An observational study was conducted of the long-term results of BM-MNC implantation in 47 lower limbs of 27 patients with TAO. The mean (±SD) follow-up period was 12.0±8.6 years. There was no major amputation event up to 10 years of follow-up in patients treated with BM-MNC implantation. The overall amputation-free survival rates were significantly higher in patients who underwent BM-MNC implantation than in internal controls and historical controls. There was no significant difference in amputation-free survival rates between the historical and internal controls. There was also no significant difference in overall survival between patients who underwent BM-MNC implantation and the historical controls., Conclusions: BM-MNC transplantation successfully prevented major limb amputation over a period of >10 years in patients with severe TAO who had no other therapeutic options.

Background: Circulating triglyceride (TG) levels are a current focus as a residual risk for cardiovascular (CV) events. We evaluated the relationship between circulating TG levels and future CV events in patients with coronary artery disease (CAD) who were treated with conventional therapy. Methods and Results: We analyzed data for 652 patients who were enrolled in the FMD-J Study A. We investigated the associations between serum TG levels and first major CV events (death from CV cause, nonfatal acute coronary syndrome (ACS), nonfatal stroke, and CAD) for a 3-year follow-up period. Patients were divided into 4 groups based on serum TG level: low-normal (<100 mg/dL), high-normal (100-149 mg/dL), borderline hypertriglyceridemia (150-199 mg/dL), and moderate hypertriglyceridemia (≥200 mg/dL). During a median follow-up period of 46.6 months, 14 patients died (9 from CV causes), 16 had nonfatal ACS, 6 had nonfatal stroke, and 54 had CAD. The Kaplan-Meier curves for first major CV event among the 4 groups were significantly different (P=0.04). After adjustment for various confounders, serum TG level ≥100 mg/dL were significantly associated with an increased risk of first major CV events compared with serum TG level <100 mg/dL., Conclusions: Serum TG level may be a surrogate marker for predicting CV events in patients with CAD.