Non-Invasive Central Venous Pressure Measurement Using Enclosed-Zone Central Venous Pressure (ezCVPTM).

BACKGROUND: Central venous pressure (CVP) is measured to assess intravascular fluid status. Although the clinical gold standard for evaluating CVP is invasive measurement using catheterization, the use of catheterization is limited in a clinical setting because of its invasiveness. We developed novel non-invasive technique, enclosed-zone (ezCVPTM) measurement for estimating CVP. The purpose of this study was to assess the feasibility of ezCVP and the relationship between ezCVP and CVP measured by a catheter.Methods and Results:We conducted 291 measurements in 97 patients. Linear regression analysis revealed that ezCVP was significantly correlated with CVP (r=0.65, P<0.0001). The Bland-Altman analysis showed that ezCVP had an underestimation bias of -2.5 mmHg with 95% limits of agreement of -14.1 mmHg and 9.6 mmHg for CVP (P<0.0001). The areas under the curves of receiver operating curve with ezCVP to detect the CVP ≥12 cmH2O (8.8 mmHg) and CVP >10 mmHg were 0.81 or 0.88, respectively. The sensitivity, specificity and positive likelihood ratio of ezCVP for the CVP ≥8.8 mmHg and CVP >10 mmHg were 0.59, 0.96 and 14.8 with a cut-off value of 11.9 and 0.79, 0.97 and 26.3 with a cut-off value of 12.7. CONCLUSIONS: These findings suggest that ezCVP measurement is feasible and useful for assessing CVP.

Target of Triglycerides as Residual Risk for Cardiovascular Events in Patients With Coronary Artery Disease　- Post Hoc Analysis of the FMD-J Study A.

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.

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.

Increasing Risk of Osteoporotic Fracture Is Associated With Vascular Dysfunction and Abnormal Vascular Structure in Both Men and Women.

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<0.001; men, r=-0.19, P=0.003; women, r=-0.25, P<0.001) and NID (total, r=-0.22, P<0.001; men, r=-0.19, P=0.003; women, r=-0.30, P<0.001) and was positively correlated with brachial artery IMT (total, r=0.12, P=0.02; men, r=0.22, P<0.001; women, r=0.33, P<0.001). On multivariate analysis FRAX remained an independent predictor of FMD, NID, and brachial artery IMT in both men and women. CONCLUSIONS: Increase in the risk of osteoporotic fracture evaluated on FRAX is associated with vascular dysfunction and abnormal vascular structure in both men and women. Osteoporosis should be monitored in order to reduce the risk of cardiovascular events.

Nitroglycerine-induced vasodilation for assessment of vascular function: a comparison with flow-mediated vasodilation.

OBJECTIVE: Nitroglycerine-induced vasodilation has been used as a control test for flow-mediated vasodilation (FMD) to differentiate endothelium-dependent from endothelium-independent response when evaluating endothelial function in humans. Recently, nitroglycerine-induced vasodilation has also been reported to be impaired in patients with atherosclerosis. The purpose of this study was to determine the relationships between nitroglycerine-induced vasodilation and cardiovascular risk factors. APPROACH AND RESULTS: We measured nitroglycerine-induced vasodilation and FMD in 436 subjects who underwent health examinations (mean age, 53 ± 19 years; age range, 19-86 years), including patients with cardiovascular diseases. There was a significant relationship between nitroglycerine-induced vasodilation and FMD (r=0.42; P<0.001). Univariate regression analysis revealed that nitroglycerine-induced vasodilation correlated with age (r=-0.34; P<0.001), systolic blood pressure (r=-0.32; P<0.001), diastolic blood pressure (r=-0.24; P<0.001), heart rate (r=-0.21; P<0.001), glucose (r=-0.23; P<0.001), and smoking pack-year (r=-0.12; P=0.01), as well as Framingham risk score (r=-0.30; P<0.001). Nitroglycerine-induced vasodilation was significantly smaller in patients with cardiovascular disease than in both subjects with and without cardiovascular risk factors (10.5 ± 5.6% versus 13.7 ± 5.4% and 15.3 ± 4.3%; P<0.001, respectively), whereas there was no significant difference in nitroglycerine-induced vasodilation between subjects with and without cardiovascular risk factors. Multivariate analysis revealed that male sex, body mass index, hypertension, diabetes mellitus, baseline brachial artery diameter, and FMD were independent predictors of nitroglycerine-induced vasodilation. CONCLUSIONS: These findings suggest that nitroglycerine-induced vasodilation may be a marker of the grade of atherosclerosis. FMD should be interpreted as an index of vascular function reflecting both endothelium-dependent vasodilation and endothelium-independent vasodilation in subjects with impaired nitroglycerine-induced vasodilation.

Borderline ankle-brachial index value of 0.91-0.99 is associated with endothelial dysfunction.

BACKGROUND: An ankle-brachial index (ABI) value of 0.91-0.99 is considered borderline and associated with an increased risk of cardiovascular events. However, there is no information on the relationship between borderline ABI and endothelial function. METHODS AND RESULTS: We measured ABI and assessed vascular function by flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation in 389 subjects who underwent health examinations. Subjects were divided into 3 groups according to ABI (normal group: 1.00-1.40, borderline group: 0.91-0.99, abnormal group: ≤0.90 or >1.40). FMD was significantly smaller in both the borderline and the abnormal group than in the normal group. There was no significant difference in the vascular responses to nitroglycerin between the normal and borderline groups. Vascular response to nitroglycerin was significantly higher in the normal group than in the abnormal group. Borderline and abnormal ABI values were significantly associated with an increased odds ratio of low tertile of FMD levels, using the normal ABI group as the reference. Multiple logistic regression analysis for FMD revealed that age, sex, hypertension, diabetes mellitus, and borderline ABI independently remained associated with FMD. CONCLUSIONS: ABI of 0.91-0.99 is associated with endothelial dysfunction. ABI examination is a simple and cost-effective method for obtaining the additional information on the initial step of atherosclerosis beyond the assessment of peripheral artery disease.

Poor oral health, that is, decreased frequency of tooth brushing, is associated with endothelial dysfunction.

BACKGROUND: Poor oral health is an independent predictor of cardiovascular outcome. Endothelial dysfunction is the initial step of atherosclerosis, resulting in cardiovascular outcomes; but there is no information on the association between oral health and endothelial function. The purpose of this study was to determine the relationships between oral health and endothelial function. METHODS AND RESULTS: A total of 190 subjects who underwent health examinations (mean age, 57±18 years), including patients with cardiovascular disease, completed a questionnaire on oral health and frequency of tooth brushing, and underwent measurement of vascular function, flow-mediated vasodilation (FMD) and nitroglycerine-induced vasodilation. The subjects were divided into 2 groups according to frequency of tooth brushing (≥twice/day and

Association of cumulative low-density lipoprotein cholesterol exposure with vascular function.

BACKGROUND: The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. OBJECTIVE: The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). METHODS: This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg·year/dL, 4000-4999 mg·year/dL, 5000-5999 mg·year/dL, and ≥6000 mg·year/dL. RESULTS: The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg·year/dL group was significantly higher than the odds ratios in the other groups. The odds ratio of the lower quartile of NID in the <4000 mg·year/dL group was significantly higher than the odds ratios in the 5000-5999 mg·year/dL and ≥6000 mg·year/dL groups. The odds ratio of the prevalence of CCA plaque in the <4000 mg·year/dL group was significantly higher than that in the ≥6000 mg·year/dL group. CONCLUSIONS: Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg·year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg·year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg·year/dL. CLINICAL TRIAL REGISTRY INFORMATION: http://www.umin.ac.jp (UMIN000012950, UMIN000012951, and UMIN000012952, UMIN000003409).

Seasonal variations in endothelium-dependent flow-mediated vasodilation and endothelium-independent nitroglycerine-induced vasodilation.

Cardiovascular mortality has been shown to vary seasonally. However, it has not been determined whether vascular function is affected by the season. The purpose of this study was to investigate the associations of vascular function with season and outdoor temperature. Between April 2007 and March 2022, measurements of flow-mediated vasodilation (FMD) of the brachial artery as an index of endothelial function and nitroglycerine-induced vasodilation (NID) as an index of endothelium-independent vasodilation were performed in 2190 subjects. There was no significant seasonal difference in FMD (spring, 3.9 ± 3.1%; summer, 3.5 ± 3.0%; fall, 3.7 ± 3.0%; winter, 3.6 ± 3.2%; P = 0.14). There was no significant correlation between FMD and daily mean outdoor temperature (r = -0.02, P = 0.25). Multivariate analyses revealed that neither season (ß = -0.020, P = 0.31) nor outdoor temperature (ß = 0.005, P = 0.81) was significantly associated with FMD after adjustment for other confounding factors. There were significant seasonal differences in NID (spring, 12.8 ± 6.3%; summer, 12.0 ± 6.1%; fall, 11.7 ± 6.1%; winter, 12.3 ± 5.9%; P = 0.02). However, multivariate analysis revealed that there was no significant association between season and NID after adjustment for other confounding factors (ß = -0.012, P = 0.56). There was no significant correlation between NID and daily outdoor mean temperature (r = -0.03, P = 0.17). Multivariate analysis revealed that outdoor temperature was not significantly associated with NID (ß = -0.006, P = 0.78). There was no significant association of FMD or NID with season or outdoor temperature, suggesting that it is not necessary to take into account the effects of season and outdoor temperature on vascular function when interpreting the results of FMD and NID measurements. Public trials registry number: UMIN000039512.

Percentage of mean arterial pressure as a marker of atherosclerosis for detecting patients with coronary artery disease.

The percentage of mean arterial pressure (%MAP) is the height of the mean arterial waveform divided by the peak amplitude of the waveform of pulse volume recording. The purpose of this study was to determine whether the cutoff value of 45% for %MAP at the ankle, which is recommended for the diagnosis of lower extremity artery disease, in combination with ankle-brachial index (ABI) is useful for detecting patients with clinical coronary artery disease (CAD) and investigate the optimal cutoff value of %MAP to diagnose patients with CAD.　We measured ABI and %MAP in 2213 subjects　(mean age: 61.2 ± 15.5 years). Multivariate analysis revealed that %MAP ≥ 45% was significantly associated with a higher risk of CAD after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.43-3.21; p < 0.001). However, the association was no longer significant after adjusting for ABI (OR, 1.39; 95% CI, 0.83-2.33; p = 0.21), whereas ABI was significantly associated with CAD (OR, 0.98; 95% CI, 0.97-0.99; p = 0.005). The optimal cutoff value of %MAP derived from a receiver operating characteristic curve to diagnose CAD was 40.3%. Multivariate analysis revealed that %MAP ≥ 40.3% was significantly associated with a higher risk of CAD (OR, 1.63; 95% CI, 1.19-2.24; p = 0.002) independent of ABI (OR, 0.98; 95% CI, 0.97-0.99; p = 0.002). The cutoff value of 40.3%, but not 45%, for %MAP may be useful for detecting patients with advanced atherosclerosis and for cardiovascular risk assessment independent of ABI. REGISTRATION INFORMATION: http://www.umin.ac.jp (University Hospital Medical Information Network Clinical Trials Registry) (UMIN000039512).

Upstroke time is a more useful marker of atherosclerosis than percentage of mean arterial pressure for detecting coronary artery disease in subjects with a normal ankle-brachial index.

Upstroke time (UT) and percentage of mean arterial pressure (%MAP) at the ankle have been shown to serve as atherosclerotic markers. The purpose of this study was to directly compare the diagnostic accuracy of UT with that of %MAP for clinical coronary artery disease (CAD) in subjects with a normal ankle-brachial index (ABI) in both legs. We measured UT and %MAP in 1953 subjects with a normal ABI. The optimal cutoff values of UT and %MAP derived from a receiver operating characteristic (ROC) curve to diagnose CAD were 148 ms and 40.4%, respectively. Multivariable analyses revealed that both UT ≥ 148 ms (odds ratio [OR], 2.72; p < 0.001) and %MAP ≥ 40.4% (OR, 1.28; p = 0.003) were significantly associated with CAD. When the subjects were divided into four groups according to the cutoff values of UT and %MAP, there was no significant difference in the risk of CAD between subjects with UT ≥ 148 ms and %MAP < 40.4% and those with UT ≥ 148 ms and %MAP ≥ 40.4% (OR, 1.45; p = 0.09). ROC curve analyses revealed that the area under the curve value of UT was significantly higher than that of %MAP (0.69 vs. 0.53, p < 0.001). The addition of UT to traditional risk factors significantly improved the diagnostic accuracy for CAD (0.82 to 0.84, p = 0.004), whereas the addition of %MAP to traditional risk factors did not improve the diagnostic accuracy for CAD (0.82 to 0.82, p = 0.84). UT is more useful than %MAP for identifying individuals with CAD among those with a normal ABI.

New device for assessment of endothelial function: plethysmographic flow-mediated vasodilation (pFMD).

Measurement of flow-mediated vasodilation (FMD) in the brachial artery by using ultrasound is a well-established technique for evaluating endothelial function. To make the measurement quicker and simpler than the measurements of conventional ultrasound FMD (uFMD), we have developed a new noninvasive method, plethysmographic FMD (pFMD), to assess vascular response to reactive hyperemia in the brachial artery. The aim of this study was to determine the accuracy of measurement of pFMD in comparison to that of measurement of conventional uFMD. This study was a multi-center, cross-sectional study. We compared pFMD by a new device using cuff pressure and volume with conventional uFMD using ultrasound in 50 men (mean age, 41 ± 9 years). pFMD significantly correlated with conventional uFMD (ß = 0.59, P < 0.001). In Bland-Altman plot analysis of pFMD and conventional uFMD, the mean difference of pFMD and conventional uFMD was 0.78%, and limits of agreement (mean difference ±2 standard deviations of the difference) ranged from -4.53% to 6.11%. We demonstrated validity of the new method for measurement of pFMD, which can automate the evaluation of endothelial function in a short time. Measurement of pFMD is simpler than measurement of conventional uFMD and may have reduced artificial bias compared to that of conventional uFMD measurement (URL for Clinical Trial: https://ethics.hiroshima-u.ac.jp/site/wp-content/uploads/2022/12/eki_giji20221213.pdf . Registration Number for Clinical Trial: E2022-0131).

A Body Shape Index as a Simple Anthropometric Marker of Abdominal Obesity and Risk of Cardiovascular Events.

BACKGROUND: A Body Shape Index (ABSI) has been reported to have associations with cardiovascular risk factors. However, there is no information on the association between ABSI and incidence of cardiovascular events. METHODS: We investigated the associations between ABSI and first major cardiovascular events (death from cardiovascular disease, nonfatal acute coronary syndrome, and nonfatal stroke) in 1857 subjects from the database of Flow-Mediated Dilation Japan registry and from Hiroshima University Vascular Function registry. RESULTS: The areas under the curves of ABSI to predict the first major cardiovascular events were superior to BMI (men: P=0.032, women: P=0.015) and waist circumference in women (men: P=0.078, women: P=0.002). The subjects were divided into two groups based on the cutoff value of ABSI for predicting first major cardiovascular events: a low ABSI group (<0.0822 in men and <0.0814 in women) and a high ABSI group (≥0.0822 in men and ≥0.0814 in women). During a median follow-up period of 41.6 months, 56 subjects died (23 from cardiovascular causes), 16 had nonfatal acute coronary syndrome, and 14 had nonfatal stroke. The Kaplan-Meier curves for first major cardiovascular events were significantly different between the two groups (men, P<0.001; women, P<0.001). Multivariate analysis revealed that high ABSI remained an independent predictor of first major cardiovascular events (men: hazard ratio, 2.33; 95% CI, 1.07 to 5.06; P=0.033; women: hazard ratio, 8.33; 95% CI, 1.06 to 65.49; P=0.044). CONCLUSIONS: High ABSI is independently associated with incidence of cardiovascular events. ABSI calculation should be performed for evaluation of risk of cardiovascular events.

Effects of BNT162b2 mRNA Covid-19 vaccine on vascular function.

The effects of Covid-19 vaccines on vascular function are still controversial. We evaluated the effects of BNT162b2 vaccine (BioNTech and Pfizer) on endothelial function assessed by flow-mediated vasodilation (FMD) and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation (NID). This study was a prospective observational study. A total of 23 medical staff at Hiroshima University Hospital were enrolled in this study. FMD and NID were measured before vaccination and two weeks and six months after the 2nd dose of vaccination. FMD was significantly smaller two weeks after the 2nd dose of vaccination than before vaccination (6.5±2.4% and 8.2±2.6%, p = 0.03). FMD was significantly larger at six months than at two weeks after the 2nd dose of vaccination (8.2±3.0% and 6.5±2.4%, p = 0.03). There was no significant difference between FMD before vaccination and that at six months after the 2nd dose of vaccination (8.2±2.6% to 8.2±3.0%, p = 0.96). NID values were similar before vaccination and at two weeks, and six months after vaccination (p = 0.89). The BNT162b2 Covid-19 vaccine temporally impaired endothelial function but not vascular smooth muscle function, and the impaired endothelial function returned to the baseline level within six months after vaccination.

Role of Small Dense Low-density Lipoprotein Cholesterol in Cardiovascular Events in Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus Receiving Statin Treatment.

AIM: There is little information on the relationships of serum small dense low-density lipoprotein cholesterol (sdLDL-C) levels and serum triglyceride (TG) levels with cardiovascular events in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) who are receiving statins. The aim of this study was to evaluate the relationships of serum TG levels and sdLDL-C levels as residual risks for cardiovascular events in patients with CAD and type 2 DM who were being treated with statins. METHODS: The subjects were divided into four groups based on TG levels and sdLDL-C levels: sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, and sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL. During a median follow-up period of 1419 days, cardiovascular events occurred in 34 patients. RESULTS: The incidences of cardiovascular events were significantly higher in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL and in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL, but not in patients with sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, than in patients with sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL. CONCLUSIONS: Under the condition of treatment with statins, patients with CAD and type 2 DM who had sdLDL-C levels of ≥ 40.0 mg/dL had a high risk for cardiovascular events even though serum TG levels were controlled at ＜150 mg/dL.

Geranylgeranylacetone, heat shock protein 90/AMP-activated protein kinase/endothelial nitric oxide synthase/nitric oxide pathway, and endothelial function in humans.

OBJECTIVE: Geranylgeranylacetone (GGA) induces expression of heat shock protein 90 (Hsp90), an adaptor molecule for assembly of endothelial nitric oxide synthase (eNOS) phosphorylation complex. The purpose of this study was to determine whether GGA enhances Hsp90 expression and augments endothelium-dependent vasodilation via upregulation of eNOS in humans. METHODS AND RESULTS: We evaluated the effects of GGA on human umbilical vein endothelial cells (HUVECs) and on forearm blood flow (FBF) responses to acetylcholine and sodium nitroprusside in 40 healthy young men. Hsp90, eNOS, AMP-activated protein kinase (AMPK), and Akt expression in HUVECs and peripheral blood mononuclear cells was detected by Western blot analysis. GGA increased Hsp90 expression and phosphorylation of eNOS and AMPK but not Akt in HUVECs and increased Hsp90 expression in peripheral blood mononuclear cells. Oral administration of GGA (600 mg) augmented the FBF response to acetylcholine. Infusion of N(G)-monomethyl-l-arginine, an NO synthase inhibitor, completely abolished GGA-induced augmentation of the FBF response to acetylcholine. GGA also augmented the acetylcholine-stimulated NO release in smokers. CONCLUSIONS: These findings suggest that GGA-induced activation of Hsp90/AMPK significantly increased NO-mediated vasodilation in healthy subjects, as well as in smokers. The use of GGA may be a new therapeutic approach for improving endothelial dysfunction.

Flow-mediated vasodilation and anatomical variation of the brachial artery (double brachial artery) in healthy subjects and patients with cardiovascular disease.

BACKGROUND: The purpose of this study was to evaluate the effect of anatomical variation of the brachial artery on flow-mediated vasodilation (FMD) in healthy subjects and patients with cardiovascular disease (CVD). METHODS AND RESULTS: There was no significant difference in the prevalence of double brachial artery between healthy subjects (6.1%) and patients with CVD (6.5%). In healthy subjects, FMD was larger in a single brachial artery than in large and small vessels of a double brachial artery (7.2±3.4% vs. 4.7±3.3% and 4.5±2.5%, P<0.01, respectively). In patients with CVD, there were no significant differences in FMD among a single brachial artery, large vessel of a double brachial artery and small vessel of a double brachial artery (3.3±1.4%, 3.1±2.3% and 3.6±2.1%). FMD in a single brachial artery was smaller in patients with CVD than in healthy subjects. There were no significant differences in FMD in the large vessel of a double brachial artery between the 2 groups or in the small vessel of a double brachial artery between the 2 groups. Nitroglycerine-induced vasodilation was similar in all arteries in healthy subjects and patients with CVD. CONCLUSIONS: When measuring FMD, the existence of a double brachial artery should be checked. FMD measured in a double brachial artery may be underestimated in healthy subjects.

Impact of overnight 1 mg dexamethasone on vascular function in patients with nonfunctioning adrenal adenomas.

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).

KCNJ5 mutation is a predictor for recovery of endothelial function after adrenalectomy in patients with aldosterone-producing adenoma.

The relationship of KCNJ5 mutation with vascular function and vascular structure in aldosterone-producing adenoma (APA) patients before and after adrenalectomy remains unclear. The purpose of this study was to evaluate the influence of KCNJ5 mutation on vascular function and vascular structure in APA and the effects of adrenalectomy on vascular function and vascular structure in APA patients with and those without KCNJ5 mutation. Flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID), brachial artery intima-media thickness (IMT), and brachial-ankle pulse wave velocity (baPWV) were measured to assess vascular function and vascular structure in 46 APA patients with KCNJ5 mutation and 23 APA patients without KCNJ5 mutation and in 69 matched pairs of patients with essential hypertension (EHT). FMD, NID, brachial IMT and baPVW were evacuated before adrenalectomy and at 12 weeks after adrenalectomy in APA patients with KCNJ5 mutation and APA patients without KCNJ5 mutation. FMD and NID were significantly lower in APA patients than in patients with EHT. There was no significant difference in FMD or NID between patients with and those without KCNJ5 mutation. In APA patients with KCNJ5 mutation, FMD and NID after adrenalectomy were significantly higher than those before adrenalectomy. In APA patients without KCNJ5 mutation, only NID after adrenalectomy was significantly higher than that before adrenalectomy. Endothelial function in APA patients with KCNJ5 mutation was improved by adrenalectomy in the early postoperative period. KCNJ5 mutation is a predictor for early resolution of endothelial function by adrenalectomy. 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: UMIN000003409).

Endothelial Function Is Preserved in Patients with Wild-Type Transthyretin Amyloid Cardiomyopathy.

Heart failure (HF) is associated with endothelial dysfunction. Vascular function per se plays an important role in cardiac function, whether it is a cause or consequence. However, there is no information on vascular function in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). The purpose of this study was to evaluate vascular function in patients with ATTRwt-CM. We measured flow-mediated vasodilation (FMD) as an index of endothelial function and nitroglycerine-induced vasodilation (NID) as an index of vascular smooth muscle function and brachial artery intima-media thickness (bIMT) and brachial-ankle pulse wave velocity (baPWV) as indices of arterial stiffness in 22 patients with ATTRwt-CM and in 22 one-by-one matched control patients using vascular function confounding factors. FMD was significantly greater in patients with ATTRwt-CM than in the controls (5.4 ± 3.4% versus 3.5 ± 2.4%, p = 0.038) and the N-terminal pro-brain natriuretic peptide (NT-proBNP) level was significantly greater in patients with ATTRwt-CM than in the controls (2202 ± 1478 versus 470 ± 677 pg/mL, p < 0.001). There were no significant differences in NID, bIMT or baPWV between the two groups. There was a significant relationship between NT-proBNP and FMD in patients with ATTRwt-CM (r = 0.485, p = 0.022). NT-proBNP showed no significant relationships with NID, bIMT or baPWV. Conclusions: Endothelial function was preserved in patients with ATTRwt-CM. Patients with ATTRwt-CM may have compensatory effects with respect to endothelial function through elevation of BNP.