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Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Background Establishing an information-sharing system between medical professionals and welfare/care professionals may help prevent heart failure (HF) exacerbations in community-dwelling older adults. Therefore, we aimed to identify the ICF categories necessary for care managers to develop care plans for older patients with HF. Methods A questionnaire was administered to 695 care managers in Hiroshima, Japan, on ICF items necessary for care planning. We compared the care managers according to their specialties (medical qualifications and welfare or care qualifications). Furthermore, we created a co-occurrence network using text mining, regarding the elements necessary for collaboration between medical and care professionals. Results There were 520 valid responses (74.8%). Forty-nine ICF items, including 18 for body functions, one for body structure, 21 for activities and participation, and nine for environmental factors, were classified as “necessary” for making care plans for older people with HF. Medical professionals more frequently answered “necessary” than care professionals regarding the 11 items for body functions and structure and three items for activities and participation (p Conclusions Our findings showed that 49 ICF categories were required by care managers for care planning, and there was a significant difference in perception between medical and welfare or care qualifications qualifications.

The effects of outpatient cardiac rehabilitation (OCR) implementation and home nursing-care services (HNS) use are not well defined in patients with heart failure (HF) with mid-range or preserved left-ventricular ejection fraction (EF) (HFmrEF or HFpEF). Through a post-hoc analysis of the HF registry in Hiroshima Prefecture of Japan (REAL-HF), we investigated the current conditions and significance of OCR and HNS in HFmrEF or HFpEF patients. The REAL-HF enrolled adult patients hospitalized with HF in eight regional core hospitals. Patients discharged home were followed for conditions of OCR and HNS and the primary endpoints (all-cause death or unscheduled readmission) for 1 year. The patients were classified into HF with reduced EF (

Using three-dimensional (3D) transesophageal echocardiography (TEE) and isometric handgrip exercise (IHE), we investigated the determinants of exercise-induced mitral regurgitation (MR) according to MR etiologies. Seventy-six patients with more than moderate MR, 40 patients with functional MR (FMR) and 36 patients with degenerative MR (DMR), underwent 3D TEE combined with IHE. Mitral valve (MV) geometry and 3D vena contracta area (3D VCA) were simultaneously evaluated at baseline and during IHE. With regard to exercise-induced MR, Δ3D VCA was calculated as the difference between 3D VCA at baseline and 3D VCA during IHE. IHE caused different changes in MV geometry between etiologies and led to exacerbation of 3D VCA at baseline. Larger Δ3D VCA was observed in the FMR group compared with the DMR group (15.9 ± 10.3 mm2 versus 7.3 ± 4.2 mm2; p < 0.0001). In multivariate analyses, tenting height and 3D VCA were selected as independent factors associated with Δ3D VCA in the FMR group (p = 0.0135 and p = 0.0201, respectively), while flail width was selected as an independent factor associated with Δ3D VCA in the DMR group (p = 0.0066). In conclusion, IHE alters mitral valve geometry and causes exacerbation of MR regardless of MR etiology and the determinants of exercise-induced MR differed between MR etiologies.

The development of a comprehensive assessment tool based on the International Classification of Functioning, Disability, and Health (ICF) for elderly patients with heart failure is urgently required. In this study, we classified the ICF categories relevant to heart failure in the elderly through a Delphi survey (3-step questionnaire survey) of 108 Registered Instructors of Cardiac Rehabilitation in the Hiroshima Prefecture. Questionnaires were conducted using postal mail or a web-based platform. The survey was conducted three times, and the survey results were provided as feedback to the participants in the second and third rounds. More than 80% of the respondents selected categories according to the ICF core set methodology. Data were collected from December 2018 to March 2019, with 67, 54, and 46 participants in the first, second, and third rounds, respectively. A total of 58 ICF items were adopted based on the results: 27 body function items, 4 body structure items, 20 activity and participation items, and 7 environmental factor items. This study is characterised by the inclusion of a large number of ICF items for mental function. This result seems to be influenced by the increasing interest in cognitive dysfunction in elderly patients with heart failure. The ICF categories selected for this study allow for a comprehensive assessment of clients for occupational therapy. The findings of this study are expected to provide a basis for an outcome measure to determine the effectiveness of occupational therapy for these patients.

Aims This study aimed to evaluate the prevalence and distribution of pulmonary venous systolic flow reversal (PVSFR) in patients with severe mitral regurgitation (MR), and to examine the relationship between PVSFR profile and cardiac parameters. Methods and results A total of 125 patients with severe MR who had transoesophageal echocardiography (TOE) performed were reviewed. Of these, 121 (96.8%) patients showed all four pulmonary venous (PV) flows by TOE. They were categorized into three groups by the MR aetiology: degenerative MR (DMR) (n = 72), ventricular functional MR (V-FMR) (n = 20), and atrial functional MR (A-FMR) (n = 16). Eighteen (16.7%) patients had PVSFR in all four PVs. Twenty-nine (26.9%) had PVSFR in three PVs, 23 (21.3%) in two PVs, and 23 (21.3%) in one PV. PVSFR appeared at right PVs more frequently compared with left PVs. A high number of PVSFR was significantly correlated with higher pulmonary capillary wedge pressure (PCWP) and 3D vena contracta area (3D-VCA). With regard to MR aetiology, the number of PVSFRs was correlated with high 3D-VCA in patients with DMR and A-FMR, while it was correlated with high PCWP in patients with V-FMR. Laminar-type PVSFR appeared more frequently in FMR compared with DMR, and it had a relationship with higher PCWP and lower right ventricular fractional area change (RVFAC). Conclusion All four PV were detected in 96.8%, and 16.8% patients had PVSFR in all four PVs. PCWP and 3D-VCA were correlated with the number of PVSFRs in severe MR patients. Laminar-type PVSFR was related to higher PCWP and lower RVFAC.

Aims We sought to investigate tricuspid valve (TV) geometry and right heart remodelling in atrial functional tricuspid regurgitation (AF-TR) as compared with ventricular functional TR with sinus rhythm (VF-TR). Methods and results Transoesophageal 3D echocardiography datasets of the TV and right ventricle were acquired in 51 symptomatic patients with severe TR (AF-TR, n = 23; VF-TR, n = 28). Three-dimensional right ventricular (RV) endocardial surfaces were reconstructed throughout the cardiac cycle and then postprocessed using semiautomated integration and segmentation software to calculate position of papillary muscle (PM) tips. Compared with VF-TR, AF-TR had more dilated and posteriorly displaced annulus and less leaflet tethering angles with more prominent right atrium and smaller RV end-systolic volume. On the XY (annular) plane, the centre of annulus was getting closer towards the anterior and posterior PM tips and was going away from the medial PM tip caused by prominent annular dilatation in AF-TR. On the Z-axis, the position of each PM tip in AF-TR was not so much displaced apically as that in VF-TR. Multiple linear regression analyses revealed that right atrial volume and right atrial/RV end-systolic volume ratio were determinants of annular area and orientation in AF-TR, respectively (both P Conclusion Right heart remodelling and its association with 3D TV geometry differ entirely between AF-TR and VF-TR, which may offer distinctive therapeutic implication.

Coronary flow reserve (CFR) reflects the functional capacity of microcirculation to adapt to blood demand during increased cardiac work. We tested the hypothesis that aging had impacts on coronary flow velocities and CFR in patients with no evidence of myocardial perfusion abnormality on single photon emission computed tomography (SPECT). Seventy-six patients undergoing transthoracic Doppler echocardiography with no evidence of myocardial perfusion abnormality on SPECT were enrolled in this study. CFR was defined as the ratio of hyperemic to resting peak diastolic coronary flow velocity. Patients were divided into the three groups based on age: 17 patients aged less than 70 years (Group I), 38 patients aged 70–79 years (Group II), and 21 patients aged 80 years or more (Group III). Compared with Group I, CFR was significantly lower in Group II (p < 0.01) and Group III (p < 0.01). Multivariate linear regression analysis showed that female (β = − 0.26, p = 0.03), cigarette smoking (β = − 0.32, p = 0.004), hemoglobin level (β = − 0.40, p = 0.001) and LV mass index (β = 0.24, p = 0.03) were determinants for resting coronary flow velocity. On the other hand, age (β = -0.30, p = 0.008), hemoglobin level (β = -0.47, p < 0.001) and LV mass index (β = 0.24, p = 0.04) were determinants for hyperemic coronary flow velocity. Age was only determinant for CFR (β = -0.48, p < 0.001). Our data suggested that that aging had a decreased effect on hyperemic coronary flow velocity rather than resting coronary flow velocity, and was further associated with impaired CFR in patients with no evidence of myocardial perfusion abnormality.

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

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

ObjectiveThe number of older patients with heart failure (HF) is increasing in Japan and has become a social problem. There is an urgent need to develop a comprehensive assessment methodology based on the common language of healthcare; the International Classification of Functioning, Disability and Health (ICF). The purpose of this study was to develop and confirm the appropriateness of a scoring methodology for 43 ICF categories in older people with HF.DesignCross-sectional survey. We applied the RAND/University of California at Los Angeles (UCLA) Appropriateness Method with a modified Delphi method.Setting and participantsWe included a panel of 26 multidisciplinary experts on HF care consisting of home physicians, cardiovascular physicians, care managers, nurses, physical therapists, a pharmacist, occupational therapist, nutritionist and a social worker.MeasuresWe conducted a literature review of ICF linking rules and developed a questionnaire on scoring methods linked to ICF categories in older people with HF. In the Delphi rounds, we sent the expert panel a questionnaire consisting of three questions for each of the 43 ICF categories. The expert panel responded to the questionnaire items on a 1 (very inappropriate) – 9 (very appropriate) Likert scale and repeated rounds until a consensus of ‘Appropriate’ and ‘Agreement’ was reached on all items.ResultsA total of 21 panel members responded to all the Delphi rounds. In the first Delphi round, six question items in four ICF categories did not reach a consensus of ‘Agreement’, but the result of our modifications based on panel members’ suggestions reached to a consensus of ‘Appropriate’ and ‘Agreement’ on all questions in the second Delphi round.ConclusionThe ICF-based scoring method for older people with HF developed in this study was found to be appropriate. Future work is needed to clarify whether comprehensive assessment and information sharing based on ICF contributes to preventing readmissions.

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

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 (ezCVPThese findings suggest that ezCVP measurement is feasible and useful for assessing CVP.

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

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

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

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

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

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

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

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

Background Nearly half of patients with heart failure have normal left ventricular ejection fraction (LVEF), but their prognosis is no better than those with reduced LVEF. Although peak oxygen consumption (VO2) is an independent predictor of mortality in heart failure, it is unclear how cardiac function during exercise contributes to peak VO2. Therefore, we explored the useful parameters measured by exercise stress echocardiography to predict peak VO2 in patients with heart failure with preserved LVEF (HFpEF). Methods and Results We assessed 80 patients being investigated for effort intolerance or dyspnea and finally analyzed 50 patients who satisfied the HFpEF criteria. Mean peak VO2 was 16.4±2.8 mL/kg/min. Twenty-three patients (46.0%) achieved a peak VO2

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Atrial fibrillation (AF) is a common disease that changes cardiac morphology, especially in the left atrium (LA). It is now known that certain categories of functional mitral regurgitation (MR) are associated with AF; however, the influence of AF on right cardiac morphology is not fully understood. Our aim in this study was to investigate the association between AF and right cardiac morphology. This was a retrospective cohort study of 86 patients with persistent AF without other cardiac disease who underwent catheter ablation (CA). Seventy-one patients had sustained sinus rhythm (SR) (SR Group) and 15 patients had sustained AF (AF Group) during the study period. We compared the changes in the right cardiac dimensions and tricuspid regurgitation (TR) between the groups 12 months after CA. Patients’ baseline echocardiographic assessments revealed that the LA volume index was significantly smaller in the SR group than in the AF group (46.8 ± 11.9 ml/m2 vs 59.3 ± 12.8 ml/m2, respectively; p

BACKGROUND Estimation of left ventricular filling pressure (LVFP) is the essential part of the echocardiographic workup for exercise intolerance. The ratio of the mitral early filling velocity to the left ventricular global longitudinal strain (E/LVGLS) has emerged as a novel index of LVFP. This study aimed to investigate the relationship between E/LVGLS and exercise capacity. METHODS AND RESULTS We retrospectively reviewed 90 patients with exertional dyspnea who underwent echocardiography and cardiopulmonary exercise test. Patients were classified into three groups according to their percent-predicted maximal oxygen consumption (ppVo2 ) (G ≧ 75, ppVo2 > 75%, n = 20; G 50-75, ppVo2 75-50%, n = 57; G

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

Impaired left ventricular (LV) diastolic function is a sensitive and early sign of myocardial ischemia. We evaluated the effects of LV size on the accuracy of diastolic parameters derived from SPECT. The study population consisted of 151 patients with known or suspected coronary artery disease who underwent both SPECT and transthoracic echocardiography. Peak filling rate (PFR), one-third mean filling rate (1/3 MFR) and the ratio of time to PFR to the RR interval (TPFR/RR) were calculated by quantitative gated SPECT. Peak early mitral annular velocity (e′) was used as the reference standard of LV diastolic function. There were 43 patients with end-systolic volume (ESV) of ≤10 ml, 43 patients with ESV of 11–20 ml and 65 patients with ESV of >20 ml. There were significant differences in PFR (p

Anticoagulation therapy with warfarin is essential for postoperative management in patients with left ventricular assist device (LVAD). In this manuscript, we report the case of a patient who developed warfarin resistance after LVAD implantation. Although we administered a novel anticoagulant drug in addition to warfarin and aspirin therapy, the patient developed a major stroke. The patient needed continuous intravenous heparinization until heart transplantation for approximately 2 years. Meticulous management of anticoagulation therapy is essential for a LVAD with warfarin resistance. To our best knowledge, our case is the first case of warfarin resistance in a patient with LVAD.

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

Background The clinical significance of three-dimensional (3D) vena contracta area (VCA) in tricuspid regurgitation (TR) is not fully elucidated. The aim of this study was to investigate the diagnostic accuracy of 3D VCA using 3D echocardiography–derived regurgitation volume as a reference standard. Methods One hundred sixteen patients with at least moderate TR underwent two-dimensional transthoracic and color Doppler 3D transesophageal echocardiography. The 3D vena contracta, which was located at the narrowest neck of the TR jet just above and toward the right atrial side of the flow convergence zone, was assessed for TR location and severity. Results As for TR location, patients with severe functional TR had the highest prevalence of central jet location among TR subgroups, whereas patients with severe primary TR showed a greater spatial extent of TR jet location involved compared with the moderate TR group (P 0.61 cm2 to evaluate severe TR was significantly higher than that for the model that incorporated only clinical and two-dimensional integrative parameters (P = .001). Conclusions Three-dimensional VCA has independent and incremental diagnostic value for evaluating severe TR. Comprehensive evaluation of TR location and severity using 3D vena contracta analysis may help in treatment selection for TR.

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

Background Patients with heart failure (HF) are reportedly at high risk for ‘all-cause’ re-hospitalization. A biomarker for HF, N-terminal pro-brain natriuretic peptide (NT-proBNP), enables to simply detect patients with possible HF (pHF). We examined the hospitalization and medical cost of Japanese patients detected by an elevated serum NT-proBNP, and also evaluated the effects of institutional team approaches for HF on their all-cause hospitalizations. Methods We retrospectively extracted all adult patients with serum NT-proBNP ≥400 pg/ml measured between January and March 2012 in Hiroshima University Hospital as pHF-positive patients. We studied their all-cause hospitalization records during the past 3-year period. We also extracted all pHF-negative patients with NT-proBNP

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

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

Electrocardiographic left ventricular hypertrophy (ECG-LVH) gradually regressed after aortic valve replacement (AVR) in patients with severe aortic stenosis. Sokolow-Lyon voltage (SV1 + RV5/6) is possibly the most widely used criterion for ECG-LVH. The aim of this study was to determine whether decrease in Sokolow-Lyon voltage reflects left ventricular reverse remodeling detected by echocardiography after AVR. Of 129 consecutive patients who underwent AVR for severe aortic stenosis, 38 patients with preoperative ECG-LVH, defined by SV1 + RV5/6 of ≥3.5 mV, were enrolled in this study. Electrocardiography and echocardiography were performed preoperatively and 1 year postoperatively. The patients were divided into ECG-LVH regression group (n = 19) and non-regression group (n = 19) according to the median value of the absolute regression in SV1 + RV5/6. Multivariate logistic regression analysis was performed to assess determinants of ECG-LVH regression among echocardiographic indices. ECG-LVH regression group showed significantly greater decrease in left ventricular mass index and left ventricular dimensions than Non-regression group. ECG-LVH regression was independently determined by decrease in the left ventricular mass index [odds ratio (OR) 1.28, 95 % confidence interval (CI) 1.03-1.69, p = 0.048], left ventricular end-diastolic dimension (OR 1.18, 95 % CI 1.03-1.41, p = 0.014), and left ventricular end-systolic dimension (OR 1.24, 95 % CI 1.06-1.52, p = 0.0047). ECG-LVH regression could be a marker of the effect of AVR on both reducing the left ventricular mass index and left ventricular dimensions. The effect of AVR on reverse remodeling can be estimated, at least in part, by regression of ECG-LVH.

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

The RhoA/Rho-associated kinase (ROCK) pathway has a key physiological role in the pathogenesis of atherosclerosis. Increased ROCK activity is associated with cardiovascular diseases. Endogenous nitric oxide (NO) has an anti-atherosclerotic effect, whereas the exogenous NO-mediated cardiovascular effect still remains controversial. The purpose of this study was to evaluate the effect of exogenous NO on ROCK activity in patients with angina pectoris. This is a prospective, open-label, randomized, controlled study. A total of 30 patients with angina pectoris were randomly assigned to receive 40 mg day−1 of isosorbide mononitrate (n = 15, 12 men and 3 women, mean age of 63 ± 12 years, isosorbide mononitrate group) or conventional treatment (n = 15, 13 men and 2 women, mean age of 64 ± 13 years, control group) for 12 weeks. ROCK activity in peripheral leukocytes was measured by western blot analysis. ROCK activities at 4 and 12 weeks after treatment were decreased in the isosorbide mononitrate group (0.82 ± 0.33 at 0 week, 0.62 ± 0.20 at 4 weeks, 0.61 ± 0.19 at 12 weeks, n = 15 in each group, P < 0.05, respectively) but not altered in the control group. ROCK1 and ROCK2 expression levels were similar in all treatment periods in the two groups. These findings suggest that the administration of exogenous NO can inhibit ROCK activity, indicating that the usage of exogenous NO could have a protective effect in patients with angina pectoris.

Background We evaluated the diagnostic value of resting echocardiographic findings including total heart calcification (THC) score in combination with dobutamine stress echocardiography (DSE) for detection of myocardial ischemia. Methods Altogether, 110 patients with suspected angina pectoris underwent resting echocardiography and DSE. On the basis of resting echocardiography, we determined the THC score, left anterior descending artery diastole-to-systole velocity ratio (LAD-DSVR), and positive myocardial velocity during isovolumic relaxation phase (VIVR) detected by color-coded tissue Doppler imaging. Myocardial ischemia was diagnosed by a 25% or greater reduction in the internal diameter of major coronary vessels with impaired fractional flow reserve (FFR ≤0.80). Results DSE had excellent specificity (89%) but modest sensitivity (52%) for wall-motion abnormality (WMA) analysis. Multivariate analysis showed that THC score ≥2 (odds ratio and 95% confidence interval: 4.49 [2.29–10.6]; P = 0.018), LAD-DSVR ≤1.5 (6.43 [1.39–20.3], P = 0.019), and duration of positive VIVR ≥71 msec (7.93 [3.72–12.1]; P

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

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

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

Background: 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. (Circ J 2014; 78: 1740–1745)

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

The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1α (SDF-1α) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 ± 3.1% to 4.2 ± 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 ± 24 mg/dL to 181 ± 25 mg/dL (P = 0.002), glucose from 160 ± 53 mg/dL to 133 ± 25 mg/dL (P

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

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

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

The aortic valve area (AVA) is usually calculated using the continuity equation (CE) in which the left ventricular outflow tract (LVOT) area is estimated assuming circular geometry. We sought to evaluate the LVOT ellipticity with 64-multidetector computed tomography (MDCT) and to assess the impact of LVOT ellipticity on the evaluation of CE-based AVA in patients with calcified aortic valves.We prospectively studied 110 patients with calcified aortic valves including 54 aortic stenosis (AS) with both 64-MDCT and transthoracic echocardiography. Double oblique transversal images for planimetry of the aortic valve and LVOT were obtained during the midsystolic phase. The short and long-axis diameters of the planimetered LVOT were measured.The MDCT planimetered LVOT area was underestimated by the diameter-derived (π × r(2)) LVOT area using echocardiography (444 ± 70 mm(2) versus 369 ± 63 mm(2); p0.001). The mean difference in AVA values calculated using the CE and planimetry was 0.43 ± 0.23 cm(2) and mean measurement error of CE-based AVA was 18%. When the CE-based AVA was corrected using the MDCT planimetered LVOT area, the measurement error decreased from 28 ± 5 to 5 ± 2% in patients with severe aortic stenosis (AVA1.0 cm(2)), whereas from 16 ± 5 to 3 ± 6% in others.Ellipticity of LVOT is associated with underestimation of AVA measurements using the CE. CE-based AVA corrected with MDCT planimetered LVOT area is useful especially in severe AS.

Objective— Cardiovascular diseases are associated with chronic activation of Rho-associated kinases (ROCKs) and endothelial dysfunction. Both increased ROCK activity and endothelial dysfunction are thought to be closely associated with conventional cardiovascular risk factors. The purpose of this study was to determine the relationships between ROCK activity, endothelial function, and cardiovascular risk factors. Methods and Results— We evaluated ROCK activity in peripheral leukocytes by Western blot analysis and flow-mediated vasodilation by ultrasonography in 242 men who had no cardiovascular or cerebrovascular diseases (mean age, 40±10 years; range, 20 to 73 years). ROCK activity was defined as the ratio of phospho myosin-binding subunit on myosin light chain phosphatase to total myosin-binding subunit. Univariate regression analysis revealed that leukocyte ROCK activity significantly correlated with body mass index ( r =0.29, P =0.003); systolic blood pressure ( r =0.25, P =0.01); low-density lipoprotein cholesterol level ( r =0.21, P =0.04); and Framingham risk factor score, a cumulative cardiovascular risk index for heart attack ( r =0.31, P r =−0.23, P =0.02), body mass index ( r =0.19, P =0.05), systolic blood pressure ( r =−0.22, P =0.03), total cholesterol level ( r =−0.21, P =0.04), low-density lipoprotein cholesterol level ( r =−0.22, P =0.04), glucose level ( r =−0.20, P =0.04), and Framingham risk factor score ( r =−0.37, P r =−0.41, P Conclusion— These findings suggest that cumulative cardiovascular risk may enhance ROCK activity and endothelial dysfunction, leading to progression of cardiovascular diseases and outcomes.