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Background: The guidelines recommend the initiation or up-titration of heart failure (HF) treatments following an HF hospitalization; however, concerns about adverse events may limit the use of mineralocorticoid receptor antagonists (MRAs). Patient profiles or disease severity might impact adverse events associated with MRA therapy in acute HF., Methods: The EARLIER trial included patients with acute HF who were randomized to eplerenone or placebo over 6 months. Adverse events (i.e., worsening renal function [WRF], hyperkalemia, hypotension, and volume depletion/dehydration) were assessed. HF-related outcome included a composite of all-cause mortality, HF re-hospitalization, investigator-reported worsening HF and out-of-hospital diuretic intensification., Results: In 297 patients (mean age: 67 ± 13 years; 73% males), adverse events were observed: 44.4% experienced WRF (>20% drop in estimated glomerular filtration rate[eGFR] and/or investigator-reported WRF), 8.4% had hyperkalemia (potassium >5.5 mmol/L and/or investigator-reported hyperkalemia), 27.9% experienced hypotension (systolic blood pressure[SBP] <90 mmHg and/or investigator-reported hypotension), and 16.8% had investigator-reported volume depletion/dehydration. Eplerenone vs. placebo did not elevate the incidence of these events (all-p-values>0.0 5). Multivariable analyses revealed that, irrespective of treatment allocation, older age (>7 5 years), prevalent diabetes, symptomatic congestion, and microalbuminuria were associated with increased risk of WRF. Baseline eGFR<60 ml/min/1.73m 2 and SBP < 90 mmHg predicted hyperkalemia and hypotension, respectively, while older patients were more likely to experience volume depletion/dehydration. However, these patient profiles did not alter the benefit of eplerenone on outcomes (HR [9 5%CI] = 0.53 [0.29 to 0.97], P = 0.04; all-p-for-interaction>0.10)., Conclusion: Eplerenone did not increase adverse events compared with placebo in acute HF. Importantly, disease severity and comorbidity burden greatly influence adverse events, but not benefit from eplerenone., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: In the EARLIER (Efficacy and Safety of Early Initiation of Eplerenone Treatment in Patients with Acute Heart Failure) trial, eplerenone did not reduce heart failure (HF) hospitalizations or all-cause mortality in 300 patients admitted for acute HF (AHF). However, the trial might have been underpowered for these endpoints, and a comprehensive overview of the effect of eplerenone on diuretic doses and patients' clinical stability is warranted., Methods: The EARLIER trial included Japanese patients hospitalized for AHF randomly assigned to eplerenone or placebo over 6 months. Cox proportional hazards and mixed-effects models were used for analyses., Results: Three hundred patients were included (mean age, 67 ± 13 years; 73% males). The median furosemide equivalent dose was 40 (20-62) mg at randomization. Patients with higher furosemide-equivalent doses had more severe signs and symptoms of congestion and a higher risk of all-cause mortality or HF hospitalization during 6-month follow-up (adjusted-hazard ratio per 10 mg/day increase = 1.25, 95% confidence interval: 1.05-1.49). Eplerenone significantly decreased furosemide-equivalent diuretic doses and b-type natriuretic levels throughout the follow-up (overall-joint-p < 0.05 for both) and reduced E/e' and inferior vena cava diameter at 4 weeks (both p < 0.05). Additionally, eplerenone significantly reduced left ventricular (LV) end-diastolic diameter at 24 weeks (p < 0.05)., Conclusions: Eplerenone treatment improved the clinical stability particularly during short period following hospitalization for AHF, translated by lower diuretic doses, natriuretic peptide levels, indirect markers of filling pressure and venous congestion, and a smaller LV volume., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background and Aims: We examined the cross-sectional and longitudinal association of arterial stiffness and pressure wave reflection with the ankle-brachial pressure index (ABI) in middle-aged Japanese subjects free of peripheral artery disease (PAD)., Methods: ABI, brachial-ankle pulse wave velocity (baPWV) and radial augmentation index (rAI) were measured annually during the 9-year observation period in 3066 men (42 ± 9 years old) with ABI ≥1.00 at baseline of the study period, and not taking any antihypertensive medication., Results: In the cross-sectional assessments, mediation analysis demonstrated that baPWV showed both direct and indirect (via the rAI) associations with ABI, and rAI showed both direct and indirect (via the heart-arm difference of systolic blood pressure) associations with the ankle-arm difference of systolic blood pressure, both at study baseline and end of study period. Mixed model linear regression analysis of the repeated-measurement data obtained over the 9-year observation period demonstrated that annual increase of baPWV (estimate = 0.73 × 10 -4 , p < 0.01) and rAI (estimate = 0.33 × 10 -3 , <0.01) was associated with ABI. When baPWV and rAI were entered into the same model, only baPWV showed a significant longitudinal association with ABI., Conclusion: In middle-aged Japanese men free of PAD, arterial stiffness may contribute to ABI directly and via pressure wave reflection. Pressure wave reflection may contribute to ABI directly and, at least in part, via attenuation of peripheral pulse pressure amplification., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aims: Pulmonary congestion is associated with poor prognosis following hospitalization for worsening heart failure (HF), although its quantification and optimal timing during HF hospitalization remains challenging. The aim of this study was to assess the prognostic value of radiographic pulmonary congestion at admission and discharge in patients with worsening HF., Methods and Results: Clinical, echocardiographic, laboratory and chest X-ray data of 292 acute decompensated HF patients were retrospectively studied (follow-up 1 year). Lung congestion was blindly scored on chest X-ray performed at admission and discharge using a systematic 6-zone approach. Primary clinical outcome was a composite outcome of re-hospitalization for worsening HF or all cause death. Patients were stratified according to the median of congestion score index (CSI) at both admission (median CSI(A) = 1.33) and discharge (median CSI(D) = 0.33). BNP levels, LVEF and eGFR did not differ between CSI categories. In multivariable Cox regression analysis, discharge CSI (HR for 1-point increase = 1.83 [1.02 to 3.27] p = 0.04) and discharge BNP were significantly associated with the composite outcome whereas NYHA class, physical signs, admission CSI and echocardiographic data were not. Furthermore, discharge CSI significantly increased reclassification on top of clinical covariates (continuous NRI = 19.6% [4.0 to 30.0] p = 0.03 and IDI = 2.2% [0.0 to 7.6] p = 0.046) while discharge BNP did not significantly improve risk reclassification., Conclusions: Residual pulmonary congestion assessed by radiographic scoring predicts poor prognosis beyond physical assessment, echocardiographic parameters and BNP. These findings further support the capital prognostic value of radiographic pulmonary congestion in patients hospitalized for worsening HF., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The endothelial dysfunction-arterial stiffness-atherosclerosis continuum plays an important pathophysiological role in hypertension. The aim of this study was to investigate the cross-sectional association between serum uric acid (SUA) and vascular markers related to this continuum, and to assess the longitudinal association between SUA and endothelial function that represents the initial step of the continuum., Methods: We evaluated the baseline associations between SUA levels and vascular markers that included flow-mediated vasodilatation (FMD), brachial-ankle pulse wave velocity (baPWV), and common carotid artery intima-media thickness (CCA-IMT) in 648 subjects receiving antihypertensive treatment. The longitudinal association between baseline SUA levels and FMD measured at 1.5 and 3 yr of follow-up was also investigated., Results: At baseline, modest, but significant correlations were observed between SUA and FMD in females (r = -0.171), baPWV in males with SUA >368.78 μmol/L (r = -0.122) and in females with a SUA level ≤ 362.83 μmol/L (r = 0.217), mean CCA-IMT in females with a SUA level ≤ 333.09 μmol/L (r = 0.139), and max CCA-IMT in females with SUA level ≤ 333.09 μmol/L (r = 0.138). A longitudinal association between SUA and FMD was less observed in males. In females, the baseline SUA was associated significantly with FMD values at 1.5 yr (r = -0.211), and SUA levels >237.92 μmol/L were associated significantly and independently with FMD values at 3 yr (r = -0.166)., Conclusions: Lower SUA levels were associated with better vascular markers of the continuum, especially in females. Furthermore, we observed a longitudinal association between SUA and endothelial function, suggesting SUA level may be a potential marker of the continuum in hypertension., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: Whether myocardial ischemia identified using myocardial perfusion imaging (MPI) can be an alternative target of coronary revascularization to reduce the incidence of cardiac events remains unclear., Methods and Results: This multicenter, prospective cohort study aimed to clarify the prognostic impact of reducing myocardial ischemia. Among 494 registered patients with possible or definite coronary artery disease (CAD), 298 underwent initial pharmacological stress 99m Tc-tetrofosmin MPI before, and eight months after revascularization or medical therapy, and were followed up for at least one year. Among these, 114 with at least 5% ischemia at initial MPI were investigated. The primary endpoints were cardiac death, non-fatal myocardial infarction and hospitalization for heart failure. Ischemia was reduced ≥5% in 92 patients. Coronary revascularization reduced ischemia (n = 89) more effectively than medical therapy (n = 25). Post-stress cardiac function also improved after coronary revascularization. Ejection fraction significantly improved at stress (61.0% ± 10.7% vs. 65.4% ± 11.3%; p < 0.001) but not at rest (67.1% ± 11.3% vs. 68.3% ± 11.6%; p = 0.144), among patients who underwent revascularization. Rates of coronary revascularization and cardiac events among the 114 patients were significantly higher (13.6%, p = 0.035) and lower (1.1% p = 0.0053), respectively, in patients with, than without ≥5% ischemia reduction. Moreover, patients with complete resolution of ischemia at the time of the second MPI had a significantly better prognosis., Conclusions: Reducing ischemia by ≥5% and the complete resolution of ischemia could improve the prognosis of patients with stable CAD., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: The ankle-brachial index (ABI) is a predictor of cardiovascular disease (CVD) and premature death. However, few studies on this marker are available in the general Asian populations. This study aimed to investigate the association between ABI measured with oscillometry and the risk of these outcomes., Methods: We conducted an individual participant data meta-analysis in 10,679 community-dwelling Japanese individuals without a history of CVD. The primary outcome was a composite of CVD events and all-cause mortality., Results: During an average of 7.8 years of follow-up, 720 participants experienced the primary outcome. The multivariable-adjusted hazard ratios (HRs) of the primary outcome significantly increased with a lower ABI. The HRs were 1.07 (95% confidence interval [CI] 0.91-1.27) for ABI of 1.00-1.09, HR 1.37 (95% CI 1.04-1.81) for ABI of 0.91-0.99, and HR 1.60 (95% CI 1.06-2.41) for ABI of ≤0.90, compared with ABI of 1.10-1.19. Furthermore, a high ABI (≥1.30) was associated with a greater risk of outcome (HR 2.42 [95% CI 1.14-5.13]). Similar tendencies were observed for CVD events alone and all-cause mortality alone. Addition of ABI to a model with the Framingham risk score marginally improved the c-statistics (p = 0.08) and integrated discrimination improvement (p < 0.05) for the primary outcome., Conclusions: The present study suggests that lower and higher ABI are significantly associated with an increased risk of CVD and all-cause mortality in the Japanese population. The ABI, which is easily measured by oscillometry, may be incorporated into daily clinical practice to identify high-risk populations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To examine the longitudinal mutual association between endothelial dysfunction and arterial stiffness, and also to determine which of the two variables was more closely associated with the progression of subclinical organ damage., Methods: The brachial-ankle pulse wave velocity (baPWV), carotid intima-media thickness (CIMT), estimated glomerular filtration rate, microalbuminuria and flow-mediated vasodilatation of the brachial artery (FMD) were measured three times at 1.5-year intervals in 674 Japanese patients receiving antihypertensive treatment., Results: The change of the baPWV during the study period was larger in the subjects with baseline FMD values in the lowest tertile as compared to those with baseline FMD values in the highest tertile. The change of the CIMT was smaller in the subjects with baseline baPWV values in the lowest tertile than in those with baseline baPWV values in the highest tertile. After the adjustment, the FMD value at the baseline was inversely associated with the baPWV at the end of the study period (beta=-0.07, p=0.01), although, the reverse association was not significant. The baPWV, but not the FMD value, at the baseline was associated with the CIMT (beta=0.06, p=0.04) measured at the end of the study period., Conclusions: In hypertension, endothelial dysfunction was associated with the progression of arterial stiffness, although the reverse association was not confirmed. The increased arterial stiffness rather than endothelial dysfunction may be more closely associated with the progression of atherosclerotic vascular damage, and the endothelial dysfunction-arterial stiffness-atherosclerosis continuum may be important in hypertension., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: 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., Methods: 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., Results: 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)., Conclusions: In men, BBA diameter was inferior to FMD for assessment of cardiovascular risk., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Although fractional flow reserve (FFR) measurements during coronary angiography are performed in routine clinical practice, few studies have evaluated FFR measurements in dialysis patients., Methods: We retrospectively studied 42 hemodialysis patients with suspected or known coronary artery disease (CAD) who underwent stress myocardial perfusion imaging and coronary angiography with FFR measurements for 61 coronary lesions. The cut-off value for FFR to detect myocardial ischemia was determined by receiver operating characteristic (ROC) curve analysis., Results: There were 61 coronary vessels measured by FFR. The FFR range was 0.34-0.93 with a mean of 0.74±0.13. The ROC curve analysis revealed that the best cut-off value of FFR for detecting myocardial ischemia was 0.76 (p<0.0001), with 70% sensitivity, 86% specificity, and 76% accuracy for myocardial ischemia. Compared with patients who had positive myocardial ischemia and an FFR≤0.76, those who had negative myocardial ischemia despite an FFR≤0.76 had less left ventricular (LV) mass index, whereas patients who had positive myocardial ischemia despite an FFR>0.76 had greater LV mass indexor serum calcium-phosphorus product., Conclusions: The cut-off value of FFR for myocardial ischemia in chronic hemodialysis patients is similar to that in other CAD patients. However, caution is necessary when FFR measurements are applied to dialysis patients with significantly increased LV mass index or serum calcium-phosphorus product., (Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: There are some cases in whom a sufficient improvement in fractional flow reserve (FFR) could not be achieved even if anatomical results indicated satisfactory stent deployment. We investigated the relation of abnormal findings between intravascular ultrasound (IVUS) and coronary pressure pullback measurement (CP-PB)., Methods: IVUS and CP-PB were investigated after stent deployment in 60 vessels in 53 patients. CP-PB criterion for adequate stent deployment was defined as a ratio of coronary pressure at the stent distal edge to the proximal edge (Psd/Psp) that is greater than 0.95., Results: Residual pressure gradient across the stent which was indicated by Psd/Psp≤0.95 was present in 11 (18%), and four of them were caused by insufficient stent expansion (incomplete apposition and asymmetric dilation), and five of them were caused by issues with stent edge (edge dissection and incomplete coverage of the plaques). Insufficient FFR recovery which was recorded at distal part of target vessel was present in 10 (17%), and the main causes corresponded to inadequate stent deployment in half of the lesions, and presence of residual lesion at a non-stent segment in the other half. There were six lesions in whom Psd/Psp was ≤0.95 but FFR was ≥0.80. Disagreement between IVUS and CP-PB findings was seen in 12 (20%)., Conclusions: Residual pressure gradient across the stent can reflect not only an insufficient stent expansion but also issues with stent edges. The decision of optimum stent deployment as assessed by IVUS and CP-PB was mismatched in 20% of cases, therefore careful attention should be paid to decoding the CP-PB findings., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: We examined the following: (1) whether the new simple markers related to the arterial stiffness/central hemodynamics [i.e. arterial pressure-volume index (API) and arterial velocity pulse index (AVI)] are clinically interchangeable with the commonly used markers [brachial-ankle pulse wave velocity (baPWV) and radial augmentation index (rAI)]; (2) whether the new simple markers reflect vascular damage as reliably as the commonly used markers; (3) which cardiovascular risk factors are reflected by these new simple markers., Methods: API, AVI, baPWV, and rAI were measured simultaneously in consecutive patients admitted for the management of cardiovascular disease and/or cardiovascular risk factors (n=322)., Results: The API was correlated with the baPWV (R=0.492, p<0.001) and the AVI correlated with the rAI (R=0.462, p<0.001). The API, AVI, baPWV, and rAI were higher in the patients admitted for coronary angiography (CAG group: n=152) than in those admitted for reasons other than coronary angiography (nonCAG group: n=170). After adjustments for confounding factors, only the AVI was found to be higher in the CAG group than in the nonCAG group. Multivariate linear regression analysis revealed that age and the systolic blood pressure were independently associated with the API and AVI after adjustments., Conclusion: In patients with cardiovascular diseases or cardiovascular risk factors, the new simple markers and the commonly used markers are not interchangeable for assessing vascular damage and/or cardiovascular risk. Further study is proposed to examine whether AVI is higher in subjects with cardiovascular disease than in those without a history of cardiovascular disease. Similar to the case for the commonly used markers, age and the blood pressure significantly influenced both the new markers; therefore, age and the blood pressure need to be taken into account while interpreting the changes in these new simple markers., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: 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., Methods: 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)., Results: 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%; P<0.001). 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)., Conclusion: 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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Despite the introduction of the novel cadmium-zinc-telluride (CZT) single-photon emission computed tomography (SPECT) in Japan; its diagnostic value in clinical practice remains largely unknown., Methods: The Semiconductor SPECT Study group is a multicenter Japanese registry which registered 1000 patients to evaluate the diagnostic utility of the CZT camera system (Discovery NM530c; GE Healthcare, Haifa, Israel). The patients underwent stress myocardial SPECT and coronary angiography within a 3-month interval. A significant stenosis was defined as ≥75% diameter narrowing based on the American Heart Association classification., Results: Technetium ( 99m Tc) radiotracer (555-1110MBq) was used in 71% and thallium-201 ( 201 Tl) (74-148MBq) in 29%. The scan times with 99m Tc-radiotracer were 5-10min for stress and 3-10min for rest, whereas those with 201 Tl were 5-9min for stress and 8-10min for rest. To detect individual coronary stenosis, the respective sensitivities, specificities, and accuracies were 74%, 85%, and 81% for left anterior descending coronary artery (LAD) stenosis, 76%, 89%, and 85% for left circumflex stenosis, and 72%, 86%, and 82% for right coronary artery stenosis. However, 66% sensitivity and 91% specificity for LAD stenosis were observed with 99m Tc-radiotracer, whereas 88% sensitivity and 63% specificity were found with 201 Tl., Conclusions: The novel CZT SPECT system facilitated a short scan time with reduced radiotracer dose, yielding an acceptable diagnostic performance for angiographical coronary artery disease, although the low sensitivity for LAD detection with 99m Tc-radiotracer needs to be refined., (Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: 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., Methods: 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)., Results: 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 trend <0.001). 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., Conclusions: 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., Clinical Trial Registration Information: URL for Clinical Trial: http://UMIN; Registration Number for Clinical Trial: UMIN000003409., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aims: The progression of arterial stiffness is accelerated by aging, although the underlying mechanisms have not yet been clarified. This prospective observational study was conducted to clarify whether longitudinal changes in the serum calcium/phosphate levels are associated with the accelerated progression of arterial stiffness with age., Methods: In a cohort of employees at a construction company (1507 middle-aged Japanese men), the serum calcium/phosphate levels and brachial-ankle pulse wave velocity (baPWV) were measured at the start and at the end of a 3-year study period., Results: A general linear model multivariate analysis revealed a significant interaction of the 2 factors {age and longitudinal changes of the serum calcium levels (delCa) during the follow-up period} on the longitudinal changes of the baPWV during the study period (delPWV). The delCa was significantly correlated with the delPWV even after adjustments for covariates in subjects aged ≥48 years. The delPWV in subjects aged ≥48 years with the delCa in the upper tertile (69 ± 137 cm/s) was significantly larger than that in the other groups even after adjustments for covariates (e.g., del PWV in subjects aged <48 years with the delCa in the lower tertile = 1 ± 94 cm/s) (p < 0.01)., Conclusions: The association between the arterial stiffness and serum calcium levels differed with age. Pathophysiological abnormalities related to increased serum calcium levels appeared to be associated with accelerated progression of arterial stiffness with age., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: For the standardization of flow-mediated vasodilatation (FMD) assessment as a clinical tool, validation of its reliability across multiple institutions and the establishment of normal/reference values based on reliable data from multiple institutions are needed., Methods and Results: In Study 1, assessment of FMD (scan recording and analysis) using an ultrasonographic semi-automatic measuring system (sFMD) was conducted at 18 participating institutions (sFMD-INST) (n = 981). All of the brachial arterial scans were also analyzed at a core laboratory (sFMD-COLB). After 111 subjects with inadequate sFMD recordings were excluded (n = 880), the correlation between the sFMD-INST and sFMD-COLB improved from R = 0.725 to R = 0.838 (p < 0.001). In Study 2, based on good-quality sFMD data obtained from 6660 subjects without cardiovascular disease (CVD) and 729 subjects with CVD from 27 institutions, reference values of sFMD are proposed by the Framingham risk score (FRS)-based risk categories and according to gender and age. The receiver-operating characteristic curve analysis revealed a significant power of sFMD values in reference ranges to discriminate between subjects with and without CVD (e.g., area under curve = 0.64 in the FRS-low risk group)., Conclusions: When the analysis was limited to cases with clear sFMD recordings, the reliability of the sFMD assessment (scan and its analysis) conducted in individual institutions appeared to be acceptable. Reference sFMD values (lower cuff occlusion) for the Japanese population are proposed based on reliable data derived from multiple institutions, and the reference values may identify patients without advanced vascular damage., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Elevated serum levels of cardiac troponin T (cTnT) and N-terminal fragment of B-type natriuretic peptide (NT-proBNP), and also increased arterial stiffness/abnormal central hemodynamics, are well-known risk factors for future cardiovascular events. The present study was conducted to clarify which of the two - the serum level of cTnT or that of NT-proBNP - might be more closely associated with the arterial stiffness/central hemodynamics., Methods: In 2374 male employees of a company (46±9 years), the following parameters were measured: second peak of the radial systolic pressure waveform (SP2), radial augmentation index (rAI), PP2 (SP2 minus the diastolic blood pressure), brachial-ankle pulse wave velocity (baPWV), and serum levels of cTnT and NT-pro BNP., Results: After adjustments for confounding variables, binary logistic regression analyses demonstrated that baPWV was associated with a significant odds ratio for serum NT-proBNP ≥125pg/mL (1.690; 95% confidence interval=1.136-2.514, p=0.002) and rAI was associated with a significant odds ratio for serum NT-proBNP ≥55pg/mL (1.205; 95% confidence interval=1.012-1.435, p=0.036). The baPWV, rAI, SP2, and PP2 were not associated with significant odds ratios for elevated serum cTnT levels (≥0.014ng/mL and ≥0.010ng/mL)., Conclusions: In the middle-aged male worksite cohort studied, increased arterial stiffness/abnormal central hemodynamics appeared to be associated with elevated serum NT-proBNP levels, rather than with minimally elevated serum cTnT levels. This difference may be one of the plausible explanations for the independency of the predictive values of the two serum markers for future cardiovascular events., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

While risk scores are invaluable tools for adapted preventive strategies, a significant gap exists between predicted and actual event rates. Additional tools to further stratify the risk of patients at an individual level are biomarkers. A surrogate endpoint is a biomarker that is intended as a substitute for a clinical endpoint. In order to be considered as a surrogate endpoint of cardiovascular events, a biomarker should satisfy several criteria, such as proof of concept, prospective validation, incremental value, clinical utility, clinical outcomes, cost-effectiveness, ease of use, methodological consensus, and reference values. We scrutinized the role of peripheral (i.e. not related to coronary circulation) noninvasive vascular biomarkers for primary and secondary cardiovascular disease prevention. Most of the biomarkers examined fit within the concept of early vascular aging. Biomarkers that fulfill most of the criteria and, therefore, are close to being considered a clinical surrogate endpoint are carotid ultrasonography, ankle-brachial index and carotid-femoral pulse wave velocity; biomarkers that fulfill some, but not all of the criteria are brachial ankle pulse wave velocity, central haemodynamics/wave reflections and C-reactive protein; biomarkers that do no not at present fulfill essential criteria are flow-mediated dilation, endothelial peripheral arterial tonometry, oxidized LDL and dysfunctional HDL. Nevertheless, it is still unclear whether a specific vascular biomarker is overly superior. A prospective study in which all vascular biomarkers are measured is still lacking. In selected cases, the combined assessment of more than one biomarker may be required., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background: Anticoagulation therapy is essential in atrial fibrillation (AF), and in Japan, less intense control is popular., Purpose: To assess the efficacy and safety with a special reference to low intensity warfarin therapy., Subjects and Methods: In 488 out of 508 patients with non-valvular AF, prothrombin time-international normalized ratio (PT-INR) was kept at 1.6-2.59, and they were followed for 49.5 months: 2098 person-years. The mean age was 73.7±9.9 years and 62% were male. The patients were divided by age: ≥70 years and <70 years, and by the intensity of warfarin therapy: PT-INR at 1.6-1.99 and at 2.0-2.59, respectively. The clinical data and event rates, ischemic stroke and major bleeding, were compared among the subgroups., Results: Heart failure, previous stroke, and higher CHADS2 score were more often reported in patients ≥70 years while males were involved more often as younger patients. A total of 166 of 339 patients ≥70 years and 69 of 149 patients <70 years belonged to the low intensity group. Ischemic stroke and major bleeding occurred in 1.47%/year and 1.27%/year, respectively but there was no difference between the two age groups and between the two intensities of warfarin therapy. Time in therapeutic range was a predictor for ischemic stroke. A fall of PT-INR to <1.6 was found in 41.9% with ischemic stroke and a rise >2.61 in 40.0% with major bleeding at the time of the events. Blunt trauma and concomitant use of antiplatelets were risks for intracranial hemorrhage in the patients ≥70 years., Conclusions: The event rates were similar between the low- (1.6-1.99) and high- (2.0-2.59) intensity warfarin therapy groups in aged patients: <70 years and ≥70 years. Time in therapeutic range and a transient fall or rise in PT-INR were risks for clinical events. Blunt head trauma and concomitant use of antiplatelets were risks for intracranial hemorrhage., (Copyright © 2014. Published by Elsevier Ltd.)

Background: The findings of our recent study entitled, "Japanese Assessment of Cardiac Events and Survival Study by Quantitative Gated SPECT (J-ACCESS)" showed that myocardial perfusion single photon emission computed tomography (MPS) can detect coronary artery disease (CAD) and help to predict future cardiac events in patients with suspected or extant CAD. However, the extent of the benefit conferred by percutaneous coronary intervention (PCI) as an initial management strategy compared with optimal medical therapy remains controversial. Little evidence supports the notion that myocardial ischemia identified using MPS is an alternative target of coronary revascularization to reduce the likelihood of developing cardiac events., Methods: The multicenter, prospective cohort J-ACCESS 4 study aims to clarify the prognostic impact of reducing myocardial ischemia determined using electrocardiogram-gated MPS in Japanese patients with coronary artery disease. We started to register patients in J-ACCESS 4 at 74 facilities during June 2012 and will continue to do so until December 2013 or until the cohort comprises 500 patients who will participate in the study from one month before, until two months after stress/rest MPS assessment. Imaging data, the background of the patients including coronary risk factors and treatment before MPS assessments will be analyzed. The patients will undergo coronary revascularization within two months after MPS and/or receive appropriate medical therapy. The second stress/rest MPS will be performed from 4 to 10 months after coronary revascularization or registration. They will be followed up for over one year after the second MPS assessment. The primary endpoints will be cardiac death, sudden death of unknown cause, non-fatal myocardial infarction, and hospitalization for heart failure. The secondary endpoints will comprise death due to all causes including non-cardiac death and any cardiovascular events. This study will be completed in 2015. Here, we describe the design of the J-ACCESS 4 study., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: An early diagnosis is essential for therapeutic decision and risk stratification in patients with suspected acute myocardial infarction (AMI). We analyzed and compared the diagnostic value of high-sensitivity troponin T (hs-TnT) and other cardiac markers in patients with an initially negative troponin T test at presentation., Methods and Subjects: The present study was a prospective, multicenter study including five participating emergency cardiovascular tertiary centers in Japan. From November 2009 through January 2011, patients with suspected AMI at the emergency room with an initial troponin T (c-TnT) test <100 ng/L were enrolled., Results: A total of 85 patients were prospectively assigned from five participating emergency cardiovascular tertiary centers in Japan. The median time from the onset of chest pain to the T0 sampling was 165 min [IQR 120-180]. The final diagnoses according to the recent universal definition and other standard cut-off values were AMI in 47, unstable angina in 12, and non AMI in 38 patients. The overall ROC-AUC value of hs-TnT, c-TnT, creatine kinase MB, and heart-type fatty acid-binding protein were 0.810, 0.716, 0.782, and 0.880, respectively. The diagnostic sensitivity and negative predictive value of hs-TnT were both 100% for the patients admitted more than 120 min from the onset, however the specificity was limited for the whole time-windows (71%). The absolute value change of the hs-TnT from T0 to T3 sampling 3h later improved the ROC-AUC up to 0.972 and the specificity was 92% at 22 ng/L (ROC-optimized cut-off) and 100% at 105 ng/L (rule-in cut-off)., Conclusions: The hs-TnT displayed 100% sensitivity and negative predictive value for the patients admitted more than 120 min from the onset, however the specificity was limited. The absolute change from T0 to T3 (22 ng/L) improved the total diagnostic performance., (Copyright © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

The chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) have been recently much focused as independent risks for cardiovascular disease. Furthermore, the complication of both has a worse prognosis compared with patients with only one of these diseases. However, the details of the underlying mechanisms of this worsened prognosis have not been clear. The cross-sectional study was conducted to examine whether the overlap of COPD augment the increase in arterial stiffness in subjects with OSA. If so, we examined the exaggeration of nocturnal hypoxemia and its related inflammation are related to this augmentation of increased arterial stiffness. In 524 male subjects with OSA diagnosed by polysomnography (apnea-hypopnea index >5/h) (52 ± 14 years old), the forced expiratory volume at 1 s/the forced vital capacity (FEV(1)/FVC) ratio, brachial-ankle pulse wave velocity (baPWV), blood C-reactive protein (CRP) and B-natriuretic peptide (BNP) levels were measured. The prevalence rate of COPD was 12% in this study subjects. Plasma BNP levels and the crude (median value, 17.2 vs. 14.1 m/s, p < 0.01) and adjusted value of baPWV were significantly higher in subjects with overlap syndrome than in those with OSA alone. However, parameters of nocturnal hypoxemia and serum CRP levels were similar between both groups. Thus, the overlap of COPD in patients with OSA augments increase in arterial stiffness without the exaggeration of nocturnal hypoxemia and inflammation. Even so, this augmentation may partially contribute to the increased cardiovascular risk in the overlap syndrome., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: As an initial management strategy for stable ischemic heart disease (IHD), coronary revascularization therapy is thought to be equal to optimal medical therapy alone regarding prognosis., Methods: Whether or not the effects of revascularization on the prognosis of patients with stable IHD are associated with the amount of ischemic myocardium detected by nuclear stress imaging was evaluated. This retrospective study analyzed data from 4629 patients with suspected or known IHD who underwent gated stress myocardial-perfusion SPECT at 117 hospitals in Japan. The follow-up periods were three years and the combined endpoints consisted of cardiac death, nonfatal myocardial infarction, and congestive heart failure requiring hospitalization. After matching propensity scores between patients who underwent early revascularization and those who did not (n=316 per group), we compared cardiac event rates in relation to the amount of ischemic myocardium., Results: Cardiac event rates did not significantly differ between patients who underwent early revascularization and those who did not (5.4% vs. 6.4%). Among patients with ≤ 5%, 6-10%, and >10% ischemic myocardium, cardiac event rates were 8%, 3% and 0% respectively, who underwent early revascularization compared with 4.5%, 6.1%, and 12.3%, respectively, among those who did not. Cardiac event rates were significantly lower among patients with >10% ischemic myocardium who underwent early revascularization compared with those who did not (0% vs. 12.3%, p=0.0062)., Conclusions: Coronary revascularization for stable IHD does not decrease major cardiac events in all patients but might do in patients with moderate to severe ischemia., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: We examined the relationship among the serum omega-3 and omega-6 fatty acid (O3FA and O6FA) levels, serum C-reactive protein (CRP) levels, and arterial stiffness/wave reflection (AS/WR) in healthy Japanese men., Methods: In 2206 Japanese healthy men, parameters related to the AS/WR (i.e., brachial-ankle pulse wave velocity and radial arterial pulse wave analysis) were measured., Results: No significant inverse relationships were observed between the serum O3FA levels and the AS/WR-related parameters. Adjusted values of the AS/WR-related parameters and serum CRP levels were higher in the subjects with serum O6FA levels in the highest tertile than in those with serum O6FA levels in the lowest tertile., Conclusions: In healthy Japanese men with known high dietary intakes of O3FAs, the serum O3FA levels may not reflect the pathophysiological abnormalities related to AS/WR. Increased serum O6FA levels appeared to be independently associated with the unfavorable conditions related to AS/WR and inflammation., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

An age-related association of blood pressure in the non-hypertensive range (non-hypertensive blood pressure) to the cardiovascular mortality has been demonstrated. This prospective study was conducted to examine the effects of age, persistence of pre-hypertension (preHYP) during the study period, and the interaction between these factors on the rate of progression of arterial stiffening. Among 1563 healthy Japanese subjects without hypertension (age range: 29-95 years), the brachial-ankle pulse wave velocity (baPWV) was measured twice (i.e., at baseline and 5-6 years later). The adjusted (including for blood pressure) value of the annual rate of increase of the baPWV during the study period (delPWV) increased in a linear manner along with the age category (categorized into 29-39 years, 40-59 years, and 60 years or older for this study) and the evolutional category of non-hypertensive blood pressure during the study period (categorized into persistence of normal blood pressure, borderline evolution, and persistence of preHYP), and a significant interaction between the two in relation to the delPWV was also noted (non-standardization coefficient=5.08 [95% confidence interval=3.24-6.92], F-value=29.40, P<0.01). In conclusion, the present study suggests that persistence of preHYP is associated with accelerated structural stiffening of the large- to middle-sized arteries, and that age may exert a synergistic effect on this acceleration of arterial stiffening. Thus, persistence of preHYP also appears, like hypertension, to be associated with progressive vascular damage, and this progression may be more pronounced in middle-aged and elderly subjects., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Obstructive sleep apnea (OSA) increases the risk of cardiovascular disease (CVD) and has been reported to be associated with chronic kidney disease (CKD). Recent studies have demonstrated that cystatin C is a prognostic biomarker of the risk of death and CVD even in patients without established CKD., Methods: In a cross-sectional study, we enrolled 267 consecutive OSA patients without CKD who had an apnea-hypopnea index (AHI) ≥ 5 events per hour in overnight polysomnography. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2) according to the modification of diet in renal disease (MDRD) equation (modified for Japanese). Serum cystatin C levels were measured in all patients., Results: Cystatin C was significantly correlated with age (r = 0.37), body mass index (BMI) (r = 0.12), AHI (r = 0.17), C-reactive protein (CRP) (r = 0.12), and Brachial-ankle pulse wave velocity (r = 0.18). Logistic regression analysis demonstrated that severe OSA defined by an AHI ≥ 30 events per hour was an independent variable for the highest quartiles of serum cystatin C levels (≥0.88 mg/L) (OR: 2.04, 95% CI: 1.04-4.01, P = 0.04) even after adjustment for age, BMI ≥ 25, hypertension, and diabetes mellitus., Conclusions: This study indicates that severe OSA independently increases serum cystatin C levels in patients without CKD. Cystatin C is considered to be a biomarker that reflects both clinically latent renal dysfunction and cardiovascular risk that are influenced by OSA., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Reports on health-related quality of life (HRQOL) of Asian populations after acute myocardial infarction (AMI) and its predictors are rare. We describe the longitudinal HRQOL course after AMI, hypothesizing that post-discharge depressive symptoms predict poor recovery of HRQOL in Japan., Methods: AMI survivors participated in a prospective cohort study of AMI patients admitted to 5 hospitals in Japan. Data from 218 consecutive male patients were analyzed. HRQOL was measured with Short-Form Health Survey-36 at 1, 6, and 12 months post-discharge. Five-question Mental Health Inventory (MHI-5) assessed presence of depressive symptoms. Multiple linear regression analyzed the relationship between depressive symptoms at 1 month and recovery of HRQOL at 6 months., Results: AMI patients at 12 months after discharge had lower HRQOL in physical function (47.8), role-physical (44.1), general health (46.4), social function (47.4), and role-emotional (45.8) than the Japanese national norm. Impairment of each domain of HRQOL was seen in 36%-71% of patients. Multivariate analysis showed that depressive symptoms at 1 month post-discharge adversely affected recovery of physical function (β = -2.62; CI: -5.00 to -0.23), role-physical (β = -3.50; CI: -6.94 to -0.06) and bodily pain (β = -2.92; CI: -5.26 to -0.59) at 6 months., Conclusions: Despite good prognosis for survival of discharged AMI patients, HRQOL did not recover to the national norm. Post-discharge depressive symptoms were significantly associated with poor recovery of the physical component of HRQOL. Increasing awareness of depressive symptoms in discharged AMI patients may improve survivor HRQOL., (Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.)

Objective: We evaluated the temporal association between arterial stiffening and the early stage of renal functional decline., Methods: In 2053 Japanese employees with an estimated glomerular filtration rate (GFR) of > or = 60 ml/min/1.73 m(2) plus no proteinuria (40+/-8 years old) at the start, brachial-ankle pulse wave velocity (baPWV) and serum C-reactive protein (CRP) were measured before and after a 5-6-year follow-up period., Results: After adjusting for confounding variables including serum CRP levels, higher baseline baPWV was associated with lower follow-up GFR (value expressed as per doubling: -16; 95% confidence interval: -24 to -9; P<0.01) and with higher annual rate of decline in GFR (value expressed as per doubling: -3; 95% confidence interval: -4 to -2; P<0.01). Every m/s higher baPWV was associated with a 36% increased odds (95% CI 1.09-1.70; P<0.01) for a development of a GFR <60 ml/min/1.73 m(2) at follow-up. In contrast, baseline GFR was not associated with follow-up baPWV (P=0.08) or the annual rate of change in baPWV (P=0.11)., Conclusion: In a Japanese occupational cohort with normal renal function/early chronic kidney disease, elevated arterial stiffness was an independent risk factor for the decline in renal function. CRP did not appear to exert any significant influence on this association., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: The presence and severity of coronary artery disease may be underestimated in patients who do not reach significant end-points of stress testing during myocardial perfusion imaging. We examined how the effect of the level of exercise may affect the ability of the quantitative gated single-photon emission computed tomography (SPECT) imaging to predict the future cardiac events (cardiac death, non-fatal myocardial infarction and severe heart failure)., Method: Of the 4629 consecutively registered patients for J-ACCESS (Japanese-assessment of cardiac event and survival study by quantitative gated SPECT), 2821 patients who underwent the exercise test were selected, and divided into two groups, which reached a target heart rate (group; n=925) or not (n=1896). Leg fatigue was the most common reason for stopping the exercise test in non-reaching groups, we conducted a study comparing group with leg fatigue group (group II)., Results: During a 3-year follow-up period, total of 25 cardiac events (2.7%) occurred in group I and total of 73 events (3.9%) occurred in group II. The incidence of cardiac death was slightly but significantly higher in group II (P.04). A summed stress score (SSS) was able to separate the high-risk from low-risk patients in group II. The maximal heart rate was not an independent predictor for cardiac events. In Cox multivariate regression analysis, higher age (70 years), history of DM, EDV at rest and LVEF at rest were predictor of cardiac major events (cardiac death, myocardial infarction, heart failure), and higher age (70 years), ESV at rest were independent predictor of cardiac hard events (cardiac death, myocardial infarction) in group II., Conclusion: Exercise SPECT imaging provides the useful prognostic information in patients who do not reach a significant end-point due to the leg fatigue. In such patients, those with normal SSS score and normal resting ESV have also a most favorable prognosis., (Copyright 2010 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Objective: Increased arterial stiffness and sympathovagal imbalance are noted in patients with obstructive sleep apnea (OSA). It has been thought that continuous positive airway pressure (CPAP) therapy can have beneficial effects on the vascular function in such cases. However, it is not yet clear whether the improvement of sympathovagal balance by CPAP might be related to reduction of the arterial stiffness, independent of changes in the blood pressure., Methods: In 50 consecutive eligible patients with OSA (apnea-hypopnea index>/=20/hour) receiving CPAP therapy, the brachial-ankle pulse wave velocity (baPWV), heart rate variability (LF, HF and LF/HF ratio), baroreceptor sensitivity (BRS), plasma levels of C-reactive protein (CRP), and endothelial function as assessed by changes in the forearm blood flow before and after reactive hyperemia (END) were measured before and after 3-months' CPAP therapy., Results: Significant decrease of the LF/HF ratio, plasma levels of CRP, baPWV and heart rate were observed after 3 months' CPAP therapy. The change in the baPWV following 3-months' CPAP therapy was significantly correlated with the change in the LF/HF ratio and mean blood pressure (MBP), but not with that of the BRS, CRP or END after the therapy. Multivariate linear regression analysis demonstrated a significant correlation between the change in the LF/HF ratio and that in the baPWV (beta=0.305, p=0.041), independent of the changes in the MBP, plasma CRP levels and heart rate., Conclusions: Improvement of the sympathovagal balance by CPAP therapy may be significantly related to decreased stiffness of the central to middle-sized arteries, independent of the changes in the blood pressure and vascular endothelial status., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objectives: Although ischemic electrocardiographic (ECG) changes during dipyridamole or adenosine infusion have been reported as a marker for severe coronary artery disease (CAD), few studies have focused on ST-segment changes with adenosine triphosphate (ATP)-loading myocardial single-photon emission computed tomography (SPECT)., Methods and Subjects: Between January 2003 and August 2008, 4650 consecutive patients underwent ATP-loading SPECT. After 1412 patients with left bundle branch block, pacemaker rhythm, or previous coronary revascularization were excluded, 16 out of 3238 patients (0.5%) showed ischemic ST-segment depression during ATP-loading myocardial SPECT. They were aged 67+/-11 years; 10 were men and 6 women. Of these patients, 8 demonstrated perfusion abnormalities, whereas the remaining 8 showed normal myocardial perfusion imaging. In 6 of the 8 patients with abnormal SPECT, coronary angiography was performed, revealing left main trunk disease in 1 patient, 3-vessel disease in 4, 1-vessel disease with proximal left ascending artery occlusion in 1, and an insignificant lesion in 1. By contrast, no major cardiac event was observed in the 8 patients with normal SPECT during follow-up for an average of 2 years., Conclusion: The prevalence of ischemic ST-segment changes during ATP loading is very rare. However, this finding should be taken into account since almost half of the patients, particularly those with perfusion abnormalities, may have severe CAD which requires coronary revascularization., (Copyright 2010 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background: Although stress-induced myocardial stunning often develops after exercise testing, determinants of this phenomenon have not been evaluated., Methods and Results: Thirty-one patients with 1-vessel coronary artery disease, limited to the left anterior descending artery (LAD), were evaluated by quantitative coronary angiography (QCA) and intracoronary pressure measurements to calculate fractional flow reserve (FFR). In addition, electrocardiogram-gated technetium-99m sestamibi myocardial imaging was acquired >30 min after exercise and 4 h later to assess the development of stunning. Exercise-induced myocardial stunning was observed in 11 patients (35%). In patients with myocardial stunning, a summed stress score (17.3+/-7.1 vs. 8.1+/-6.2, p<0.001), summed difference score (10.3+/-4.1 vs. 2.7+/-1.9, p<0.0001), and wall motion difference score (4.8+/-2.8 vs. 0.9+/-1.1, p<0.0001) were greater than in those without, while diameter stenosis calculated by QCA (55.1+/-17.3% vs. 29.8+/-17.3%, p<0.0001) was greater and FFR reduced significantly (0.54+/-0.13 vs. 0.83+/-0.06, p<0.0001). Of note, 4 out of 21 patients (19%) with <50% LAD stenosis developed myocardial stunning, whereas only one patient with FFR of 0.64 or greater showed stunning. The best cut-off value was determined as 0.64 for FFR and 46% for QCA, providing 91% sensitivity and 100% specificity for FFR (chi-square=57.2), but 91% sensitivity and 80% specificity for diameter stenoses measured by QCA (chi-square=17.8)., Conclusions: The major determinant for exercise-induced myocardial stunning was a severe flow-limiting coronary stenosis, which was more important than anatomical evaluation based on luminal narrowing alone., (Copyright 2010 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Adenosine is widely used as a pharmacologic agent for stress myocardial perfusion imaging. Vasospasm as a side effect of adenosine has been reported a few times in other countries, but it has not been reported in Japan. A 65-year-old woman was admitted to our hospital because of chest pain at rest and during exercise. She underwent myocardial scintigraphy, to rule out myocardial ischemia. After adenosine infusion, she felt chest pain and the electrocardiogram (ECG) showed ST elevation in inferior leads. Adenosine infusion was stopped immediately. Her chest pain resolved, and the ECG reverted to baseline. Perfusion image presented reverse redistribution in inferior segments, and coronary angiography revealed insignificant lesions. Transient ST elevation during adenosine infusion is thought to be due to coronary vasospasm, judging from scintigraphic and angiographic findings.

Objectives: We sought noninvasively to diagnose left main trunk (LMT) disease using myocardial perfusion imaging (MPI)., Methods: Five hundred and eight patients with suspected coronary artery disease (CAD) underwent both stress MPI and coronary angiography. The extent and severity of perfusion abnormalities were assessed using a 20-segment model. In addition, perfusion defects in both left anterior descending and left circumflex arterial territories were defined as a left main (LM) pattern defect, and those in 3-coronary arterial territories as a 3-vessel pattern defect., Results: In 42 patients with LMT disease, a summed stress score (19.4 ± 10.0 vs. 13.5 ± 10.0; p < 0.0001) and a summed rest score (12.1 ± 9.7 vs. 7.0 ± 7.8; p = 0.002) were greater than in 466 patients without LMT disease, while a summed difference score was similar (7.3 ± 7.7 vs. 6.5 ± 6.1; p = NS). The prevalence of an LM-pattern defect was low in both groups (12% vs. 8%; p = NS). However, a 3-vessel pattern defect (33% vs. 7%; p < 0.0001), lung uptake of radiotracers (38% vs. 11%; p < 0.0001), and transient ischemic dilation (31% vs. 13%; p = 0.003) were more frequently observed in patients with LMT disease than in those without. Logistic regression analysis showed that a 3-vessel pattern defect (OR=3.5, 95% CI = 1.4-8.8; p = 0.007), lung uptake of radiotracers (OR = 2.5, 95% CI = 1.1-5.7; p = 0.03), and previous myocardial infarction (MI) (OR = 2.4, 95% CI = 1.0-5.7; p = 0.05) were the most important parameters to detect LMT disease. After excluding 163 patients with previous MI, a repeat analysis revealed that lung uptake of radiotracers (OR = 8.2, 95% CI = 2.3-29.2; p = 0.001) and an LM-pattern defect (OR = 6.3, 95% CI = 1.4-27.2; p < 0.02) were independent predictors for LMT disease., Conclusion: In the identification of LMT disease, lung uptake of radiotracers was a single best parameter, which was independent of the presence or absence of previous MI.

Objective: This study was conducted to clarify whether the brachial-ankle pulse wave velocity (baPWV) might serve as a marker of target organ damage in middle-aged hypertensive subjects., Methods and Results: Multivariate linear regression analysis demonstrated that while the baPWV showed a significant relationship to the intima-media thickness of the carotid artery (IMT), no such relationship was observed between the baPWV and the left ventricular mass index as assessed by echocardiography or the estimated glomerular filtration rate in either the 162 hypertensive patients who had never previously received antihypertensive medication or the 269 hypertensive patients who were under antihypertensive medication for at least 1 year. Receiver-operator characteristic (ROC) curve analysis suggested that a baPWV=18m/s was the best cutoff value to identify increased IMT in hypertensive patients who had never previously received antihypertensive medication (area under curve=0.77). Binary logistic regression analysis demonstrated that the odds ratio (OR) of a baPWV of ≥18m/s for identifying increased IMT {OR=7.38 (1.94-28.05)} was significant, even after adjustments. In hypertensive patients who had been under antihypertensive medication for at least 1 year, however, the area under the curve and OR were only modest., Conclusion: The baPWV may be a marker of carotid atherosclerosis, rather than of left ventricular hypertrophy or renal insufficiency, especially in middle-aged hypertensive subjects (subjects in their 30s to 60s), not only in those who have never previously received antihypertensive medication, but also in those who are under antihypertensive medication.

Background: The present study was conducted to clarify whether azelnidipine might have beneficial effects on autonomic functions, and whether such beneficial effects might affect the vascular functions (i.e., arterial stiffness and endothelial function)., Methods and Results: This study with a cross-over design was conducted in 21 hypertensive patients (65 +/- 9 years old) being treated with calcium channel blockers (CCBs) other than azelnidipine or benidipine (i.e., during the study period, the CCB was switched to either azelnidipine 16 mg/day or benidipine 4 mg/day, administered alternately for 8 weeks each). Blood examinations were conducted and the heart rate variability, baro-receptor sensitivity (BRS), brachial-ankle pulse wave velocity (baPWV) and flow-mediated vasodilatation (FMD) in the brachial artery were measured after treatment with each of the two drugs. While the blood pressure levels decreased to a similar degree after both treatments, the BRS (8.8 +/- 5.5 ms/mmHg vs. 6.4 +/- 2.9 ms/mmHg, p < 0.01) and high-frequency power component (HF: 139 +/- 152 ms2/Hz vs. 88 +/- 97 ms2/Hz) were higher after treatment with azelnidipine than after treatment with benidipine (p < 0.05). However, the baPWV, FMD and plasma levels of malonyldialdehyde low-density lipoprotein cholesterol and nitric oxides were similar after treatment with both drugs., Conclusion: Azelnidipine has greater beneficial effects on the autonomic functions than benidipine although the degree of reduction of blood pressure induced by the two drugs was similar. However, this greater beneficial effect of azelnidipine on the autonomic functions did not produce any distinguishable differences in effects of azelnidipine and benidipine on the arterial stiffness and endothelial functions.

Objectives: Although the Heston index, derived left ventricular (LV) volumetric analysis, is reported to best represent transient LV dilation on non-gated single-photon emission computed tomography (SPECT), its diagnostic performance has not been proven to identify extensive coronary artery disease (CAD) as assessed by coronary angiogram. Accordingly, we sought to evaluate the diagnostic utility of Heston index to detect multi-vessel CAD., Methods: Post-stress and resting electrocardiogram-gated 99mTc-sestamibi SPECT was performed in 223 patients with suspected or known CAD. All of the patients underwent coronary angiography within 3 months of gated SPECT. The summed stress, summed rest, and summed difference scores were calculated using a 20-segment model. The left ventricular end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) were calculated automatically with the QGS program. In addition, stress-to-rest ratios of EDV, ESV, and (ESVx5+EDV) were calculated; the latter was defined as Heston index., Results: In the 104 patients with multi-vessel CAD, the summed stress score (17.5+/-10.0 vs. 11.7+/-9.2, p<0.001), the summed difference score (9.1+/-6.3 vs. 4.3+/-4.2, p<0.0001), the Heston index (1.17+/-0.15 vs. 1.02+/-0.13, p<0.0001), the stress-to-rest ratio of EDV (1.05+/-0.10 vs. 0.99+/-0.09; p<0.0001), and that of ESV (1.23+/-0.21 vs. 1.04+/-0.17; p<0.0001, respectively) were greater than in the 119 patients with one-vessel CAD or insignificant lesion. The best cut-off value was determined as 1.09 for Heston index, giving a sensitivity of 76%, specificity of 77% for detection of multi-vessel CAD. Multiple stepwise logistic regression analysis showed that Heston index >or =1.09, summed stress score > or =14, and summed difference score > or =9 were the independent predictors of detecting multi-vessel CAD, yielding a sensitivity of 76% and specificity of 77% (global chi 2, 88.8)., Conclusions: The Heston index is simple and achieves higher diagnostic value in the detection of multi-vessel CAD, compared with conventional analysis alone.

A 75-year-old female was admitted for cerebral infarction and arteriosclerosis obliterans. Computed tomography with contrast medium revealed occlusion of the superficial femoral artery (SFA). Percutaneous transluminal angioplasty (PTA)was performed for the SFA (length 30 cm), but massive thrombus was seen in the SFA. PTA was continued using a Filtrap deployed at the popliteal artery to prevent distal embolism and the thrombus was captured by the Filtrap. Finally antegrade blood flow was observed. However, the following day, acute stent thrombosis occurred and emergent PTA was performed. Suboptimal stent expansion and dissection were found. Balloon angioplasty was performed using a Filtrap and another stent was deployed. Final angiography revealed good blood flow in the SFA. Filtrap may reduce the risk of distal embolism during PTA for the lower limb.

Background: Although measuring blood pressure at the bilateral brachia is common in medical practice, its clinical significance in patients with suspected coronary artery disease (CAD) has not been fully clarified., Methods: To define the significance of inter-arm systolic blood pressure difference in patients with suspected CAD, and to assess the relationship between inter-arm pressure difference and CAD, simultaneous brachial and ankle blood pressure measurements and stress myocardial single-photon emission computed tomography (SPECT) were performed in 386 consecutive patients with suspected CAD, excluding those with previous myocardial infarction or coronary revascularization., Results: Subclavian artery stenosis, defined as > or = 15 mmHg inter-arm systolic blood pressure difference, was found in 27 patients (7%). Age (65 +/- 12 vs 65 +/- 11 years), male sex (21/27 vs 244/359), prevalence of hypertension(63% vs 56%), hypercholesterolemia (63% vs 62%), diabetes mellitus(33% vs 38%), cigarette smoking (44% vs 41%) and family history of CAD (15% vs 12%) were similar between patients with subclavian artery stenosis and those without. The incidence of decreased ankle-brachial pressure index (ABI) was higher (37% vs 12%, p = 0.001), and percentage ischemic myocardium as assessed by SPECT was greater (9.0 +/- 8.5% vs 5.6 +/- 6.6%, p < 0.05) in patients with subclavian artery stenosis than in those without. Furthermore, significant correlations were observed between inter-arm pressure difference and percentage ischemic myocardium (r = 0.13; p = 0.01), and ABI (r = -0.26, p < 0.0001). Among 386 patients, 283 underwent coronary angiography, and 63% of those who had inter-arm blood pressure difference had CAD. Furthermore, 83% of those CAD patients had multi-vessel CAD, which is regarded as a high-risk subset for subsequent cardiac events., Conclusions: Inter-arm pressure difference is often found in patients with suspected CAD, and is associated with significant CAD and peripheral artery disease. Thus, inter-arm pressure difference may be regarded as a simple marker for coronary and peripheral artery diseases.

The present study attempted to establish whether elevated serum levels of alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) are independent (of each other) markers of systemic inflammation and oxidative stress as assessed by the plasma levels of C-reactive protein (CRP) and lipid peroxides (lipOX), regardless of the presence of underlying metabolic syndrome (as defined by the modified Adult Treatment Panel III (ATPIII) criteria). The plasma levels of CRP and lipOX were determined in 1483 middle-age Japanese men (42+/-9 years). A general linear model analysis indicated that elevated serum ALT and/or serum GGT (levels in the respective highest quartiles) were significantly related to the logarithms of the plasma levels of CRP (Beta=0.08 (0.05-0.11) and 0.08 (0.05-0.11), respectively) and the logarithm of the plasma levels of lipOX (Beta=0.03 (0.01-0.05) and 0.03 (0.01-0.05), respectively), regardless of the presence of underlying metabolic syndrome (MetS) (p<0.01). In addition, the presence of MetS and elevated serum levels of both of these liver enzymes additively increased the plasma levels of CRP and lipOX. Thus, it is proposed that elevated serum ALT and elevated serum GGT are independent markers of the activation of systemic inflammation and increased oxidative stress, independent of their relationship to MetS, and that the presence of MetS and elevations of both of these liver enzymes may additively worsen the atherogenic state.

Mutations in genes for sarcomeric proteins such as titin/connectin are known to cause dilated cardiomyopathy (DCM). However, disease-causing mutations can be identified only in a small proportion of the patients even in the familial cases, suggesting that there remains yet unidentified disease-causing gene(s) for DCM. To explore the novel disease gene for DCM, we examined CRYAB encoding alphaB-crystallin for mutation in the patients with DCM, since alphaB-crystallin was recently reported to associate with the heart-specific N2B domain and adjacent I26/I27 domain of titin/connectin, and we previously reported a N2B mutation, Gln4053ter, in DCM. A missense mutation of CRYAB, Arg157His, was found in a familial DCM patient and the mutation affected the evolutionary conserved amino acid residue among alpha-crystallins. Functional analysis revealed that the mutation decreased the binding to titin/connectin heart-specific N2B domain without affecting distribution of the mutant crystallin protein in cardiomyocytes. In contrast, another CRYAB mutation, Arg120Gly, reported in desmin-related myopathy decreased the binding to both N2B and striated muscle-specific I26/27 domains and showed intracellular aggregates of the mutant protein. These observations suggest that the Arg157His mutation may be involved in the pathogenesis of DCM via impaired accommodation to the heart-specific N2B domain of titin/connectin and its disease-causing mechanism is different from the mutation found in desmin-related myopathy.

The present study examined whether the menopause augments the age-related increase in brachial-ankle pulse-wave velocity (PWV). In total, 3149 women (ranging in age from 21 to 94 years) undergoing an annual health screening examination were enrolled in a cross-sectional study. Conventional atherosclerotic risk factors were examined, and the brachial-ankle PWV of each subject was determined. The relationship between age and the brachial-ankle PWV assumed the form of a quadratic curve, and the slope of the curve was relatively steeper after the menopause (brachial-ankle PWV = 0.17 x age2 - 0.58 x age + 812) than before (brachial-ankle PWV = 0.23 x age2 - 8.92 x age + 1058). A logistic regression analysis conducted for subjects between the ages of 45 and 56 years (mean age of menopause +/- 2 standard deviations) demonstrated that women who had experienced the menopause at least 6 years previously demonstrated a significant risk of belonging to the highest PWV tertile {adjusted odds ratio: 2.08 (95% confidential interval: 1.04-4.17)}, independent of age and other atherosclerotic risk factors (hypertension, hypercholesterolemia, diabetes mellitus, obesity, and smoking). Thus, this study suggested that the menopause augments the age-related increase in arterial stiffness during the early postmenopausal phase and that this augmentation is probably related, at least in part, to estrogen deficiency. The contribution of this menopause-related increase in arterial stiffness to the risk of cardiovascular disease in postmenopausal women should be further evaluated.

Objectives: To investigate the quality of life (QOL) of Japanese patients with ischemic heart disease., Methods: The QOL data of 753 patients with chronic and stable ischemic heart disease was assessed using SF-36 Japanese version 1.2 and compared with Japanese national norms. Physical (PCS) and Mental Component Summary (MCS) scores were calculated to examine the correlation with patient background. Patients were also asked about subjective symptoms during the QOL investigation., Results: Mean age was 63.6 +/- 7.5 years old and the male/female ratio was 85.7/14.3. About one third (30.7%) of the patients were symptomatic and about half (52.6%) had a history of myocardial infarction. Compared to Japanese national norms, physical functioning, role-physical, social functioning, general health and role-emotional were lower, and body pain, vitality and mental health were higher. PCS was significantly lower and MCS was significantly higher in aged patients than in younger patients (p < 0.0001, p < 0.0001). PCS and MCS were significantly lower in the symptom (+) group than in the symptom (-) group (p = 0.0009, p < 0.0001). PCS decreased as the number of anti-angina medications for the patients increased (p = 0.0002). PCS was significantly lower and MCS was significantly higher in the beta blocker (+) group than in the beta blocker (-) group (p < 0.0001, p < 0.03). Multivariate logistic regression analysis showed that age ( > or = 63 years old), symptom (+), duration of disease (> or = 3 years) and beta blocker (+) influenced the QOL., Conclusions: The QOL level of patients with ischemic heart disease was found to depend on the clinical condition and treatment, so the optimal treatment for ischemic heart disease must be established to improve QOL.

Objectives: Measurements of changes in plaque temperature may predict plaque rupture. The present study investigated variations in temperature within the atherosclerotic coronary artery using a pressure guide wire with thermal sensor (dual sensor guide wire)., Methods and Results: Seventy-seven patients (78 lesions), who had no significant lesion at the orifice of the culprit coronary artery, were studied. The patients had acute myocardial infarction (22 patients), unstable angina pectoris (20 patients), and stable angina pectoris (35 patients). The thermal sensor was calibrated at the orifice of the coronary artery, and then inserted into the culprit coronary artery. deltaT was defined as the difference between the intracoronary temperature at the position of the pressure gradient and at the orifice. deltaT was higher in patients with acute myocardial infarction and unstable angina pectoris than in patients with stable angina pectoris (0.09 +/- 0.07 and 0.07 +/- 0.07 vs 0.03 +/- 0.04 degrees C, p < 0.001, p = 0.02, respectively). There was no significant difference in deltaT between patients with acute myocardial infarction and unstable angina pectoris (p = 0.48). Patients with acute myocardial infarction and unstable angina pectoris showed a significant relationship between deltaT and C-reactive protein (r = 0.59, p = 0.0004)., Conclusions: The variations in intracoronary temperature of the culprit coronary arteries in patients with acute coronary syndrome were higher than those in patients with stable angina pectoris. These variations may be related to inflammation of vulnerable plaque.

Objectives: Regional myocardial systolic function in hypertensive left ventricular hypertrophy was assessed using the newly developed myocardial strain imaging., Methods: This study included 17 patients with hypertensive left ventricular hypertrophy (LVH group) and 22 normal subjects (N group). The transmural location of the strain peak value (StPP), and the strain peak value (StPV) in the end-systolic phase were measured at the posterior wall by myocardial strain imaging. Left ventricular mass index was simultaneously measured in both groups., Results: StPV was significantly lower in the LVH group than the N group (1.00 +/- 0.36 vs 1.38 +/- 0.42, p < 0.01) and StPP was significantly moved to the epicardium side compared with the N group (31 +/- 10% vs 11 +/- 5%, p < 0.0001). StPV decreased and StPP increased with greater left ventricular mass index (r = -0.61, p < 0.0001; r = 0.72, p < 0.0001, respectively)., Conclusions: Myocardial systolic impairment in hypertensive left ventricular hypertrophy may occur from the endocardium side, and the impairment may progress with increased left ventricular hypertrophy.

Atherosclerotic cardiovascular disease, osteopenia, and pulmonary dysfunction are the serious health problems, and several experimental studies have suggested that inflammation has a role in them. The present study was conducted to evaluate the usefulness of the plasma CRP is as a common marker for detecting these diseases in the general population in their subclinical stages. In a cross-sectional study, we measured the pulse wave velocity (PWV), quantitative osteo-sono-assessment index (OSI), pulmonary functions, and the plasma level of C-reactive protein (CRP) in 7283 consecutive healthy subjects (age 50+/-11 years). The PWV was higher and the OSI and pulmonary function parameters were below normal in subjects with an elevated CRP level (> or =0.2 mg/dl) than in subjects with a CRP level within the normal range. We divided the subjects into quartiles for each of these parameters and found that the first quartiles represented patients with subclinical states of the aforementioned abnormal conditions. Logistic regression analysis demonstrated that the odds ratios of an elevated CRP level were individually significant in subjects with an elevated CRP level for each abnormality in women and for abnormal PWV and pulmonary dysfunction in men. In conclusion, in addition to being a marker of elevated atherosclerotic cardiovascular risk, elevated plasma CRP seems to be a marker of the early stages of osteopenia and pulmonary dysfunction in healthy subjects.