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DOI： 10.1002/joa3.12714

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Language：Japanese   Publisher：医学図書出版(株)  

症例は38歳女性。特記すべき既往なし。突然の左上肢巧緻運動障害と心窩部痛,呼吸困難を認めた。4日後左下肢知覚障害および不全麻痺が出現し脳神経外科受診。頭部MRIで右大脳半球,左後頭葉に散在性脳梗塞を認め,心原性脳塞栓が疑われ循環器内科紹介となった。入院時の心電図は104bpmと洞頻脈,aVLとV5～V6誘導に小さなQ波,IIIとaVF誘導に陰性T波を認めたが非特異的所見であった。血液生化学検査で心筋逸脱酵素(CK/CK-MB)は正常範囲内だが,高感度トロポニンT0.682ng/mL,NT-proBNP395pg/mLと上昇し何らかの心筋障害が示唆された。経胸壁心臓超音波で左室駆出率は72%と保たれていたが全周性に心嚢液貯留を認め,急性心筋炎を強く疑った。受診3週間前にSARS-CoV-2 mRNAワクチン(COVID-19ワクチンモデルナ筋注)の2回目の接種が完了し,時系列からCOVID-19ワクチン関連心筋炎が考えられた。画像および病理所見より考察する。(著者抄録)

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AIMS: This study aimed to investigate the impact of baseline blood pressure (BP) on adverse outcomes in patients with atrial fibrillation (AF), using a pooled analysis performed on data from J-RISK AF, a large-scale cohort of Japanese patients with AF. METHODS AND RESULTS: Of the 16 918 patients from five major AF registries including the J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and Hokuriku-Plus AF Registry, 15 019 non-valvular AF (NVAF) patients with baseline BP values (age, 70.0 ± 11.0 years; men, 69.1%) were analysed. Incidence rates of adverse events were evaluated between patients divided into baseline systolic BP quartiles or at 150 mmHg. During the follow-up period of 730 days, ischaemic stroke, major bleeding, all-cause death, and cardiovascular death occurred in 277, 319, 718, and 275 patients, respectively. Hazard ratios (HRs) for ischaemic stroke and major bleeding were comparable among the quartiles, whereas HRs for all-cause and cardiovascular deaths in the lowest quartile with systolic BP <114 mmHg were significantly higher [HR 1.43, 95% confidence interval (CI) 1.13-1.81; and HR 1.47, 95% CI 1.01-2.12, respectively] than in the third quartile, even after adjusting for known confounding factors. In patients with a systolic BP of ≥150 mmHg, adjusted HR for major bleeding was significantly higher than that of <150 mmHg (HR 1.64, 95% CI 1.12-2.40). CONCLUSION: In Japanese patients with NVAF, a baseline systolic BP <114 mmHg was significantly associated with higher all-cause and cardiovascular mortality. In contrast, a systolic BP ≥150 mmHg was an independent risk factor for major bleeding.

DOI： 10.1093/ehjopen/oeac081

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A case of a giant popliteal venous aneurysm that caused massive pulmonary thromboembolism with an arteriovenous fistula draining into the adjacent proximal femoral vein is reported herein. Deep veins in the lower leg were occluded by thrombi. The inlet and outlet orifice inside the aneurysm was closed and aneurysmorraphy was performed. The fistula was retained on the estimation that it would maintain the blood flow and prevent thrombus formation inside the femoral vein. The aneurysm was shrunk, the femoral vein was patent, and the fistula was not observed 1 year later, although it still existed 1 week after the operation.

DOI： 10.3400/avd.cr.22-00044

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Although time in target range (TTR) of systolic blood pressure (BP), an index of consistency of BP control, is reportedly associated with major cardiovascular outcomes, the impact of BP-TTR on adverse events in patients with nonvalvular atrial fibrillation (NVAF) has not been thoroughly investigated. Thus, we performed a post hoc analysis to clarify it in patients with NVAF using data of the J-RHYTHM registry. Of 7,406 outpatients with NVAF, 7,226 (age, 70 ± 10 years; men, 71%), in whom BP was measured 4 times or more (15 ± 5 times) during the 2-year follow-up period or until occurrence of an event, constituted the study group. Systolic BP-TTR, with a target range of 110 to 130 mm Hg, was calculated by Rosendaal linear interpolation method. Overall systolic BP-TTR was 50 ± 28%. Thromboembolism, major hemorrhage, all-cause death, and cardiovascular death occurred in 110 (1.5%), 121 (1.7%), 168 (2.3%), and 60 patients (0.8%), respectively. Each 1% increase in systolic BP-TTR was significantly associated with a decreased incidence of all adverse events in the unadjusted model; whereas, significant association was observed only for cardiovascular death (adjusted hazard ratio 0.983, 95% confidence interval 0.971 to 0.995, p = 0.006) after adjusting for known confounders and systolic BP at the time closest to an event. In contrast, each 1% increase in systolic BP time in subtarget range of <110 mm Hg was significantly associated with an increased risk of thromboembolism (hazard ratio 1.014, 95% confidence interval 1.005 to 1.024, p = 0.002). In conclusion, systolic BP-TTR and BP time in subtarget range would be useful for risk evaluation of cardiovascular death and thromboembolism, respectively, in patients with NVAF.

DOI： 10.1016/j.amjcard.2022.06.045

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DOI： 10.1253/circj.CJ-22-0383

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DOI： 10.1253/circj.CJ-20-1212

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A 76-year-old woman was admitted to our department for pneumonia. Although she gradually recovered, she complained of chest and back pain and went into shock. Electrocardiogram showed ST-segment elevation in the inferior leads; thus, an acute inferior myocardial infarction (MI) was strongly suspected. Emergent coronary angiography revealed subtotal right coronary artery (RCA) occlusion, and intravascular ultrasound showed flattening of the RCA ostium. Although the coronary artery flow improved after percutaneous coronary intervention with rescue stent implantation, the patient was still in a prolonged state of shock. Contrast-enhanced computed tomography revealed a ruptured thoracic aortic aneurysm (TAA) with a massive posterior mediastinal hematoma. We presumed that the acute MI and shock were caused by compression of the RCA ostium by the mediastinal hematoma and hemorrhage with TAA rupture, respectively. The patient was urgently transferred to another hospital for surgery. To the best of our knowledge, there has been no report on acute MI due to coronary artery compression by a mediastinal hematoma associated with TAA rupture. A staged therapeutic approach, involving preoperative coronary stent implantation, could be used to save the patient. <Learning objective: A case of acute myocardial infarction (MI) due to compression of the coronary artery by a mediastinal hematoma associated with thoracic aortic aneurysm (TAA) rupture is extremely rare. Although a standard therapeutic strategy for TAA rupture complicated by acute MI caused by coronary compression has not been established, preoperative coronary stent implantation could be used to save the patient.>.

DOI： 10.1016/j.jccase.2021.09.002

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BACKGROUND: Atrial fibrillation (AF) is a heterogeneous condition caused by various underlying disorders and comorbidities. A cluster analysis is a statistical technique that attempts to group populations by shared traits. Applied to AF, it could be useful in classifying the variables and complex presentations of AF into phenotypes of coherent, more tractable subpopulations. OBJECTIVES: This study aimed to characterize the clinical phenotypes of AF using a national AF patient registry using a cluster analysis. METHODS: We used data of an observational cohort that included 7406 patients with non-valvular AF enrolled from 158 sites participating in a nationwide AF registry (J-RHYTHM). The endpoints analyzed were all-cause mortality, thromboembolisms, and major bleeding. RESULTS: The optimal number of clusters was found to be 4 based on 40 characteristics. They were those with (1) a younger age and low rate of comorbidities (n = 1876), (2) a high rate of hypertension (n = 4579), (3) high bleeding risk (n = 302), and (4) prior coronary artery disease and other atherosclerotic comorbidities (n = 649). The patients in the younger/low comorbidity cluster demonstrated the lowest risk for all 3 endpoints. The atherosclerotic comorbidity cluster had significantly higher adjusted risks of total mortality (odds ratio [OR], 3.70; 95% confidence interval [CI], 2.37-5.80) and major bleeding (OR, 5.19; 95% CI, 2.58-10.9) than the younger/low comorbidity cluster. CONCLUSIONS: A cluster analysis identified 4 distinct groups of non-valvular AF patients with different clinical characteristics and outcomes. Awareness of these groupings may lead to a differentiated patient management for AF.

DOI： 10.1016/j.ijcha.2021.100885

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BACKGROUND: Various risk factors have been identified for the new onset or rapid deterioration of chronic kidney disease (CKD). However, it is thought that many risk factors that have not yet been clarified remain. METHODS: Based on the results of specific annual health checkups at Tama City (n = 18 383) in 2017 and 2018, we analyzed the factors that cause new-onset CKD and the risk factors that rapidly worsen renal function. For new-onset CKD, proteinuria and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 were examined separately. Rapid deterioration of renal function was defined as an eGFR ≥25% less than the previous year. RESULTS: Multivariate analysis showed that in addition to age and impaired glucose tolerance, anemia and atrial fibrillation (AF) were risk factors for the new appearance of proteinuria. Risk factors for a decrease in eGFR to <60 mL/min/1.73 m2 were age and hyperuricemia. Age, systolic hypertension, urinary protein and urinary occult blood, high triglycerides and anemia were significant risk factors for the rapid deterioration of renal function in patients with CKD Stage ≥3. CONCLUSIONS: From the results of specific annual health checkups at Tama City, AF, anemia and hyperuricemia were identified as risk factors for new-onset CKD over a short period of 1 year. Anemia was also a factor for the rapid deterioration of kidney function in subjects with renal dysfunction.

DOI： 10.1093/ckj/sfab014

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AIMS: The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing. METHODS AND RESULTS: Endomyocardial biopsy and whole-exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0-64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non-synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy-susceptibility and 41 arrhythmia-susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A-band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I-band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033). CONCLUSIONS: Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large-scale studies are required to confirm whether these ultrastructural findings are related to the causative genes.

DOI： 10.1002/ehf2.13596

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BACKGROUND: Machine learning (ML) has emerged as a promising tool for risk stratification. However, few studies have applied ML to risk assessment of patients with atrial fibrillation (AF). HYPOTHESIS: We aimed to compare the performance of random forest (RF), logistic regression (LR), and conventional risk schemes in predicting the outcomes of AF. METHODS: We analyzed data from 7406 nonvalvular AF patients (median age 71 years, female 29.2%) enrolled in a nationwide AF registry (J-RHYTHM Registry) and who were followed for 2 years. The endpoints were thromboembolisms, major bleeding, and all-cause mortality. Models were generated from potential predictors using an RF model, stepwise LR model, and the thromboembolism (CHADS2 and CHA2 DS2 -VASc) and major bleeding (HAS-BLED, ORBIT, and ATRIA) scores. RESULTS: For thromboembolisms, the C-statistic of the RF model was significantly higher than that of the LR model (0.66 vs. 0.59, p = .03) or CHA2 DS2 -VASc score (0.61, p < .01). For major bleeding, the C-statistic of RF was comparable to the LR (0.69 vs. 0.66, p = .07) and outperformed the HAS-BLED (0.61, p < .01) and ATRIA (0.62, p < .01) but not the ORBIT (0.67, p = .07). The C-statistic of RF for all-cause mortality was comparable to the LR (0.78 vs. 0.79, p = .21). The calibration plot for the RF model was more aligned with the observed events for major bleeding and all-cause mortality. CONCLUSIONS: The RF model performed as well as or better than the LR model or existing clinical risk scores for predicting clinical outcomes of AF.

DOI： 10.1002/clc.23688

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：(一社)日本循環器学会  

BACKGROUND: Development of heart failure is associated with fluid balance, including that of extracellular water (ECW) and intracellular water (ICW). This study determined whether sodium-glucose cotransporter 2 (SGLT2) inhibitors affect fluid balance and improve heart failure in patients after acute myocardial infarction (AMI). METHODS: EMBODY was a prospective, randomized, double-blinded, placebo-controlled trial of Japanese patients with AMI and type 2 diabetes. Overall, 55 patients who underwent bioelectrical impedance analysis (BIA) were randomized to receive once daily 10 mg empagliflozin or placebo 2 weeks after AMI onset. We investigated the time course of body fluid balance measured using the BIA device, "InBody®." Primary endpoints were changes in body fluid balance from weeks 0 to 24. RESULTS: Changes between baseline and week 24 in the empagliflozin and placebo groups were -0.21 L (p=0.127) and +0.40 L (p=0.001) in ECW [p=0.001], and -0.23 L (p=0.264) and +0.74 L (p<0.001) in ICW [p<0.001], respectively. In a stratified analysis, the rise in ECW and ICW was significantly attenuated in the empagliflozin group in contrast to the placebo group in participants with body mass index ≥25 but not in those with <25 kg/m2. CONCLUSIONS: Early SGLT2 inhibitor administration may attenuate changes in ECW and ICW.

DOI： 10.1016/j.cardfail.2021.07.022

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INTRODUCTION: Plasma volume status (PVS), a parameter of the discrepancy between actual plasma volume (PV) and ideal PV, has been recently evaluated as a prognostic marker in patients with heart failure. This subgroup analysis of the EMBODY trial was designed to determine whether a sodium-glucose cotransporter 2 (SGLT2) inhibitor affects the alleviation of heart failure and improvement of PVS in patients after acute myocardial infarction (AMI) with congestive heart failure (CHF). METHODS: The EMBODY trial was a prospective, multicenter, randomized, double-blind, placebo-controlled trial to identify the effect of an SGLT2 inhibitor on cardiac sympathetic hyperactivity in patients with AMI and type 2 diabetes mellitus (T2DM) in Japan. In total, 105 patients were randomized (1:1) to receive 10 mg empagliflozin or a placebo (once daily), 2 weeks after the onset of AMI. In this subanalysis, we investigated the time-course of PVS at baseline and weeks 4, 12, and 24. RESULTS: Overall, 96 patients were included in the subgroup analysis set (age 64.3 ± 10.9 years, 80.2% men; 46 in the empagliflozin group and 50 in the placebo group). Body weight and PVS decreased in the empagliflozin group compared with the placebo group at 24 weeks (- 2.2 vs. + 0.1 kg, P < 0.001, and - 5.1 vs. - 0.3%, P < 0.001, respectively). Decreased PVS, defined as a change in PVS of < - 4.5%, was associated with the administration of empagliflozin (odds ratio 2.61, 95% confidence interval 1.11-6.15, P = 0.028). N-terminal pro b-type natriuretic peptide levels decreased in both the empagliflozin and placebo groups (1028.7-370.3 pg/mL, P < 0.001, and 1270.6-673.7 pg/mL, P < 0.01, respectively). CONCLUSION: Empagliflozin reduced the body weight and PVS. Early SGLT2 inhibitor administration in patients with AMI, CHF, and T2DM can therefore be effective in reducing the body weight and PVS. TRIAL REGISTRATION: UMIN 000030158.

DOI： 10.1007/s13300-021-01103-0

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BACKGROUND: Recently, identification of independent risk factors for ischemic stroke in Japanese non-valvular atrial fibrillation (NVAF) patients was made by analyzing the 5 major Japanese registries: J-RHYTHM Registry, Fushimi AF Registry, Shinken Database, Keio interhospital Cardiovascular Studies, and the Hokuriku-Plus AF Registry.Methods and Results:The predictive value of the risk scheme in Japanese NVAF patients was assessed. Of 16,918 patients, 12,289 NVAF patients were analyzed (mean follow up, 649±181 days). Hazard ratios (HRs) of each significant, independent risk factor were determined by using adjusted Cox-hazard proportional analysis. Scoring system for ischemic stroke was created by transforming HR logarithmically and was estimated by c-statistic. During the 21,820 person-years follow up, 241 ischemic stroke events occurred. Significant risk factors were: being elderly (aged 75-84 years [E], HR=1.74), extreme elderly (≥85 years [EE], HR=2.41), having hypertension (H, HR=1.60), previous stroke (S, HR=2.75), type of AF (persistent/permanent) (T, HR=1.59), and low body mass index <18.5 kg/m2(L, HR=1.55) after adjusting for oral anticoagulant treatment. The score was assigned as follows: 1 point to H, E, L, and T, and 2 points to EE and S (HELT-E2S2score). The C-statistic, using this score, was 0.681 (95% confidence interval [CI]=0.647-0.714), which was significantly higher than those using CHADS2(0.647; 95% CI=0.614-0.681, P=0.027 for comparison) and CHA2DS2-VASc scores (0.641; 95% CI=0.608-0.673, P=0.008). CONCLUSIONS: The HELT-E2S2score may be useful for identifying Japanese NVAF patients at risk of ischemic stroke.

DOI： 10.1253/circj.CJ-20-1075

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AIMS: Although the reno-protective effects of sodium-glucose cotransporter 2 inhibitors are known in patients with heart failure or type 2 diabetes mellitus (T2DM), this effect has not been confirmed in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The prospective, multicentre, randomized, double-blind, placebo-controlled EMBODY trial investigated patients with AMI and T2DM in Japan. The eligible patients included adults aged 20 years or older, diagnosed with AMI and T2DM, and who could be discharged within 2-12 weeks after the onset of AMI. One hundred and five patients were randomized (1:1) to receive once daily 10 mg empagliflozin or placebo within 2 weeks of AMI onset. In this sub-analysis, we investigated the time course of renal functional parameters such as serum creatinine levels and estimated glomerular filtration rate (eGFR) from baseline to Weeks 4, 12, and 24. Ninety-six patients (64 ± 11 years, 78 male) were included in the full analysis (n = 46 and 50 in the empagliflozin and placebo groups, respectively). We used serum creatinine and eGFR as indicators of renal function. In the placebo group, eGFR decreased from 66.14 mL/min/1.73 m2 at baseline to 62.77 mL/min/1.73 m2 by Week 24 (P = 0.023) but remained unchanged in the empagliflozin group (from 64.60 to 64.36 mL/min/1.73 m2 , P = 0.843). In the latter group, uric acid improved from 5.8 mg/dL at baseline to 4.9 mg/dL at Week 24 (P < 0.001). In the earlier analysis of 56 patients with eGFR ≥ 60 mL/min/1.73 m2 , the eGFR decreased and the serum creatinine increased from baseline to 24 weeks in the placebo group, significantly different to the empagliflozin group (-6.61 vs. +0.22 mL/min/1.73 m2 , P = 0.008 and +0.063 vs. -0.001 mg/dL, P = 0.030, respectively). The changes in serum creatinine and eGFR from baseline to Week 24 were significantly correlated with those in uric acid in the placebo group (r = 0.664, P < 0.001 and r = -0.675, P < 0.001, respectively) but not in the empagliflozin group. CONCLUSIONS: Empagliflozin prevented the kidney functional decline in patients with AMI and T2DM, especially those with baseline eGFR ≥ 60 mL/min/1.73 m2 . Early administration of sodium-glucose cotransporter 2 inhibitors in these patients is considered desirable for renal protection.

DOI： 10.1002/ehf2.13509

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DOI： 10.1253/circj.CJ-21-0342

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DOI： 10.1253/circj.CJ-19-1131

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Background: Given the high prevalence of heart failure (HF) in the elderly, it is essential to establish medical coordination between general practitioners (GPs) and acute care hospitals (ACHs) in an aging society. The aim of this study was to elucidate the status of acceptance of elderly patients with HF and their management requirements in a comprehensive community health system. Furthermore, we investigated GPs' interest in using information and communications technology (ICT) in patient care. Methods and Results: We sent a questionnaire survey to 1,800 GPs in January 2015 and received 392 replies. The overall prevalence of home visits was 55%, with no differences according to GP background characteristics or geographic area. However, less than half (44%) reported accepting patients with symptomatic HF for treatment in their clinic. In addition, only 3 GPs reported accepting and providing emergency visits for patients with refractory HF. In particular, GPs who were not certificated cardiologists, female, and older showed poorer acceptance of symptomatic HF patients. More than half the GPs wanted the prompt acceptance by ACHs of emergency patients, followed by strengthening of home care support at discharge and support for end-of-life care. Half the GPs were interested in telemedicine. Conclusions: ACHs must promptly accept patients with HF in cases of emergency and strengthen nursing care support at discharge. It is also necessary to consider how to support older and female GPs.

DOI： 10.1253/circrep.CR-20-0132

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Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit-to-visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J-RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2-year follow-up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all-cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP-SD (<8.20, 8.20-10.49, 10.50-13.19, and ≥13.20 mm Hg), hazard ratios (HRs) for all adverse events were significantly high in the highest quartile compared with the lowest quartile (HR, 2.00, 95% CI, 1.15-3.49, P=0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36-4.97, P=0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11-3.07, P=0.018 for all-cause death) after adjusting for components of the CHA2DS2-VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP-coefficient of variation was used instead of BP-SD. Conclusions Systolic BP visit-to-visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/; Unique Identifier: UMIN000001569.

DOI： 10.1161/JAHA.120.018585

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DOI： 10.1093/ehjcr/ytaa358

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Atrial fibrillation (AF) increases the risk of thromboembolism, and risk assessment for thromboembolism is necessary for the management of AF patients. CHADS2 and CHA2DS2-VASc scores have been adopted in international guidelines for AF management, but the significance of each risk factor included in these risk scores are sometimes controversial, and the performance of these scores is only modest. There are several other risk factors not included in the scores such as renal dysfunction, low body weight, type of AF (paroxysmal or non-paroxysmal) as well as echocardiographic parameters and blood biomarkers, and physicians should assess patients risk in an integrated manner.

DOI： 10.1093/eurheartj/suaa176

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BACKGROUND: Atrial fibrillation (AF) and chronic kidney disease (CKD) are known risk factors for each other. In Tama City in Tokyo, 12-lead ECG and serum creatinine concentration have been included as essential examinations in specific health checkups to diagnose AF and CKD. In the present study, we investigated the impact of CKD classification on new-onset AF in the general population.Methods and Results:Among 13,478 subjects aged 40-74 years at entry (age, 65.6±7.8 years; men, 42.0%), renal impairment with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2and proteinuria were found in 15.5% and 4.6%, respectively. CKD severity in individual subjects was classified according to a heatmap of the Japanese Society of Nephrology as 81.3% in the green, 15.1% in the yellow, 2.5% in the orange, and 0.9% in the red. Of those without AF in 2012, it had developed in 115 up to 2017; thus, the new-onset AF incidence rate was 2.6/1,000 person-years. Hazard ratios and 95% confidence intervals for new-onset AF in each CKD classification were 1.50 (0.93-2.41, P=0.097) in the yellow, 2.53 (1.03-6.23, P=0.044) in the orange, and 4.65 (1.47-14.70, P=0.009) in the red compared with the green as a reference. CONCLUSIONS: CKD classification was significantly associated with new-onset AF in the general population. Thus, it would be useful for risk stratification of new-onset AF. Renal function evaluation is recommended in health checkups.

DOI： 10.1253/circj.CJ-20-0329

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BACKGROUND: Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. RESULTS: Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. CONCLUSIONS: This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. TRIAL REGISTRATION: The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .

DOI： 10.1186/s12933-020-01127-z

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Background: Renal impairment is a risk factor for various adverse events, especially for death. In general, creatinine clearance (CrCl) is used for dose-adjustments of many drugs including oral anticoagulants, and estimated glomerular filtration rate (eGFR) is adopted for the diagnosis of chronic kidney disease. Predictive ability of CrCl versus eGFR for outcomes in patients with non-valvular atrial fibrillation (NVAF) remains controversial; therefore, this was compared using data from the J-RHYTHM Registry. Methods: Out of 7406 outpatients with NVAF from 158 institutions, 6004 (age, 69.7 ± 9.9 years; men, 71.2%) having data of CrCl (mL/min, by the Cockcroft-Gault formula), eGFR (mL/min/1.73 m2, by the equations of the Japanese Society of Nephrology), and body surface area (BSA) were analyzed. C-statistics (area under the receiver-operating characteristic curve) of CrCl and eGFR for events were compared by DeLong's test. Results: Thromboembolism, major hemorrhage, and all-cause death occurred in 107 (1.8%), 117 (1.9%), and 154 (2.6%) patients during the 2-year follow-up period. C-statistics of CrCl for each event were 0.609 (95% confidence interval, 0.559-0.658), 0.599 (0.548-0.657), and 0.746 (0.706-0.786); and those of eGFR were 0.542 (0.487-0.597), 0.573 (0.519-0.626), and 0.677 (0.631-0.723), respectively. C-statistics of CrCl for thromboembolism and all-cause death were significantly higher than those of eGFR (P < 0.001 for both). These results were consistent when BSA-unadjusted eGFR was used instead of eGFR (P = 0.002 for thromboembolism and P < 0.001 for all-cause death). Conclusions: CrCl was superior to eGFR in the prediction of adverse outcomes, i.e., thromboembolism and all-cause death in Japanese patients with NVAF.

DOI： 10.1016/j.ijcha.2020.100559

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Importance: Despite the development of risk stratification schemes that have been widely used to determine the risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF), risk stratification schemes in Asian patients with NVAF remain undetermined. Objective: To determine risk factors for ischemic stroke in Japanese patients with NVAF. Design, Setting, and Participants: This cohort study analyzed individual patient data from 5 AF registries in Japan: J-RHYTHM (Japanese Rhythm Management Trial for Atrial Fibrillation) Registry, Fushimi AF Registry, Shinken Database, Keio Interhospital Cardiovascular Studies (Keio Study), and Hokuriku-Plus AF Registry. Patients with atrial fibrillation were registered from 158 institutions in the J-RHYTHM Registry, 80 in the Fushimi AF Registry, a single hospital in Shinken Database, 11 in the Keio Study, and 19 in the Hokuriku-Plus AF Registry. Patients with valvular AF or lacking data were excluded. Data were collected and integrated in March 2016, and those from the Keio Study were updated in April 2018. Data were analyzed from April 2018 to February 2020. Main Outcomes and Measures: Significant risk factors for ischemic stroke were determined by adjusted Cox proportional hazards analysis. Results: In total, 12 289 patients with NVAF (3758 [31%] female; mean [SD] age 70.2 [11] years) were analyzed with a mean (SD) follow-up period of 649 (181) days (1.8 [0.5] years). During 21 820 person-years of follow-up, 241 cases of ischemic stroke were reported. Risk factors associated with ischemic stroke after adjustment for oral anticoagulant use at enrollment were age (75-84 years: hazard ratio [HR], 1.74; 95% CI, 1.32-2.30; P < .001; and ≥85 years: HR, 2.41; 1.63-3.56; P < .001), hypertension (HR, 1.60; 95% CI, 1.15-2.23; P = .006), previous stroke (HR, 2.75; 95% CI, 2.09-3.62; P < .001), persistent or permanent AF (HR, 1.59; 95% CI, 1.21-2.10; P = .001), and body mass index less than 18.5 (HR, 1.55; 95% CI, 1.05-2.29; P = .03). Neither diabetes nor heart failure were identified as risk factors for ischemic stroke. Conclusions and Relevance: Previous stroke, advanced age, hypertension, persistent or permanent AF, and low body mass index were independent risk factors associated with ischemic stroke in Japanese patients with NVAF.

DOI： 10.1001/jamanetworkopen.2020.2881

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BACKGROUND: To clarify the influence of hemoglobin concentration and platelet count on adverse outcomes of Japanese patients with non-valvular atrial fibrillation (NVAF), a post hoc analysis of the J-RHYTHM Registry was performed. METHODS: A consecutive series of outpatients with atrial fibrillation were enrolled from 158 institutions and followed up for 2 years or until an event occurred (thromboembolism, major hemorrhage, or all-cause death). Among 7406 patients with NVAF, 6536 with complete blood count data (69.8 ± 9.9 years, 71.0% men) were divided into 4 groups according to the baseline hemoglobin level (<10.0, 10.0-11.9, 12.0-13.9, and ≥14.0 g/dL) or platelet count (<10.0, 10.0-19.9, 20.0-29.9, and ≥30.0 × 104/μL). RESULTS: Incidence rates of major hemorrhage (p = 0.004 for trend), all-cause death (p < 0.001 for trend), and composite events (p < 0.001 for trend) increased as hemoglobin levels decreased, and composite events (p = 0.045 for trend) increased as platelet counts decreased. After adjusting for multiple confounders, the incidence of all-cause death and composite events was higher with hemoglobin levels <12.0 g/dL than a hemoglobin level ≥14.0 g/dL. In contrast, platelet count was not associated with any events. This was also true when multivariate analysis was performed using the stepwise forward method. CONCLUSIONS: A low hemoglobin level (<12.0 g/dL) was an independent risk factor for all-cause death and composite events in Japanese patients with NVAF. However, platelet count did not impact outcomes. CLINICAL TRIAL REGISTRATION: http://www.umin.ac.jp/ctr/ (unique identifier: UMIN000001569).

DOI： 10.1016/j.ijcard.2019.11.127

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Background: Since 2012, Tama City has promoted the early detection of chronic kidney disease (CKD), through an initiative that measures serum creatinine as part of the specific health checkups. We examined preventive measures against CKD deterioration based on the outcomes of this initiative. Methods: The complications, medication status, body mass index, smoking status and other determining factors were surveyed among CKD-diagnosed participants over 3 years between 2013 and 2015. Moreover, factors aggravating CKD were investigated via a survey of medical and dental visits based on health insurance claim data over the same period. Results: There was an increased rate of comorbid hypertension with each increase in the CKD stage. Comorbidity rates of diabetes mellitus, dyslipidemia, obesity, and smoking increased until CKD stage G4, and then decreased from stage G5. A substantial number of participants with CKD stage G3b and above were not medicated despite comorbidities like hypertension, diabetes mellitus and dyslipidemia. While the rate of regular visits at medical institutions was seen to increase significantly in accordance with the worsening degree of CKD, there were also individuals who, despite having severe CKD, did not visit medical institutions specializing in internal medicine. The rate of dental visits decreased as the CKD stage increased, and further decreased as the diabetic control status worsened. Conclusions: CKD patients should become aware of the importance of the dental visit because only a limited number of patients with advanced CKD received dental care.

DOI： 10.14740/jocmr4085

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DOI： 10.1253/circj.CJ-66-0187

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Acute aortic dissection (AAD) cases are thought to have high blood pressure (BP) on admission; however, little data are available on BP prior to admission. The purpose of this study was to investigate systolic blood pressure (SBP) very early after symptom onset and before hospital transfer in patients with AAD to determine whether SBPs were high, and also whether SBPs were higher or lower compared with SBPs at hospital admission. We obtained results using three-year data derived from the Tokyo Acute Aortic Super Network Database. First, we selected 830 patients with AAD for which the "duration from symptom onset to first medical contact by ambulance crews" (SO-FMC) was within 60 min. We examined the SBPs of such patients. Next, we selected 222 patients with AAD whose SBPs were measured both at FMC, within 15 min after symptom onset, and at hospital admission, and compared SBPs at FMC with those at hospital admission. Among types A (n = 190) and B (n = 117), in patients with an SO-FMC <= 15 min, the median SBP was 100 mmHg and 178 mmHg (p < 0.001), respectively; 9% and 50% (p < 0.001) of such patients, respectively, exhibited an SBP >= 180 mmHg; and 43% and 10% (p < 0.001) of such patients, respectively, had an SBP < 90 mmHg. Of patients with types A (n = 124) and B (n = 98) AAD whose SBPs were measured both at FMC, within 15 min after symptom onset, and at hospital admission, SBPs at FMC were higher than those at hospital admission for the SBP >= 180 mmHg subgroups of both type A ( 194 mmHg vs. 159 mmHg, p < 0.001) and type B (199 mmHg vs. 186 mmHg, p < 0.001). Approximately 10 min after symptom onset and before hospital transfer, the measured SBPs of many patients with type A AAD were not necessarily high. However, the SBPs of cases with type B AAD were high as previously reported for SBP on admission. In addition, for the subgroup of SBP >= 180 mmHg at FMC within 15 min after symptom onset, SBPs at FMC were significantly higher than those at hospital admission for both types A and B; the higher SBP at symptom onset may have been partially associated with being a trigger of AD.

DOI： 10.1007/s00380-019-01419-9

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Background: Preventing frailty of elderly is an urgent issue in Japan. The "Yubi-wakka" (finger-ring) test was developed and validated as a predictor of sarcopenia, disability and even mortality. To clarify the prevalence of "frailty" defined by this test and the relationship between other indexes cross-sectionally and prospectively, we conducted this study. Methods: Five thousand four hundred and five subjects who were 65 to 74 years old participated in this study. In a sitting position, the subjects surrounded their calf using their own finger-ring, and whether the calf was larger, just fit, or smaller than the finger-ring was determined. We analyzed these "Yubi-wakka" (finger-ring) test results and other clinical indexes. We used Student's t-tests and the Chi-squared tests to compare the data between the groups, and logistic regression tests to adjust for multiple variables. Results: In total, 38.8% of the subjects' calves were judged as being "larger", 45.6% as "just fit" and 15.6% as "smaller", which was the positive test result. The positive rate differed among medical facilities without any known different characteristics. The comparison between the "larger" and "smaller" groups revealed that body weight, red blood cell count, serum lipids, uric acid and liver enzymes were significantly different between the groups. Metabolic syndrome was more common in the "larger" group. In multiple analysis, low body mass index was an independent risk factor in both sexes. Positive urinary glucose, higher aspartate aminotransferase, systolic blood pressure and low alanine transaminase were risk factors for positive test results for males. Smoking, high hemoglobin and old age were risk factors for positive test results in females. Conclusions: The test was simple and feasible enough for the primary care setting, without the requirement of any devices. However, the positive rate varied among the clinics. The subjects' age was limited to under 75 years, and the test possibly detected individuals without metabolic syndrome and fatty liver. We are also planning to increase the subjects' age range and collect data prospectively.

DOI： 10.14740/jocmr3917

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BACKGROUND: Because the influence of digitalis use on the death of patients with non-valvular atrial fibrillation (NVAF) remains controversial, a subanalysis of the J-RHYTHM Registry was performed.Methods and Results:A consecutive series of outpatients with AF from 158 institutions was enrolled and followed for 2 years or until the occurrence of an event. Among 7,406 patients with NVAF, 7,018 (age, 69.7±10.0 years; men, 71.1%) with information on antiarrhythmic drug and digitalis use at baseline were divided into 2 groups based on digitalis use. The influence of digitalis on death was investigated using a propensity score-matching model. In 802 patients treated with digitalis, all-cause death was significantly higher than in 6,216 patients with no digitalis use during the 2-year follow-up period (4.4% vs. 2.4%, unadjusted P<0.001). Digitalis use was significantly associated with all-cause death in the crude model (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.28-2.68, P=0.001). However, after propensity score-matching, the association was not significant (HR 1.31, 95% CI 0.70-2.46, P=0.405). Older age, male sex, heart failure, coronary artery disease, and lower body mass index were significantly associated with all-cause death in NVAF patients treated with digitalis. CONCLUSIONS: Digitalis use was not independently associated with all-cause death, and several clinical confounding factors might contribute to increased mortality in NVAF patients treated with digitalis.

DOI： 10.1253/circj.CJ-19-0267

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DOI： 10.1093/eurheartj/ehy738

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BACKGROUND: Although National Health Insurance special health checkups have been useful for the diagnosis of metabolic syndrome, they are insufficient to identify atrial fibrillation (AF). In Tama City in Tokyo, 12-lead electrocardiogram has been included as an essential examination in special health checkups to diagnose AF since 2008. Methods and Results: In subjects aged 40-74 years at entry, prevalence of AF was 0.8% (men, 1.7%; women, 0.2%) in 2008 and 1.4% (men, 2.9%; women, 0.4%) in 2015. Of 10,430 subjects without AF in 2008 (mean age, 64.9±7.1 years; men, 40.4%), AF developed in 133 between 2008 and 2015. The incidence rate of new-onset AF was 2.5/1,000 person-years during an observation period of 52,707 person-years. On multivariate Cox regression analysis in subjects without a history of cardiac disease, hypertension (HR, 1.58; 95% CI: 1.01-2.47, P=0.045) and body mass index (BMI; /1-kg/m2increase; HR, 1.07; 95% CI: 1.00-1.12, P=0.049) were significant risk factors for new-onset AF in addition to age and male sex. CONCLUSIONS: Prevalence of AF increased between 2008 and 2015. Age, male sex, hypertension, and BMI were significant predictors for future incidence of AF in the general population without overt cardiac disease. Controlling hypertension and BMI may prevent new-onset AF in the general population.

DOI： 10.1253/circj.CJ-18-1038

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DOI： 10.1093/eurheartj/ehy246

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INTRODUCTION: Protection from lethal ventricular arrhythmias leading to sudden cardiac death is one of the most important problems after myocardial infarction. Cardiac sympathetic hyperactivity is related to poor prognosis and fatal arrhythmias and can be non-invasively assessed with heart rate variability, heart rate turbulence, T-wave alternans, late potentials, and 123I-meta-iodobenzylguanide (123I-MIBG) scintigraphy. Sodium glucose cotransporter 2 (SGLT2) inhibitors potentially reduce sympathetic nervous system activity that is augmented in part due to the stimulatory effect of hyperglycemia. The EMBODY trial is designed to determine whether the suppression of cardiac sympathetic activity induced by the SGLT2 inhibitor is accompanied by protection against adverse cardiovascular outcomes. METHODS: The EMBODY trial is a prospective, multicenter, randomized, double-blind, placebo-controlled trial in patients with acute MI and type 2 diabetes in Japan. A total of 98 patients will be randomized (1:1) to receive once-daily placebo or empagliflozin, an SGLT2 inhibitor, 10 mg. The primary end point is the change from baseline to 24 weeks in heart rate variability. Secondary end points include the change from baseline for other sudden cardiac death surrogate-markers such as heart rate turbulence, T-wave alternans, late potentials, and 123I-MIBG scintigraphy imaging. Adverse effects will be evaluated throughout the trial period. PLANNED OUTCOMES: The EMBODY trial will evaluate the potential cardioprotective effect of empagliflozin and will provide additional important new data regarding its preventative effects on sudden cardiac death. TRIAL REGISTRATION: Unique Trial Number, UMIN000030158 ( https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000034442 ). FUNDING: Nippon Boehringer Ingelheim and Eli Lilly and Company.

DOI： 10.1007/s13300-018-0480-7

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BACKGROUND: The relationship between warfarin treatment quality and prognosis for Japanese patients with nonvalvular atrial fibrillation (NVAF) has not been studied thoroughly. Methods and Results: Data from the J-RHYTHM Registry were used to determine the time in therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time in elderly patients (≥70 years). Target INR was 1.6-2.6. Of 7,406 patients with NVAF in the database, 3,832 elderly patients (mean [±SD] age 77.0±5.0 years) constituted the study group. Of these patients, 459 did not receive warfarin and 3,373 received warfarin. Patients on warfarin were subdivided into 4 TTR groups: <40%, 40-59.9%, 60-79.9%, and ≥80%. During the 2-year follow-up, the incidence of thromboembolism and all-cause death was lower in patients with higher TTR (Ptrend<0.001); however, the incidence of major hemorrhage was higher in patients with TTR <40%. In multivariate analysis, compared with the no-warfarin group, TTR 60-79.9% and ≥80% were associated with lower thromboembolic risk, with hazard ratios (HR) of 0.34 (95% confidence interval [CI] 0.17-0.67; P=0.002) and 0.35 (95% CI 0.18-0.68; P=0.002), respectively, and lower all-cause death (HR 0.37 [95% CI 0.22-0.65; P<0.001] and 0.43 [95% CI 0.26-0.71; P=0.001], respectively). TTR <40% was associated with major hemorrhage (HR 5.57; 95% CI 2.04-15.25; P=0.001). CONCLUSIONS: In elderly Japanese patients with NVAF, TTR should be maintained ≥60% to prevent thromboembolism and all-cause death. TTR <40% should be avoided to prevent major hemorrhage.

DOI： 10.1253/circj.CJ-18-0587

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DOI： 10.1253/circj.CJ-18-0759

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BACKGROUND: It is unclear whether renal dysfunction affects warfarin control in patients with non-valvular atrial fibrillation (NVAF). Methods and Results: Using a dataset from the J-RHYTHM Registry, time in therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time, and creatinine clearance (CrCl) were determined in elderly patients aged ≥70 years. Target INR values were 1.6-2.6 following Japanese guidelines. Incidences of thromboembolism, major hemorrhage, and all-cause death were determined over 2 years. Of 7,406 NVAF patients enrolled in the registry, 2,782 elderly patients (mean age, 75 years) had data for CrCl measured at baseline and TTR. TTR values were lower in the lower CrCl groups (P<0.001 for trend). CrCl <30 mL/min was independently associated with TTR <65% (odds ratio, 1.49; 95% confidence interval, 1.13-1.95; P=0.004). In the multivariate analysis, TTR <65% was independently associated with thromboembolism (hazard ratio, 2.26; 95% confidence interval, 1.37-3.72; P=0.001), but CrCl was not (CrCl <30 mL/min, 1.68, 0.41-6.85, P=0.473). However, CrCl <30 mL/min and TTR <65% were independently associated with all-cause death (5.32, 1.56-18.18, P=0.008 and 1.60, 1.07-2.38, P=0.022, respectively) and the composite event (thromboembolism, major hemorrhage and all-cause death) (2.03, 1.10-3.76, P=0.024 and 1.58, 1.22-2.04, P=0.001, respectively). CONCLUSIONS: Elderly NVAF patients with renal dysfunction had poor warfarin control, which was associated with higher risk of thromboembolism and all-cause death.

DOI： 10.1253/circj.CJ-18-0242

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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DOI： 10.1253/circj.CJ-18-0045

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Aims: To clarify the influence of renal function on adverse outcomes in patients with non-valvular atrial fibrillation (NVAF), a post hoc analysis of the J-RHYTHM Registry was performed. Methods and results: A consecutive series of outpatients with atrial fibrillation (AF) were enrolled from 158 institutions and followed for 2 years or until the occurrence of an event. Among 7406 patients with non-valvular AF, 6052 patients (69.8 ± 10.0 years, 71.2% men) with creatinine clearance (CrCl) value at baseline were divided into four groups according to CrCl level (<30, 30-49.9, 50-79.9, and ≥80 mL/min). Patients with CrCl <80 mL/min showed increased incidence of thromboembolism, major haemorrhage, all-cause and cardiovascular death, and composite events as compared with patients with CrCl ≥80 mL/min. After adjustment for multiple confounders, lower CrCl values emerged as independent predictors for thromboembolism [CrCl 30-49.9, hazard ratio (HR) 2.27, 95% confidence interval (CI) 1.09-4.72, P = 0.029; and CrCl 50-79.9, HR 1.99, 95% CI 1.07-3.72, P = 0.030] and all-cause death (CrCl <30, HR 6.44, 95% CI 3.03-13.7, P < 0.001; and CrCl 30-49.9, HR 3.14, 95% CI 1.54-6.41, P = 0.002), with CrCl ≥80 mL/min serving as a reference, whereas not for major haemorrhage. Warfarin treatment was associated with lower rates of composite events in patients with lower CrCl values of <80 mL/min. Conclusion: Renal impairment was an independent predictor of adverse clinical outcomes except for major haemorrhage in Japanese patients with non-valvular AF. Warfarin was associated with lower rates of composite events in patients with lower CrCl values. Clinical Trial Registration: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000001569.

DOI： 10.1093/ehjqcco/qcx032

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DOI： 10.1253/circj.CJ-16-1185

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© 2017 The Authors. Background: Breast cancer is currently the most common type of cancer in Japanese females. Unlike most other types of cancer, breast cancer develops more frequently in middle-aged females than in elderly females. Methods: Of all Japanese female breast cancer patients aged ≥ 20 years whom the BioBank Japan Project originally enrolled between 2003 and 2008, 2034 were registered within 90 days after their diagnosis. We described the lifestyle and clinical characteristics of these patients at study entry. Furthermore, we examined the effect of these characteristics on all-cause mortality. Results: In the female patients registered within 90 days after diagnosis, the frequency of stage 0 or unclassified, stage I, II, III and IV were 11.4%, 47.9%, 37.0%, 2.9% and 0.8%, respectively. The proportion of histological types was 12.9% for non-invasive carcinoma (ductal carcinoma and lobular carcinoma), 81.0% for invasive carcinoma (papillotubular carcinoma, solid tubular carcinoma, scirrhous carcinoma and special types), 0.2% for Paget's diseases and 5.8% for others. Those positive for the estrogen and progesterone receptors accounted for 75.8% and 62.1% of all patients, respectively. Among 1860 female participants registered within 90 days, 218 participants died during 144,54 person-years of follow-up. More advanced stage, elevation of serum carcinoembryonic antigen and carbohydrate antigen 15-3 levels and absence of the estrogen receptor at study entry were crudely associated with an increased risk of all-cause mortality after adjustment for age. Conclusions: This study showed the association of several clinical characteristics with all-cause mortality in female breast cancer patients.

DOI： 10.1016/j.je.2016.12.012

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© 2017 The Authors. Background: Controlling serum cholesterol is critical to prevent cardiovascular disease in patients with dyslipidaemia. Guidelines emphasise the need to select treatment for dyslipidaemia based on specific patient profiles; however, there is little information about the serum cholesterol levels of patients in each profile in Japan. Therefore, we aimed to describe the serum cholesterol levels and prevalence of uncontrolled cases in Japanese patients with dyslipidaemia. Methods: We included data for patients with dyslipidaemia between 2003 and 2007 from the BioBank Japan Project (66 hospitals). Then, we reported their serum cholesterol levels by age, body mass index, glycaemic control (glycated haemoglobin A1c), blood pressure, smoking, drinking, comorbidity and medication profiles. Results: We included 22,189 male and 21,545 female patients. The mean serum low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG) and non-HDL-C levels in males were 117.4 mg/dL, 51.0 mg/dL, 187.6 mg/dL and 153.6 mg/dL, respectively; the corresponding levels in females were 129.5 mg/dL, 60.5 mg/dL, 144.9 mg/dL and 157.9 mg/dL, respectively. In both males and females, the LDL-C levels were the highest in the following profiles: age 19e44 years, body mass index 18.5e22 kg/m2, glycated haemoglobin A1c < 6.0%, never smoker, chronic respiratory disease as a comorbidity and no medication use. Conclusions: These data provide details of serum cholesterol levels by risk-factor profile in patients with dyslipidaemia and could add evidence of treatment decisions.

DOI： 10.1016/j.je.2016.12.014

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BACKGROUND: To clarify the influence of hypertension and blood pressure (BP) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J-RHYTHM Registry was performed. METHODS AND RESULTS: A consecutive series of outpatients with atrial fibrillation was enrolled from 158 institutions. Of 7937 patients, 7406 with nonvalvular atrial fibrillation (70.8% men, 69.8±10.0 years) were followed for 2 years or until an event occurred. Hypertension was defined as a systolic BP ≥140 mm Hg, a diastolic BP ≥90 mm Hg, a history of hypertension, and/or antihypertensive drug use. Hypertension was an independent risk factor for major hemorrhage (hazard ratio 1.52, 95% CI 1.05-2.21, P=0.027) but not for thromboembolism (hazard ratio 1.05, 95% CI 0.73-1.52, P=0.787). When patients were divided into quartiles according to their systolic BP at the time closest to the event or at the end of follow-up (Q1, <114; Q2, 114-125; Q3, 126-135; and Q4, ≥136 mm Hg), odds ratios for both events were significantly higher in Q4 than in Q1 (thromboembolism, odds ratio 2.88, 95% CI 1.75-4.74, P<0.001; major hemorrhage, odds ratio 1.61, 95% CI 1.02-2.53, P=0.041) after adjustment for components of CHA2DS2-VASc score, warfarin use, and antiplatelet use. A systolic BP of ≥136 mm Hg was an independent risk factor for thromboembolism and major hemorrhage. CONCLUSIONS: BP control appears to be more important than a history of hypertension and baseline BP values at preventing thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr. Unique identifier: UMIN000001569.

DOI： 10.1161/JAHA.116.004075

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC  

Obesity is a risk factor for atrial fibrillation (AF); however, obesity is associated with lower mortality in patients with established AF, a phenomenon known as the obesity paradox. Previous studies reported inconsistent results regarding effects of body weight on risk of cardiogenic embolism in patients with AF. To determine relation between body mass index (BMI) and prognosis among Japanese patients with nonvalvular AF (NVAF), a post hoc analysis was conducted using observational data in the J-RHYTHM Registry. Subjects were categorized as underweight (BMI <18.5), normal (18.5 to 24.9), overweight (25.0 to 29.9), or obese (≥30 kg/m(2)). End points included thromboembolism, major hemorrhaging, all-cause mortality, and cardiovascular mortality. Of the 7,406 patients with NVAF, 6,379 patients (70 ± 10 years old; BMI, 23.6 ± 3.9 kg/m(2)) having baseline BMI data constituted the study group. During the 2-year follow-up period, 111 patients had thromboembolism, 124 experienced major hemorrhage, and 159 died. Multivariate analysis with the Cox proportional hazards model showed that none of the BMI categories were independent predictors of thromboembolism. However, being underweight was an independent predictor of all-cause mortality (hazard ratio [HR] 2.45; 95% confidence interval [CI] 1.62 to 3.69; p <0.001) and cardiovascular mortality (HR 3.00, 95% CI 1.52 to 5.91, p = 0.001) when normal weight was used as the reference. Additionally, being overweight was a predictor of lower all-cause mortality (HR 0.60, 95% CI 0.37 to 0.95, p = 0.029). In conclusion, being underweight is associated with higher risks of all-cause and cardiovascular mortality compared with having a normal weight. Being overweight or obese is not associated with increased mortality among Japanese patients with NVAF.

DOI： 10.1016/j.amjcard.2016.04.036

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

BACKGROUND: The proportion of patients with atrial fibrillation (AF) treated with anticoagulation varies from country to country. In Japan, little is known about regional differences in frequency of warfarin use or prognosis among patients with non-valvular AF (NVAF). METHODS AND RESULTS: In J-RHYTHM Registry, the number of patients recruited from each of 10 geographic regions of Japan was based on region population density. A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, significant differences in various clinical characteristics including age, sex, type of AF, comorbidity, and CHADS2score, were detected among the regions. The highest mean CHADS2score was recorded in Shikoku. Frequency of warfarin use differed between the regions (P<0.001), with lower frequencies observed in Hokkaido and Shikoku. Baseline prothrombin time international normalized ratio differed slightly but significantly between the regions (P<0.05). On univariate analysis, frequency of thromboembolic events differed among the regions (P<0.001), with the highest rate seen in Shikoku. An inverse correlation was detected between frequency of thromboembolic and of major hemorrhagic events (P=0.062). On multivariate analysis, region emerged as an independent risk for thromboembolism. CONCLUSIONS: Thromboembolic risk, frequency of warfarin use, and intensity and quality of warfarin treatment differed significantly between geographic regions of Japan. Region was found to be an independent predictor of thromboembolic events. (Circ J 2016; 80: 1548-1555).

DOI： 10.1253/circj.CJ-16-0300

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

BACKGROUND: Concomitant use of vitamin K antagonist (VKA) and aspirin (ASA) is becoming increasingly prevalent among atrial fibrillation (AF) patients. We quantified the net clinical benefit of adding ASA to a VKA using nationwide prospective AF registry data. METHODS: We studied 6074 patients (VKA monotherapy: 83% and VKA+ASA: 17%) between January 2009 and July 2009, and followed them for a mean follow-up period of 2years. The risk of strokes and bleeding was calculated by the CHA2DS2-VASc and HAS-BLED scores. The net clinical benefit was defined as the annual rate of ischemic strokes and systemic emboli prevented by VKAs minus intracranial hemorrhages attributable to the VKA+ASA, multiplied by an impact weight of 1.5. RESULTS: Patients on a VKA+ASA were older with more medical comorbidities than those on VKA alone. Using VKA monotherapy as a reference, higher major bleeding rates and all-cause death were evident in those on VKA+ASA. The net clinical benefit of VKA+ASA for the overall cohort was -0.1%/year (95% confidence interval, -0.74% to 0.46%). There was a trend toward a negative net clinical benefit from VKA+ASA in patients with a CHA2DS2-VASc≥2 and HAS-BLED≤2 (-1.17%/year). The VKA+ASA yielded a positive net clinical benefit in patients with a CHA2DS2-VASc≥2 and HAS-BLED≥3 (1.16%/year). The result patterns were relatively constant using impact weight of 1.0 and 2.0. CONCLUSIONS: Our estimates of the net clinical benefit can provide a useful anchoring point for adding ASA to VKA in patients with AF.

DOI： 10.1016/j.ijcard.2016.03.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

BACKGROUND: Hypertension is one of the main comorbidities associated with dyslipidemia. This study aimed to examine the extent to which dyslipidemia increases the risk of developing hypertension in a Japanese working-age male population. METHODS AND RESULTS: We analyzed data from 14 215 nonhypertensive male workers (age 38±9 years) who underwent annual medical checkups. Subjects were followed up for a median of 4 years to determine new-onset hypertension, defined as blood pressure (BP) ≥140/90 mm Hg or use of antihypertensive medication. The associations between serum lipid levels and development of hypertension were examined. During the follow-up period, 1483 subjects developed hypertension. After adjusting for age, body mass index, impaired fasting glucose/diabetes, baseline BP category, alcohol intake, smoking, exercise, and parental history of hypertension, subjects with a total cholesterol (TC) level ≥222 mg/dL were at a significantly increased risk of developing hypertension (hazard ratio: 1.28; 95% CI: 1.06-1.56) compared to subjects with a TC level ≤167 mg/dL. Similar results were observed for subjects with high low-density lipoprotein cholesterol (LDLC) and non-high-density lipoprotein cholesterol (HDLC) levels. A U-shaped relationship was found between HDLC level and risk of hypertension; compared to the third quintile, the multiadjusted hazard ratio was 1.22 (95% CI: 1.03-1.43) in the lowest quintile and 1.34 (95% CI: 1.12-1.60) in the highest quintile. CONCLUSIONS: Elevated serum levels of TC, LDLC, and non-HDLC were associated with an increased risk of hypertension in working-age Japanese men. For HDLC, risk of hypertension was increased at both low and high levels.

DOI： 10.1161/JAHA.115.003053

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER  

BACKGROUND: Prior ischemic stroke or transient ischemic attack (TIA) is a high risk for thromboembolism in patients with nonvalvular atrial fibrillation (NVAF). To clarify rates of thromboembolic and hemorrhagic events, and target intensities of warfarin for secondary prevention, a subanalysis was performed using data from the J-RHYTHM Registry. METHODS: Of 7937 outpatients with atrial fibrillation, 7406 with NVAF (men 70.8%, 69.8 ± 10.0 years) were followed for 2 years or until an event occurred. Event rates and effect of warfarin were compared between patients with (secondary prevention) and without (primary prevention) prior stroke/TIA. RESULTS: Prevalence of male sex, diabetes mellitus, and mean age were higher in the secondary prevention group, showing a higher CHADS2 (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and history of stroke or TIA) score than the primary prevention group (3.5 ± 1.0 versus 1.4 ± 1.0, P < .001). In the secondary prevention group, 93.4% of patients received warfarin and their time in therapeutic range was 62.8%. During follow-up, thromboembolism occurred more frequently in the secondary than in the primary prevention group (2.8% versus 1.5%, P = .004), especially in patients without warfarin. Major hemorrhage also occurred more frequently in the secondary prevention group (3.0% versus 1.7%, P = .006). Compared with patients not taking warfarin, combined rates of both events were lower at an international normalized ratio (INR) of 1.6-2.59 in patients taking warfarin in the secondary as well as in the primary prevention groups. CONCLUSIONS: Both thromboembolism and major hemorrhage occurred more frequently in NVAF patients with prior ischemic stroke/TIA. Target INR should be 1.6-2.59 for secondary as well as primary prevention of thromboembolism in Japanese NVAF patients.

DOI： 10.1016/j.jstrokecerebrovasdis.2015.11.020

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BACKGROUND: The J-RHYTHM Registry 2 was a multicenter, prospective observational study that extended the follow-up period of the J-RHYTHM Registry in order to investigate long-term outcomes and effects of non-vitamin K antagonist oral anticoagulants (NOACs) in Japanese patients with atrial fibrillation (AF). METHODS AND RESULTS: Among 6,616 patients with nonvalvular AF (NVAF) (men 71.0%, 69.7±9.9 years, CHADS2score 1.7±1.2), event rates were compared among patients receiving warfarin (n=3,964), NOACs (n=923), and no anticoagulation therapy (No-OAC, n=753) at the end of follow-up, except for 976 patients lacking anticoagulant data. During the 5-year follow-up period, thromboembolism occurred in 196 (4.9%), 19 (2.1%), and 45 (6.0%) patients, respectively; major hemorrhage in 233 (5.9%), 22 (2.4%), and 36 (4.8%); all-cause death in 230 (5.8%), 13 (1.4%), and 105 (13.9%), (P<0.001 for each). After adjusting for the components of the CHA2DS2-VASc score and antiplatelet drug use, the odds ratio (OR) in the Warfarin group was significantly lower for all-cause death compared with that in the No-OAC group (OR 0.30, 95% confidence interval [CI] 0.23-0.39, P<0.001), whereas ORs in the NOACs group were significantly lower for all events (OR 0.42, 95% CI 0.24-0.74, P=0.003 for thromboembolism; OR 0.53, 95% CI 0.31-0.93, P=0.027 for major hemorrhage; and OR 0.10, 95% CI 0.06-0.18, P<0.001 for all-cause death, respectively). CONCLUSIONS: NOACs could be beneficial for reducing event rates of all types in Japanese NVAF patients.

DOI： 10.1253/circj.CJ-16-0066

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Language：English   Publisher：(NPO)日本高血圧学会  

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© 2015 The Japanese Society of Hypertension All rights reserved. The aim of this study was to develop a risk prediction model for incident hypertension in a Japanese male population. Study participants included 15 025 nonhypertensive Japanese male workers (mean age, 38.8±8.9 years) who underwent an annual medical checkup at a company. The participants were followed-up for a median of 4.0 years to determine new-onset hypertension, defined as a systolic blood pressure (BP) ≥140 mm Hg, a diastolic BP ≥90 mm Hg, or the initiation of antihypertensive medication. Participants were divided into the following two cohorts for subsequent analyses: the derivation cohort (n=12 020, 80% of the study population) and the validation cohort (n=3005, the remaining 20% of the study population). In the derivation cohort, a multivariate Cox proportional hazards model demonstrated that age, body mass index, systolic and diastolic BP, current smoking status, excessive alcohol intake and parental history of hypertension were independent predictors of incident hypertension. Using these variables, a risk prediction model was constructed to estimate the 4-year risk of incident hypertension. In the validation cohort, the risk prediction model demonstrated high discrimination ability and acceptable calibration, with a C-statistic of 0.861 (95% confidence interval 0.844, 0.877) and a modified Hosmer-Lemeshow χ 2 statistic of 15.2 (P=0.085). A risk score sheet was constructed to enable the simple calculation of the approximate 4-year probability of incident hypertension. In conclusion, a practical risk prediction model for incident hypertension was successfully developed in a working-age Japanese male population.

DOI： 10.1038/hr.2014.159

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.jjcc.2014.08.009

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The aim of this study was to develop a risk prediction model for incident hypertension in a Japanese male population. Study participants included 15,025 nonhypertensive Japanese male workers (mean age, 38.8±8.9 years) who underwent an annual medical checkup at a company. The participants were followed-up for a median of 4.0 years to determine new-onset hypertension, defined as a systolic blood pressure (BP) ⩾140 mm Hg, a diastolic BP ⩾90 mm Hg, or the initiation of antihypertensive medication. Participants were divided into the following two cohorts for subsequent analyses: the derivation cohort (n=12,020, 80% of the study population) and the validation cohort (n=3005, the remaining 20% of the study population). In the derivation cohort, a multivariate Cox proportional hazards model demonstrated that age, body mass index, systolic and diastolic BP, current smoking status, excessive alcohol intake and parental history of hypertension were independent predictors of incident hypertension. Using these variables, a risk prediction model was constructed to estimate the 4-year risk of incident hypertension. In the validation cohort, the risk prediction model demonstrated high discrimination ability and acceptable calibration, with a C-statistic of 0.861 (95% confidence interval 0.844, 0.877) and a modified Hosmer-Lemeshow χ2 statistic of 15.2 (P=0.085). A risk score sheet was constructed to enable the simple calculation of the approximate 4-year probability of incident hypertension. In conclusion, a practical risk prediction model for incident hypertension was successfully developed in a working-age Japanese male population.

DOI： 10.1038/hr.2014.159

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOC  

BACKGROUND: To clarify the effects of warfarin therapy in very old patients with non-valvular atrial fibrillation (NVAF), a post-hoc analysis was performed using the data of the J-RHYTHM Registry. METHODS AND RESULTS: A consecutive series of AF outpatients was enrolled from 158 institutions. Of 7,937 patients, 7,406 with NVAF (men, 70.8%; 69.8±10.0 years) were followed for 2 years or until an event occurred. Patients were divided into 3 age groups (<70, 70-84, and ≥85 years) and 5 subgroups according to international normalized ratio (INR; <1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Prevalence of female sex, permanent AF, hypertension, coronary artery disease, heart failure, and history of ischemic stroke/transient ischemic attack was higher in the older groups. In the oldest group, 79.7% of patients received warfarin and their time in therapeutic range, using the Japanese target INR of 1.6-2.6, was 67.1%. Rate of thromboembolic events was lower in the age groups <70 and 70-84 years (P=0.027 and P<0.001, respectively) for patients receiving warfarin compared with those who were not. In the oldest group, the rate of thromboembolism plus major hemorrhage was lower at INR 1.6-2.59. CONCLUSIONS: Warfarin could have beneficial effects even in very old NVAF patients if INR is kept between 1.6 and 2.59.

DOI： 10.1253/circj.CJ-15-0621

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BACKGROUND: Warfarin is widely used for prevention of thromboembolism in patients with valvular atrial fibrillation (AF), and an international normalized ratio (INR) of prothrombin time between 2.0 and 3.0 is recommended. Optimal intensity of anticoagulation with warfarin in Japanese patients with valvular AF, however, has not been clarified thoroughly as yet. METHODS AND RESULTS: We evaluated the status of anti-thrombotic therapy and incidence rates of events in 410 patients with mitral stenosis and/or mechanical valve replacement (valvular AF) among 7,816 patients with AF followed in the J-RHYTHM Registry. Patients were divided into 5 groups based on INR (<1.6, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0) at the time of event or at the end of follow-up in order to determine the target INR for patients with valvular AF. Warfarin was prescribed in 407 (99.3%) of valvular AF patients. During a 2-year follow-up period, thromboembolism and major hemorrhage occurred in 12 (2.9%) and in 15 (3.7%) patients, respectively. Among patients receiving warfarin, 2-year incidence rates of thromboembolism were 10.3%, 1.6%, 0.6%, 3.0%, and 0.0% (P=0.003 for trend), and those of major hemorrhage were 1.5%, 1.6%, 3.2%, 6.1%, and 21.1% (P<0.001 for trend), respectively. CONCLUSIONS: I NR between 1.6 and 2.6 could be optimal to prevent thromboembolism without increasing major hemorrhage in Japanese patients with valvular AF. INR 2.6-2.99 would also be effective, but is associated with a modestly increased risk of major hemorrhage.

DOI： 10.1253/circj.CJ-14-1057

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Language：English   Publisher：AMER DIABETES ASSOC  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

BACKGROUND: The aim of this study was to examine the predictive value of serum cystatin C (CysC) and that of creatinine-based estimated glomerular filtration rate (eGFRCreat) for the risk of incident hypertension in a middle-aged male population. METHODS: Serum CysC levels were measured in 904 nonhypertensive, Japanese male subjects (mean age = 44±6 years) who received an annual general health examination in a company. Serum creatinine levels were simultaneously measured, and eGFRCreat was calculated. Subjects were followed-up for a maximum period of 4 years, and annual blood pressure measurements were recorded. RESULTS: During the follow-up period, 124 subjects developed hypertension, defined as systolic/diastolic blood pressure ≥140/90 mmHg or use of antihypertensive medications. In the Kaplan-Meier analysis, both the third quintile of CysC and that of eGFRCreat showed the lowest 4-year cumulative incident rate of hypertension. The multiadjusted hazard ratio for incident hypertension was significantly increased in the highest quintile of CysC compared with the third quintile (2.60; 95% confidence interval (CI) = 1.41-4.77; P = 0.002), as well as compared with the lowest 4 quintiles combined (1.89; 95% CI = 1.26-2.84; P = 0.002). However, eGFRCreat did not show significant hazard ratios for incident hypertension in any of the adjusted models. CONCLUSIONS: Elevated serum CysC levels could predict the risk of incident hypertension in this study population with a maximum follow-up period of 4 years. In contrast, eGFRCreat did not show predictive value for the risk of incident hypertension.

DOI： 10.1093/ajh/hpt164

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© 2014 by Nova Science Publishers, Inc. All rights reserved. Pulmonary embolism (PE) is a fatal complication of venous thromboembolism (VTE). Several clinical situations are recognized as risk factors for VTE such as major orthopedic surgery. In most cases, PE develops as a consequence of deep vein thrombosis (DVT), which is a common complication after surgery especially of total knee or hip arthroplasty (TKA, THA). Since PE and/or DVT often cause recurrent VTE and serious complications such as chronic thromboembolic pulmonary hypertension, anticoagulation therapy should be recommended to prevent fatal PE and to minimize the risk of developing recurrent VTE. Currently, standard pharmacological treatment for VTE involves the overlapping intravenous or subcutaneous administration of low molecular-weight heparin (LMWH), unfractionated heparin (UFH), or fondaparinux with oral vitamin K antagonists (VKAs). Although warfarin, a most popular oral VKA, is widely used for the secondary prevention of VTE, warfarin treatment sometimes must be abandoned due to ineffectiveness of or intolerance to warfarin. In these cases, alternatives to warfarin should be considered. Although novel oral anticoagulants (NOACs), including thrombin inhibitor dabigatran, factor Xa inhibitors rivaroxaban and apixaban, are recently available to prevent cardiogenic ischemic stroke for patients with nonvalvular atrial fibrillation (NVAF), the use of NOACs for the prevention of VTE remains limited. However, NOACs can also be chosen as a therapeutic option for patients with VTE because recent reports have demonstrated that the clinical outcomes of the treatment with NOACs are comparable or superior compared with conventional treatments. In this chapter, recent investigations will be summarized to show the efficacy and safety of NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) for the prevention and treatment of VTE.

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BACKGROUND: Currently, β-blockers are used most frequently for the purpose of heart rate (HR) control in patients with atrial fibrillation (AF) in worldwide. Carvedilol is one of common β-blockers and known to be effective for hypertension and heart failure. However, little can be found the information about the HR-lowering effect of carvedilol in patients with AF without heart failure. Therefore, we conducted this study to investigate the effect of carvedilol on HR in 3-minute electrocardiogram (ECG) and total heart beats (THBs) in 24-hour Holter ECG monitoring in patients with persistent or permanent AF. METHODS: A total of 13 hypertensive patients (73 ± 12 years, 7 males) with AF and HR 90 bpm or more were enrolled. All patients received carvedilol from 5 mg/day. The dose of drug was titrated every 4 weeks and raised to 10 or 20 mg/day if HR was 80 bpm or more. RESULTS: Mean HR was decreased from 101.9 ± 13.9 to 85.2 ± 15.2 bpm (P < 0.05) after treatment with carvedilol. THBs were also significantly decreased from 128 to 115 × 1,000/day (P < 0.001). Percent reduction in HR and THBs were 13.9% and 10.7%, respectively. The scores of Atrial Fibrillation Quality of Life Questionnaire (AFQLQ) did not change. Only one patient was required to discontinue carvedilol due to congestive heart failure. CONCLUSIONS: We observed that carvedilol certainly reduced HR in patients with chronic AF. We believe that the effect of carvedilol on the reduction in HR can contribute to the management of AF patients treated with rate-control strategy.

DOI： 10.4021/jocmr1581w

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Background: Excess salt intake increases blood pressure (BP). Identifying individuals with excess salt intake is, therefore, important for the prevention of hypertension. Aim: To examine the predictive value of subjective evaluation of salty foods intake for the risk of incident hypertension in a middle-aged population. Methods: A total of 970 non-hypertensive workers (mean age, 44 ± 6 years) was followed for a maximum period of 4 years, and their BP was measured annually. At baseline, all participants were asked about their subjective frequency of salty foods intake (seldom, sometimes or always), and they were divided into three groups according to their answers. Hypertension was defined as systolic/diastolic BP ≥ 140/90mmHg or use of antihypertensive medications. Results: There were no significant differences in the 4-year cumulative incident rate of hypertension among the 'seldom', 'sometimes' and 'always' groups (15.8%, 14.3% and 10.3%, respectively, log-rank test P = 0.44). In a multivariate Cox proportional hazards model, age, body mass index and the baseline BP category were independent predictors for developing hypertension, whereas the frequency of salty foods intake was not a predictor (adjusted hazard ratio (95% confidence interval), 0.99 (0.64-1.54) in the 'sometimes' group and 0.64 (0.33-1.28) in the 'always' group as compared with the 'seldom' group). Conclusion: The subjective evaluation of salty foods intake did not predict the 4-year risk of incident hypertension in this study population. Further investigations with a longer follow-up period are needed to clarify whether the present insignificant results are maintained for more than 4 years. © 2013 Royal Australasian College of Physicians.

DOI： 10.1111/imj.12259

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An enlarged arterial diameter is associated with an increased risk for cardiovascular disease. This study examined the relationship of noninvasively measured brachial artery cross-sectional area with cardiovascular risk factors and arterial stiffness in a middle-aged male population. Absolute volumetric changes of the brachial artery were measured with a newly developed oscillometric method during a general health examination in 387 men (mean age: 38±9 years) without known cardiovascular disease. Based on the measurement, the estimated area (eA) of the brachial artery at end-diastole was obtained. Brachial artery volume elastic modulus (VE) and brachial-ankle pulse wave velocity (baPWV) were simultaneously measured as indices of arterial stiffness by the same device. The relationships of eA with cardiovascular risk factors, including age, obesity, hypertension, dyslipidemia, impaired fasting glucose/diabetes mellitus (IFG/DM), hyperuricemia, smoking and their associated continuous variables, as well as VE and baPWV, were examined. Overall, the mean eA was 12.9 ± 2.9 mm². The eA was significantly higher in subjects with obesity, hypertension or IFG/DM than in those without each of these risk factors. In a multiple linear regression analysis, body mass index (β=0.31, P<0.001), age (β=0.25, P<0.001), systolic blood pressure (β=0.16, P=0.004) and pulse rate (β=-0.13, P=0.005) were independent determinants of eA. In contrast, neither VE nor baPWV were selected as independent determinants of eA. In conclusion, enlarged brachial artery cross-sectional area was significantly associated with cardiovascular risk factors such as age, body mass index and systolic blood pressure, but it was not associated with increased arterial stiffness.

DOI： 10.1038/hr.2013.56

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BACKGROUND: Insulin resistance associated with compensatory hyperinsulinemia plays a significant role in the pathogenesis of cardiovascular diseases, including vasospastic angina (VSA). However, the effects of insulin resistance associated with hyperinsulinemia on the long-term prognosis in patients with VSA remain unclear. METHODS: A total of 265 selected patients with VSA and 56 control subjects with atypical chest pain were enrolled in the present study. Patients with VSA had a positive acetylcholine (ACh) provocation test with normal coronary angiograms, and control subjects had a negative ACh test and normal coronary angiograms. A 75-g oral glucose tolerance test was performed, and the plasma glucose and immunoreactive insulin (IRI) levels were measured before, and 30 min and 120 min (IRI 120) after the 75-g glucose load. RESULTS: During the median follow-up period of 90.0 months, thirty-one patients developed cardiac events, including 6 sudden cardiac deaths and 25 readmissions for acute coronary syndrome. Cardiac events occurred in 38.9% of the patients with an IRI 120 ≥ 80 μU/ml and only 1.6% of the patients with an IRI 120<80 μU/ml (log rank 77.220, p<0.001). A multivariate analysis showed that an IRI 120 ≥ 80 μU/ml (hazard ratio 27.49, 95% confidence interval: 4.66-162.10, p<0.001) was an independent predictor of cardiac events. CONCLUSIONS: These data indicate that insulin resistance associated with compensatory hyperinsulinemia increases the risk of cardiac events in VSA patients.

DOI： 10.1016/j.ijcard.2012.06.016

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DOI： 10.1016/j.jccase.2013.06.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

BACKGROUNDS: Left ventricular (LV) dyssynchrony reduces LV systolic function in patients with heart failure (HF). However, it remains unknown whether this relationship is independent of impaired LV myocardial perfusion. METHODS AND RESULTS: A total of 105 patients with chronic HF (age 71 ± 13 years; 71 men) were enrolled in the present study. (99m)Tc-sestamibi (MIBI) gated myocardial scintigraphy was performed at rest to assess LV myocardial perfusion as evaluated by the total defect score of perfusion Single Photon Emission Computed Tomography images (TDS-MIBI), LV systolic function as evaluated by LV ejection fraction (LVEF), and LV systolic dyssynchrony as evaluated by the maximal difference of time to end systole (MD-TES), which is the time lag between the earliest and the latest end systole among 17 LV segments analyzed with a novel program, "cardioGRAF". The mean ± SD (minimum and maximum range) of the MD-TES was 147.8 ± 117.5 (14.0-458.3)ms. The MD-TES was significantly higher in patients with LVEF<45% (199.4 ± 117.6 ms) than in those with LVEF ≥ 45% (60.5 ± 41.2 ms, p<0.001). In a multiple logistic regression analysis, the MD-TES showed an increased odds ratio for LVEF<45% (2.46 [95% CI; 1.51-4.01] per increment in decile of MD-TES rank, p<0.001), after adjusting for the TDS-MIBI, history of myocardial infarction, and other potential confounders. CONCLUSIONS: LV dyssynchrony is a significant determinant of LV systolic dysfunction in patients with HF, and this relationship is independent of impaired LV myocardial perfusion and history of myocardial infarction.

DOI： 10.1016/j.ijcard.2012.03.091

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

OBJECTIVES: The aim of this study was to examine the relationship between subjective evaluations of the frequency of salty food intake and both urinary sodium excretion and blood pressure (BP) in a middle-aged population. METHODS: Urinary sodium and creatinine concentrations in a spot sample and brachial BP were measured in 419 subjects (mean age 37±9 years, 385 men) during a health examination at a company in Kanagawa, Japan, 2011. Twenty-four-hour urinary sodium excretion was estimated from sodium and creatinine concentrations in the spot sample. The subjects were asked about the frequency of salty food intake on a self-reported questionnaire, choosing their answer from 'seldom', 'sometimes', or 'always' based on their own subjective evaluation. The amount of daily salt intake was converted from 24-h urinary sodium excretion. RESULTS: The prevalence of high salt intake, defined as greater than the daily average salt intake of Japanese according to the National Health and Nutrition Survey in 2010, gradually increased from the 'seldom' to the 'sometimes', and then 'always' categories (10.3, 13.4, and 24.0%, respectively; P=0.013 for trend). The 24-h urinary sodium excretion among these groups also tended to be different; however, the differences did not reach a significantly significant level (145±41, 152±34, and 160±40 mEq/day, respectively; P=0.076). Both systolic and diastolic BP were similar among the groups. CONCLUSIONS: Although some of our findings raise the possibility of a relationship between a subjective evaluation of the frequency of salty food intake and urinary sodium excretion, further studies are needed to confirm the relationship. In contrast, no relationship with BP was found.

DOI： 10.1007/s12199-012-0323-5

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New categorization for patients with dyslipidemia has been proposed in Japanese Atherosclerosis Society Guideline for Prevention of Atherosclerotic Cardiovascular Diseases 2012, in which patients for primary prevention with chronic kidney disease (CKD) are assigned to category III and stricter lipid control are required. However, achievement rates of serum lipid management goals (SLMGs) in patients with CKD are unclear. We retrospectively recategorized 172 outpatients (62±12 years, 87 male/85 female) who received 2.5 mg/day of rosuvastatin. Achievement rates of SLMGs were evaluated in patients with and without CKD. Of 42 patients with CKD, 32 were in category III and 10 were in secondary prevention, whereas 130 patients without CKD were divided into all categories. Overall LDL-C and non HDL-C levels were decreased from 162 ±34 to 102±29mg/dL (p<0.001) and from 193±38 to 127±33mg/dL (p<0.00l). Achievement rates of LDL-C and non HDL-C in all subjects were 80% (67%, 94%, 79% and 58% in each category) and 79% (67%, 96%, 76% and 58%). In 127 patients who were newly treated with a statin, the rates were 88% and 87%, indicating high. In patients with CKD, the rates were 74% and 76%, whereas 82% and 80% in patients without CKD, indicating that the rates were lower in patients with CKD than those without CKD. Especially in selected 15 patients with CKD in category IE who were newly categorized from category n, the rates were 67% and 73%. In conclusions, since the SLMGs in some patients with CKD have been required lower levels according to new categorization, lipid-lowering therapy in patients with CKD may be currently insufficient.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MEDICAL ASSOC NIPPON MEDICAL SCH  

The prognostic value of heart rate variability (HRV) in patients with cardiac conditions has been investigated for many years. However, the HRV is superior to annual health examinations for predicting the longevity of very elderly residents of long-term care facilities is unknown. Annual health examinations and subsequently ambulatory Holter ECG recording were performed in 2008 for 71 very elderly subjects, who were then followed up for 3 to 48 months. The patients were divided into 2 groups on the basis of whether they were alive (86 ± 14 years, n=37) or deceased (90 ± 16 years, n=34) at end of follow-up. To assess cardiac autonomic function, HRV was obtained with the MemCalc/Chiram software program after Holter ECG. Age, sex, body-mass index, plasma levels of C-reactive protein and albumin, and the low-frequency/high-frequency ratio did not differ between the 2 groups. However, the standard deviation of all NN intervals (SDNN) and the coefficient of variation of RR intervals (CVRR) were higher in living subjects than in deceased subjects (SDNN: 73.2 ± 13.5 milliseconds vs. 53.2 ± 9.8 milliseconds, CVRR: 9.3% ± 1.7% vs. 7.6% ± 1.3%, p<0.05). The relative risks with an SDNN <65 milliseconds was 1.85 (p<0.05) and that with a CVRR <8% was 1.84 (p<0.05). Kaplan Meier analysis showed that SDNN and CVRR were useful markers for the longevity of very elderly subjects. The present data suggest that annual health examination data does not predict longevity, but that HRV does. The modulation of parasympathetic tone in daily activities plays an important role in the longevity of very elderly residents of long-term care facilities.

DOI： 10.1272/jnms.80.420

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.1097/JCP.0b013e318240a472

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Objective : The aim of this study is to evaluate the efficacy of rosuvastatin 2.5 mg/day and atrovastatin 10 mg/day on serum lipid parameters in patients with dyslipidemia who have more than middle risk for the primary prevention. We also evaluate the renal safety of these potent statins. Methods : We collected clinical data from patients with dyslipidemia who categorized the risk category II and III of the Japan Atherosclerosis Society Guideline and prescribed rosuvastatin 2.5 mg/day or atrovastatin 10 mg/day for more than eight weeks. We evaluated changes of lipid parameters before and after the treatment, and compared them between two treatment groups. We estimated the proportion of achieving LDL cholesterol (LDL-C) management goal for each risk category. We also evaluated parameters of renal function. Results : Total 77 patients enrolled into the study. LDL-C significantly decreased by 46.3% in rosuvastatin group (RSV) and by 43.3% in atorvastatin group (ATV) (p<0.05, respectively). HDL cholesterol (HDL-C) increased by 5.2% in RSV and by 5.6% in ATV Triglyceride decreased by 2.2% in RSV (not significant) and by 20.8% in ATV (p<0.05). There were no significant differences in changes of all lipid parameters between two groups. The proportions of achieving LDL-C goal in category III were 100% in RSV and 76.9% in ATV. Changes of parameters of renal function were not significantly in both groups. Conclusions : In patients with dyslipidemia who have more than middle risk for the primary prevention, RSV was shown to be equivalent to or more effective than ATV and be safe with no effect on renal function.

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Morning hypertension is a risk for stroke and cardiovascular events. We herein treated hypertensive patients attending an outpatient clinic with cilnidipine and assessed its efficacy against morning hypertension. Cilnidipine was administered to treat 35 patients with hypertension. In addition to their office blood pressure (BP), home BP in 20 patients and 24-hour ambulatory blood pressure monitoring (ABPM) in 5 patients were evaluated. The values of home BP in the morning (M) and the evening (E) were obtained, and ME average ([M+E]/2) and ME difference (M-E) as indicators of morning hypertension were calculated. The patients were divided into four groups based on distribution of ME average and ME difference, a normal blood pressure group (Group I), a morning surge type group (Group II), a sustained hypertension group (Group III), and a morning predominant hypertension group (Group IV). Systolic and diastolic office BP and home BP significantly decreased by cilnidipine. The distribution of patients in groups I, II, III, and IV significantly improved between before treatment (0%, 0%, 72.8%, and 27.2%, respectively) and after 12 weeks of treatment (56.3%, 12.5%, 31.1%, and 0%, respectively) (p=0.020). Systolic BP measured from 6 a.m. to 9 a.m. by ABPM significantly decreased in comparison with before treatment (p = 0.001). In conclusions, a single morning dose of cilnidipine improved morning hypertension as well as office BP, suggesting that it is a very useful antihypertensive drug for the treatment of morning hypertension, which requires strict management.

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Background: Beta-blockers (BB) have been widely used in the management of hypertension and acute myocardial infarction (AMI), and both national and international guidelines have recommended them as first-line agents. Calcium channel antagonists (CCA) are also effective in the treatment of hypertension and angina pectoris. However, the efficacy of CCA in the prevention of cardiovascular events in post-myocardial infarction (MI) patients in comparison to that of BB remains unclear. Methods and Results: A total of 120 post-MI patients (71 patients who were at least 1 month after the onset AMI and 49 stable coronary artery disease patients with a history of MI) were randomly assigned to receive a BB (atenolol, 25-50 mg/day, n=60) or a CCA (benidipine, 4-8 mg/day, n=60). All patients with AMI within the previous 1 month or with vasospastic angina were excluded from the present study. The baseline clinical characteristics were generally similar in the BB and CCA groups. The rate of primary composite outcome was 26.3% in the BB group in comparison to 13.3% in the CCA group, with no significant between-group differences (hazard ratio with the CCA group 0.640, P=0.276). Both treatments were well tolerated with few severe adverse events. Conclusions: CCA treatment was found to be as effective as BB in reducing cardiovascular events in post-MI patients.

DOI： 10.1253/circj.CJ-10-1078

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Variant angina is a form of angina pectoris that shows transient ST-segment elevation on electrocardiogram during an attack of chest pain. Ischemic episodes of variant angina show circadian variation and often occur at rest from midnight to early morning. Ischemic episodes also occur during mild exercise in the early morning. However, they are not usually induced by strenuous exercise in the afternoon. Other important clinical features of variant angina include the high frequency of asymptomatic ischemic episodes and the syncope that sometimes occur during the ischemic episodes. Syncope is due to severe arrhythmias, including ventricular tachycardia, ventricular fibrillation, and high-degree atrioventricular block. Coronary artery spasm is the mechanism of ischemic episodes in variant angina. The incidence of coronary artery spasm shows a racial difference and is higher in Japanese than in Caucasians. Coronary arteriograms are normal or near-normal in most Japanese patients with variant angina. Deficient basal release of nitric oxide (NO) due to endothelial dysfunction, and enhanced vascular smooth muscle contractility with the involvement of the Rho/Rho-kinase pathway are reported to play important roles in the pathogenesis of coronary artery spasm. Other precipitating factors of coronary artery spasm include imbalance in autonomic nervous activity, increased oxidative stress, chronic low-grade inflammation, magnesium deficiency, and genetic susceptibility. The genetic risk factors associated with coronary artery spasm include gene polymorphisms of endothelial NO synthase (NOS), paraoxonase, and other genes. Calcium channel blockers are extremely effective in preventing coronary spasm. The long-acting nitrate, nicorandil, and Rho-kinase inhibitor are also useful for inhibiting coronary artery spasm. Because variant angina can lead to acute myocardial infarction, fatal arrhythmias, and sudden death, early treatment is important. The prognosis of patients with variant angina is favorable, if early complications can be overcome. However, because coronary artery spasm cannot be suppressed in some patients, even with multiple medications, medications to suppress intractable coronary artery spasm must be developed.

DOI： 10.1272/jnms.78.4

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DOI： 10.1253/circj.CJ-10-0526

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Proinflammatory cytokine responses might occur in elderly individuals with cardiovascular (CV) disease, cerebro-vascular (CVA) disease, and/or pulmonary disease (PD). Spiritual activation is an important coping mechanism, since psychiatric depression is an important risk factor for these individuals. Thirty-three very elderly individuals (87 ± 8 years) with previous CVD, CVA and/or PD participated in weekly 30 minute sermons by chaplains for over 20 months of chaplain liturgy (CL group). All underwent Holter ECG during the procedures and cardiac autonomic activities were assessed by maximum entropy analysis. Plasma IL-10 and IL-6 levels were compared with 26 age-matched (85 ± 10 years) individuals who did not participate in these activities (non-CL group). Both high frequency (HF) and pNN50 of heart rate variability (HRV) were higher in the CL group than in the non-CL group (HF, 190 ± 55 versus 92 ± 43 nu, P < 0.05; pNN50, 10.5 ± 16% versus 3.6 ± 3.8%, P < 0.05), whereas LF/HF was lower (1.4 ± 1.5 versus 2.2 ± 2.8, P < 0.05). Levels of IL-10/IL-6 were higher in the CL group (3.96 ± 5.0 versus 1.79 ± 1.6, P < 0.05). Hospitalization rates due to CVD and/or PD were lower in the CL group than in the non-CL group (4/33 versus 11/26, P < 0.05). We conclude that spiritual activation can modify proinflammatory cytokines and suppress CVD, CVA and/or PD via vagal modifications. Spiritual activation might be helpful for health in these very elderly individuals.

DOI： 10.1536/ihj.52.299

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International Normalized Ratio of Prothrombin time (INR) is widely used for the appropriate oral anticoagulant therapy with warfarin in patients with atrial fibrillation. The INR values are affected by International Sensitivity Index (ISI) of the reagent since the INR is calculated by (PT ratio) ISI. Although the thromboplastin reagent with ISI indicated nearly 1.0 is recommended, high-ISI reagents with over 1.5 of ISI were employed in total up to 23% in the registered institutions of J-RHYTHM Registry. Furthermore, there were significant differences in the average values of ISI and the daily warfarin dose among ten geographical divisions. Therefore, we investigated the influence of high-ISI reagents on the daily warfarin dose. The average values of ISI, INR, and warfarin dose were 1.20±0.28, 1.9±0.5, and 2.9±1.2 mg/day, respectively. The average daily warfarin dose negatively correlated with the ISI values (R=-0.22, P=0.007). The average daily warfarin dose in the institutions employed high-ISI reagents were significant lower than that in the institutions with less than 1.5 of ISI (2.6±0.4 vs. 2.9±0.4 mg/day, P=0.001). In conclusions, these data suggested that high-ISI reagents should be avoided for clinical use. © 2011, Japanese Heart Rhythm Society. All rights reserved.

DOI： 10.4020/jhrs.27.OP50_2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC  

Cigarette smoking impairs arterial function and promotes atherosclerosis. However, whether smoking status is associated with cardiac overload has not yet been fully examined, particularly from an epidemiologic viewpoint. The present study examined the relation of smoking status to serum levels of N-terminal probrain natriuretic peptide (NTpro-BNP), a marker of cardiac overload, in middle-aged men without overt cardiovascular disease. Serum NTpro-BNP levels were measured in a work-site based population of 969 men (mean age 44 ± 6 years) who did not have any history or presence of cardiovascular disease. Smoking status was evaluated by self-reported questionnaire. Four hundred fifty-nine, 222, and 288 subjects were never, former, and current smokers, respectively. NTpro-BNP levels were significantly higher in current smokers (21.7 ± 2.3 pg/ml) than in never smokers (17.9 ± 2.1 pg/ml, p <0.001). This significant difference was maintained even after adjusting for age, obesity, heart rate, hypertension, dyslipidemia, impaired fasting glucose/diabetes mellitus, left ventricular hypertrophy, estimated glomerular filtration rate, high-sensitivity C-reactive protein, alcohol consumption, and regular exercise. Current smokers had an increased odds ratio (3.04, 95% confidence interval 1.64 to 5.61, p <0.001) for elevated NTpro-BNP (>54.5 pg/ml) compared to never smokers, even after adjusting for the studied variables. In contrast, former smokers did not show a significantly increased odds ratio for elevated NTpro-BNP. NTpro-BNP levels showed a weak, but significant negative correlation with duration of smoking cessation (partial r = -0.15, p = 0.034) in former smokers. In conclusion, these results suggest that cigarette smoking increases cardiac overload, whereas smoking cessation ameliorates these conditions. © 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjcard.2010.06.075

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The prevalence of coronary artery disease (CAD) in patients with peripheral arterial disease (PAD) approaches 50%. The incidence of perioperative cardiac complications is high in patients undergoing peripheral vascular surgery (PVS). However, the long-term efficacy of coronary artery revascularization in patients with PAD prior to PVS remains controversial. We retrospectively analyzed the long-term outcomes of 114 patients who underwent elective PVS. Coronary angiography (CAG) was performed routinely in all patients prior to the surgery. Preoperative CAG revealed CAD in 52 patients and no CAD in 62 patients (No-CAD group). Of the 52 patients with CAD, 15 patients with effort angina (more than CCS class 2), myocardial ischemia proven by pharmacological stress scintigraphy, and/or multivessel disease with impaired left ventricular systolic function underwent coronary revascularization (CAD-R group). The remaining 37 patients with CAD were treated medically (CAD-M group). The rates of postoperative events within 30 days were 26.7% in the CAD-R group, 10.8% in the CAD-M group, and 8.1% in the No-CAD group, respectively (P = 0.13), and the rates of long-term cardiovascular events were 33.3, 21.6, and 21.0%, respectively (P = 0.60). Therefore, the acute and long-term clinical outcomes in the CAD-R group were comparable with the other groups. In this study, the patients with CAD who showed inducible myocardial ischemia and/or multivessel disease with impaired left ventricular systolic function underwent coronary artery revascularization prior to the elective PVS. The patients who underwent coronary revascularization prior to the PVS exhibited comparable long-term outcomes compared with the patients who showed CAD but without inducible myocardial ischemia and with those without CAD. These data suggest that the evaluation of CAD and myocardial ischemia to determine the therapeutic strategy for CAD before elective PVS would be needed.

DOI： 10.1007/s12928-009-0001-8

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We report a case who had confirmed tumor cells in the biopsy specimens by transvenous endomyocardial biopsy with intra-procedural consultation and fast smear cytology. A 57-year-old female was admitted to our hospital because of shortness of breath and left back pain. Transthoracic echocardiography (TTE) and contrast-enhanced computed tomography (CT) scans demonstrated a large mass in the right atrium and multiple liver tumors thought to be due to spread of the disease. Coronary angiography showed the right coronary artery was involved in the mass. In order to confirm the histological diagnosis, we attempted transvenous endomyocardial tumor biopsy under fluoroscopic guidance. However, we failed to obtain adequate tissue material. Due to several risks associated with a surgical procedure such as an open surgical biopsy, transvenous endomyocardial tumor biopsy was again attempted with the aid of transesophageal echocardiography (TEE). Intra-procedural consultation and fast smear cytology enabled us to finish the procedure. Hematoxylineosin stained sections demonstrated spindle-shaped cells. Immunohistochemical stains of these cells were positive for anti-factor VIII antigen, CD31, and CD34. These findings indicated a definite diagnosis of angiosarcoma. Since there was no surgical indication for this tumor, the patient underwent chemotherapy with docetaxel and radiotherapy. Three months later, CT scans showed a reduction in the size of the cardiac tumor.

DOI： 10.1536/ihj.51.367

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Background: Rapid and accurate methods for screening are necessary for the diagnosis of acute cardiovascular diseases (ACVD), including acute coronary syndrome (ACS), pulmonary thromboembolism, and acute aortic dissection. In this study, the utility of rapid D-dimer measurement for the screening of ACVD was evaluated. Methods and results: Consecutive 279 emergent patients in whom ACVD was suspected or not ruled out were enrolled. The median D-dimer concentration of ACVD group (1.10 μg/ml) was significantly higher than that in the non-ACVD group (0.69 μg/ml, p < 0.05). Sensitivity, specificity, positive predictive value, and negative predictive value of D-dimer (with cut-off level of 0.75 μg/ml) for the discrimination of ACVD from non-ACVD was 75%, 55%, 38%, and 85%, respectively. In ACVD group, the level of D-dimer in the large vessel disease subgroup was significantly higher than that in the ACS subgroup (6.99 μg/ml and 0.89 μg/ml, respectively; p < 0.05). The well-balanced cut-off point for discriminating the two subgroups was D-dimer level of 5.0 μg/ml. D-dimer (with cut-off level of 0.75 μg/ml) showed significantly higher positive test rate for the detection of ACS in very early phase (within 2 h from the onset) compared with troponin T (p < 0.05). Conclusions: Rapid measurement of D-dimer is useful for the screening of ACVD in the emergency setting. © 2009 Japanese College of Cardiology.

DOI： 10.1016/j.jjcc.2008.12.001

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Music therapy (MT) has been used in geriatric nursing hospitals, but there has been no extensive research into whether it actually has beneficial effects on elderly patients with cerebrovascular disease (CVD) and dementia. We investigated the effects of MT on the autonomic nervous system and plasma cytokine and catecholamine levels in elderly patients with CVD and dementia, since these are related to aging and chronic geriatric disease. We also investigated the effects of MT on congestive heart failure (CHF) events. Eighty-seven patients with pre-existing CVD were enrolled in the study. We assigned patients into an MT group (n = 55) and non-MT group (n = 32). The MT group received MT at least once per week for 45 minutes over 10 times. Cardiac autonomic activity was assessed by heart rate variability (HRV). We measured plasma cytokine and catecholamine levels in both the MT group and non-MT group. We compared the incidence of CHF events between these two groups. In the MT group, rMSSD, pNN50, and HF were significantly increased by MT, whereas LF/HF was slightly decreased. In the non-MT group, there were no significant changes in any HRV parameters. Among cytokines, plasma interleukin-6 (IL-6) in the MT group was significantly lower than those in the non-MT group. Plasma adrenaline and noradrenaline levels were significantly lower in the MT group than in the non-MT group. CHF events were less frequent in the MT group than in the non-MT group (P < 0.05). These findings suggest that MT enhanced parasympathetic activities and decreased CHF by reducing plasma cytokine and catecholamine levels.

DOI： 10.1536/ihj.50.95

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To clarify the significance of adenosine triphosphate disodium stress myocardial perfusion imaging (ATP-MPI), we directly compared the findings of ATP-MPI with those of exercise stress myocardial perfusion imaging (Ex-MPI). ATP-MPI, Ex-MPI, and coronary angiography (CAG) were performed within 60 days in 17 coronary artery disease patients with mean age of 62.1 ± 7.9 years. CAG revealed single-vessel disease (SVD) in 10 patients and multivessel disease (MVD) in seven patients. The summed stress score (SSS) of ATP-MPI was significantly higher than that of Ex-MPI (10.0 [7.8-14.3] vs. 8.0 [4-18], P < 0.05). No difference in the SSS was observed between ATP-MPI and Ex-MPI in patients with SVD (8.0 [6.0-9.0] vs. 8.0 [6.0-10.0], NS), whereas this difference was significant in patients with MVD (15.0 [14.0-22.8] vs.9 [7.3-16.3], P < 0.05). There was no difference in the summed rest score between ATP-MPI and Ex-MPI. The univariate logistic analysis showed that "MVD" was the significant factor influencing to the overt discrepancy between ATP-MPI and Ex-MPI (odds ratio: 9.0, 95% confidence interval: 1.07-75.84, P = 0.043). The accuracy of ATP-MPI and Ex-MPI in detecting the territory of stenotic coronary vessel or previous myocardial infarction was 98.0% and 92.1% (NS), respectively. In conclusion, ATP-MPI is useful for detecting potential ischemic areas that cannot be detected by Ex-MPI, particularly in patients with MVD. © 2008 Japanese College of Cardiology.

DOI： 10.1016/j.jjcc.2008.04.001

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

BACKGROUND: The Rho/Rho-kinase signaling pathway is known to be involved in the pathogenesis of coronary artery spasm. Previous studies reported the efficacy of the Rho-kinase inhibitor, fasudil, in the prevention and relief of coronary spasm. The usefulness of fasudil in combination with conventional vasodilating agents, however, has not been fully examined in patients with vasospastic angina. METHODS AND RESULTS: A total of 26 patients (mean age, 61±11 years) with documented vasospasm in the left anterior descending coronary artery were examined by the acetylcholine stress test. Coronary diameter at the spasm site was measured at baseline and after the administration of vasodilator agents in the following order: intracoronary nitroglycerin (NTG) (300 μg), intravenous fasudil (30 mg, n=15, fasudil group) or saline (n=11, saline group), and again NTG during coronary angiography. The increase in diameter observed following the first NTG administration was found to be similar in the fasudil and saline groups (38.3±23.5% and 42.3±17.1%, respectively). The additional change in diameter on fasudil treatment (16.9±11.2% increase over the diameter after the first NTG administration) was significantly larger than that with saline (-2.8±7.6%, P<0.001). The second administration of NTG did not affect the diameter of the spasm site in either group. CONCLUSIONS: Fasudil further dilated the site of coronary spasm, which had already been treated with NTG in patients with vasospastic angina. These findings support and extend the previous results that showed the feasibility of employing fasudil as a novel therapeutic approach for coronary spasm. © 2008 Lippincott Williams & Wilkins, Inc.

DOI： 10.1097/MCA.0b013e3282f3420c

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

A 52-year-old man with Down's syndrome was implanted with a DDDR pacemaker for advanced atrioventricular block. He was admitted with development of skin eczema and partial exposure of the generator 1 year after reimplantation. There was no evidence of infection on laboratory data. A skin patch test was positive for the metal of the generator (purity 99.9% titanium) after 72 hours. These findings indicated pacemaker contact dermatitis. After the patient was reimplanted with a pacemaker wrapped with a polytetrafluoroethylene sheet, there has been no recurrence of the contact dermatitis during a follow-up period of 3 years. © 2006, The Authors.

DOI： 10.1111/j.1540-8159.2006.00535.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE CIRCULATION SOCIETY  

Background: Recent studies have suggested that the Rho/Rho-kinase mediated pathway (Rho-kinase pathway) regulates the vasomotion of arteries in pathological conditions. However, it remains unclear regarding whether this pathway regulates the coronary vasomotion of atherosclerotic lesions. Methods and Results: The coronary diameter at the concentric stenotic site, which is considered to reflect the whole circumferential atherosclerosis, in patients with stable angina pectoris (SAP; n=11) and the control site in patients with SAP and chest pain syndrome (CPS; n=9), was measured at baseline and after the intracoronary administration of nitroglycerin (200 μg) and the subsequent intravenous infusion of fasudil (30 mg for 30 min), a Rho-kinase inhibitor, during coronary angiography. The change in the diameter with fasudil at the concentric stenotic site (22.0±10.0%) was significantly higher than that with nitroglycerin (4.7±6.0%, p<0.001) in patients with SAP. Meanwhile, the vasodilatory effect of nitroglycerin and fasudil at the control site was similar in both group of patients (25.5±17.3% and 21.9±14.9% in SAP and 34.4±20.8% and 33.2±23.6% in CPS, respectively). Conclusions: The vasodilatory effect of the subsequent administration of fasudil surpassed that of nitroglycerin at the concentric coronary stenosis in patients with SAP, thus suggesting that the Rho-kinase pathway regulates the coronary vasomotion of atherosclerotic lesions.

DOI： 10.1253/circj.70.402

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INTERNATIONAL HEART JOURNAL ASSOCIATION  

Bradykinin (BK) is one of the triggers of ischemic preconditioning. Protein kinase C (PKC) and mitochondrial ATP-dependent potassium (KATP) channels are central factors in cardioprotection afforded by BK. However, the role of nitric oxide (NO) in the early phase protection of preconditioning with BK is not well understood. We assessed the signaling pathway of the early phase protection of pharmacological preconditioning afforded by BK. Isolated perfused rat hearts (n = 8/ group) were subjected to 30-minute global ischemia and 50-minute reperfusion. Left ventricular systolic pressure (LVSP) was recorded prior to the global ischemia and at the end of reperfusion. Preconditioning with BK was induced by two cycles of 5-minute infusion of BK (0.5 μmol/L) and 5-minute washout prior to the global ischemia. To examine participants in the signaling pathway, 5-hydroxydecanoate (5-HD), 200 μmol/L), chelerythrine (CH, 5 μmol/L), or Nω-nitro-Larginine methyl ester (L-NAME, 50 μmol/L) was added to the perfusate for 5 minutes prior to the infusion of BK. Pharmacological preconditioning by BK improved postischemic recovery of LVSP (+ 45.1% versus control, P < 0.01). Protection by BK was abolished by coadministration of CH, 5-HD, or L-NAME. BK affords myocardial protection in the early phase of pharmacological preconditioning through a pathway that includes endogenous NO, PKC, and mitochondrial KATP channels. Copyright © 2005 by the International Heart Journal Association.

DOI： 10.1536/ihj.46.877

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background - Although the late phase of ischemic preconditioning (PC) is known to confer cardioprotection in healthy animal models, it is unknown whether this phenomenon exists in the presence of hypercholesterolemia. The goal of this study was to determine whether the infarct-sparing effect of late PC is affected by hypercholesterolemia and, if so, whether a tetrahydrobiopterin (BH4)-dependent mechanism is responsible for the loss of late PC. Methods and Results - Conscious rabbits fed a normal diet or a 1% cholesterol diet for 6 weeks were subjected to ischemic PC (six 4-minute coronary occlusion/4-minute reperfusion cycles) and, 24 hours later, underwent a 30-minute occlusion followed by 3 days of reperfusion. A total of 125 rabbits were used. In normocholesterolemic rabbits, ischemic PC reduced infarct size, an effect that was abrogated by administration of the BH4 synthesis inhibitor N-acetylserotonin (15 mg/kg IV) before the 30-minute occlusion. In hypercholesterolemic rabbits, however, ischemic PC failed to reduce infarct size. Myocardial BH4 levels in the ischemic zone increased 24 hours after ischemic PC in normocholesterolemic rabbits but not in hypercholesterolemic rabbits. In addition, in normocholesterolemic rabbits, pretreatment with N-acetylserotonin completely abolished the ischemic PC-induced increase in myocardial BH4 levels. Conclusions - This study demonstrates that (1) hypercholesterolemia abrogates both the infarct-sparing effect of late PC and the concomitant upregulation of myocardial BH4, and (2) inhibition of myocardial BH4 synthesis in the absence of hypercholesterolemia is sufficient to abolish the infarct-sparing effect of late PC. The results support the concept that hypercholesterolemia abrogates late PC by preventing the upregulation of BH4, an essential cofactor for inducible nitric oxide synthase. © 2005 American Heart Association, Inc.

DOI： 10.1161/CIRCULATIONAHA.105.566190

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

The infarct-sparing effect of the late phase of ischemic preconditioning (late PC) lasts for 72 hours. Upregulation of both cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) has been shown to be essential to the protection in the initial stage of late PC (24 hours after PC); however, the mechanisms underlying the protection in the final stage of late PC (48 to 72 hours after PC) are unknown. Conscious rabbits were preconditioned with six cycles of 4-minute coronary occlusion/4-minute reperfusion. At 72 hours after PC, powerful protection against infarction was associated with increased myocardial levels of COX-2 mRNA, protein, and cardioprotective prostaglandins (PGI2 and PGE2). The COX-2-selective inhibitor NS-398 completely blocked the protection. Surprisingly, iNOS expression was not increased at 72 hours; instead, upregulation of neuronal NO synthase (nNOS) was evident at both the mRNA (+266±20%, P>0.005) and the protein levels (+195±66%, P<0.005), which was accompanied by an increase in myocardial nitrite/nitrate (+20±4%, P<0.05). The nNOS-selective inhibitors N-propyl-L-arginine or S-ethyl N-[4-(trifluoromethyl)phenyl]isothioarea completely blocked the protection of late PC at 72 hours, whereas the iNOS-selective inhibitor S-methylisothiourea had no effect. In line with these findings, the disappearance of protection at 120 hours after PC was associated with the return of nNOS mRNA, protein, and activity to control levels. Although expression of COX-2 protein was still elevated at 120 hours, only a marginal increase in PGI2 and PGE2 levels was detected. In contrast to 72 hour after PC, nNOS was not upregulated at 24 hour after PC. We conclude that (1) the cardioprotection observed in the final stage of late PC (72 hour) is mediated by nNOS, not by iNOS, in concert with COX-2, and (2) nNOS-derived NO is required to drive COX-2 activity. These data identify, for the first time, a cardioprotective role of nNOS and demonstrate, surprisingly, that the mechanism of late PC differs at 72 hours (nNOS) versus 24 hours (iNOS).

DOI： 10.1161/01.RES.0000133679.38825.a6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Although protein tyrosine kinases (PTKs) signaling has been implicated in the late phase of ischemic preconditioning (PC), it is unknown whether PTK signaling is necessary for the development of nitric oxide (NO) donor-induced late PC. Thus conscious rabbits underwent a sequence of six 4-min coronary occlusion (O)/4-min reperfusion (R) cycles followed by a 5-h recovery period of reperfusion for 3 consecutive days (days 1, 2, and 3). On day 0 (24 h before the 6 O/R cycles on day 1), rabbits received no treatment (control), the NO donor diethylenetriamine (DETA)/NO (DETA/NO), the PTK inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), or DETA/NO plus PP2 (DETA/NO + PP2). In control rabbits (n = 6), the six O/R cycles on day 1 resulted in delayed functional recovery, indicating severe myocardial stunning. In rabbits pretreated with DETA/NO (n = 5) on day 1, myocardial stunning caused by the six O/R cycles on day I was markedly attenuated, with a significant reduction (-60%) in the total deficit of wall thickening (WTh) compared with controls, indicating that DETA/NO induced a late PC effect against stunning. However, in rabbits pretreated with DETA/NO + PP2 (n = 5), the total deficit of WTh was significantly greater than that in rabbits treated with DETA/NO alone and was similar to that in controls, indicating that PP2 prevented the development of DETA/NO-induced late PC. In rabbits pretreated with PP2 on day 0 (n = 4), the total deficit of WTh was similar to that in controls, indicating that PP2 does not affect myocardial stunning in itself. We conclude that a PTK-dependent signaling mechanism is necessary for the development of NO donor-induced late PC against myocardial stunning in conscious rabbits.

DOI： 10.1152/ajpheart.00789.2002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

OBJECTIVES: The goal of this study was to investigate the effect of three different doses of acetylsalicylic acid (aspirin) (ASA) on the late phase of ischemic preconditioning (PC) against myocardial stunning. BACKGROUND: Although recent evidence indicates that the late phase of ischemic PC is mediated by cyclooxygenase-2 (COX-2), the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit COX-2 activity on late PC has not been evaluated; ASA is the most widely used NSAID. Therefore, we determined whether ASA impedes the development of late PC. METHODS: Conscious rabbits underwent a protocol consisting of three days of six 4-min coronary occlusion/4-min reperfusion cycles. RESULTS: Neither 5 mg/kg nor 10 mg/kg x 3 of ASA interfered with the protective effects of late PC against stunning. In contrast, the late PC effect was completely abrogated by 25 mg/kg of ASA. Low-dose (5 mg/kg) ASA effectively inhibited platelet aggregation but did not prevent the increase in COX-2 activity, whereas the highest dose (25 mg/kg) completely blocked COX-2 activity. CONCLUSIONS: The administration of ASA either at antithrombotic doses (5 mg/kg), which are widely used to prevent cardiovascular events in patients, or at analgesic/antipyretic doses (10 mg/kg) does not interfere with the cardioprotective effects of late PC against myocardial stunning. In contrast, high doses of ASA (25 mg/kg), which are used as antirheumatic therapy, abrogate both COX-2 activity and late PC, suggesting that nonselective doses of NSAIDs should be used with caution in patients with atherosclerotic cardiovascular disease because they may deprive the heart of its innate defensive response. © 2003 by the American College of Cardiology Foundation.

DOI： 10.1016/S0735-1097(03)00086-X

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Although activation of δ-opioid receptors is known to induce both early and late preconditioning (PC) against myocardial infarction, the mechanisms for this salubrious effect are unclear. Furthermore, it is unknown whether δ-opioid receptors can also induce late PC against myocardial stunning. By using conscious rabbits (n = 120) in this study, we found that the δ-opioid receptor agonist (±)-4-{(α-R*)- α-[(2S*,5R*)- 4-allyl-2,5-dimethyl-1-piperazinyl]-3-hydroxybenzyl}-N,N-diethylbenzamide (BW-373U86) induced late PC against myocardial stunning 24 h after treatment and that this effect was abolished by the selective cyclooxygenase-2 (COX-2) inhibitors N-[2-(cyclohexyloxy)4-nitrophenyl]methanesulfonamide (NS-398) and celecoxib. This protective effect was also abrogated by the selective δ1-opioid receptor antagonist 7-benzylidenenaltrexone, indicating that the δ1-opioid receptor is necessary for BW-373U86-induced late PC. BW-373U86 did not induce early PC against stunning. In addition, BW-373U86 induced late PC against infarction, which was blocked by NS-398. At 24 h after BW-373U86 administration, myocardial COX-2 protein expression and PGE2 and 6-keto-PGF1α levels were significantly increased. These results demonstrate that activation of δ-opioid receptors induces late PC against both stunning and infarction via a COX-2-dependent mechanism.

DOI： 10.1152/ajpheart.00150.2002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been shown to metabolize toxic aldehydes generated by lipid peroxidation, suggesting that it may serve as an antioxidant defense. To investigate its role in the late phase of ischemic preconditioning (PC), conscious rabbits underwent 6 cycles of 4-minute coronary occlusion/4-minute reperfusion. Twenty-four hours later, there was a marked increase in AR protein and activity and in the myocardial content of sorbitol, a unique product of AR catalysis. Pretreatment with Nω-nitro-L-arginine, a nitric oxide synthase inhibitor, or chelerythrine, a protein kinase C inhibitor (both given at doses that block late PC in this model), prevented the increase in AR protein 24 hours later, demonstrating that ischemic PC upregulates AR via nitric oxide- and protein kinase C-dependent signaling pathways. The AR-selective inhibitors tolrestat and sorbinil prevented AR-mediated accumulation of sorbitol and abrogated the infarct-sparing effect of late PC, demonstrating that enhanced AR activity is necessary for this cardioprotective phenomenon to occur. Inhibition of AR did not affect infarct size or the myocardial accumulation of the lipid peroxidation product 4-hydroxy trans-2-nonenal (HNE) in nonpreconditioned rabbits. The accumulation of HNE was inhibited by late PC, and this effect was abrogated by sorbinil. Taken together, these results establish AR as an essential mediator of late PC. Furthermore, the data suggest that myocardial ischemia/reperfusion injury is due in part to the generation of lipid peroxidation products and that late PC diminishes this source of injury by upregulating AR.

DOI： 10.1161/01.RES.0000029970.97247.57

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Background - Although NO has been shown to serve both as the trigger and the mediator of the late phase of ischemic preconditioning (PC), it is unknown whether NO acts via activation of soluble guanylate cyclase (sGC). The objective of this study was to investigate the role of sGC in late PC in conscious rabbits using the selective sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Methods and Results - A total of 172 conscious rabbits were used. When nonpreconditioned rabbits were subjected to a sequence of 4-minute coronary occlusion/4-minute reperfusion cycles, myocardial cyclic guanosine monophosphate (cGMP) levels increased significantly at the end of the third and sixth occlusions. In rabbits preconditioned 24 hours earlier (on day 1) with six occlusion/reperfusion cycles, myocardial cGMP levels on day 2 were significantly higher than in nonpreconditioned rabbits even before ischemia but did not increase further during a second sequence of 4-minute occlusion/reperfusion cycles. Administration of ODQ before the six occlusion/reperfusion cycles on day 1 did not prevent the development of late PC against either stunning or infarction on day 2. In contrast, administration of ODQ on day 2 completely ablated the late PC effect against both stunning and infarction. Conclusions - These results indicate that enhanced synthesis of cGMP by sGC is not necessary for ischemia to trigger a late PC effect but is required for the protection to become manifest 24 hours later. This implies that NO participates in late PC via two distinct mechanisms; ie, it triggers late PC on day 1 via a cGMP-independent mechanism and it mediates late PC on day 2 via a cGMP-dependent mechanism.

DOI： 10.1161/01.CIR.0000019408.67709.B5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Cyclooxygenase-2 (COX-2) is known to mediate the cardioprotective effects of the late phase of ischemic preconditioning (PC); however, the signaling pathways involved in COX-2 induction following ischemic PC are unknown. In addition, although inducible nitric oxide synthase (iNOS) has been identified as a co-mediator of late PC together with COX-2, the interaction between iNOS and COX-2 in the heart is unknown. Using conscious rabbits, we found that the induction of COX-2 expression 24 hours after ischemic PC was blocked by pretreatment with inhibitors of protein kinase C (PKC), Src protein tyrosine kinases (PTKs), and nuclear factor-κB (NF-κB) but not by inhibitors of NOS or scavengers of reactive oxygen species (ROS). The selective iNOS inhibitors SMT and 1400W, given 24 hours after PC, abrogated the increase in myocardial prostaglandin E2 (PGE2) and 6-keto-PGF1α, whereas the selective soluble guanylate cyclase inhibitor ODQ had no effect. COX-2 selective inhibitors (celecoxib and NS-398) did not affect iNOS activity. These results demonstrate that (i) ischemic PC upregulates cardiac COX-2 via PKC-, Src PTK-, and NF-κB-dependent signaling pathways, whereas generation of NO and ROS is not necessary, and (ii) the activity of newly synthesized COX-2 following PC requires iNOS-derived NO whereas iNOS activity is independent of COX-2-derived prostanoids, indicating that COX-2 is located downstream of iNOS in the protective pathway of late PC. The data also indicate that iNOS modulates COX-2 activity via cGMP-independent mechanisms. To our knowledge, this is the first demonstration that iNOS-derived NO drives prostanoid synthesis by COX-2 in the heart. NO-mediated activation of COX-2 may be a heretofore unrecognized mechanism by which NO exerts its salubrious effects in the late phase of PC.

DOI： 10.1161/01.RES.0000012202.52809.40

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Language：English   Publisher：ELSEVIER SCIENCE BV  

More than 10 years after its discovery, the function of cyclooxygenase-2 (COX-2) in the cardiovascular system remains largely an enigma. Many scholars have assumed that the allegedly detrimental effects of COX-2 in other systems (e.g. proinflammatory actions and tumorigenesis) signify a detrimental role of this protein in cardiovascular homeostasis as well. This view, however, is ill-founded. Recent studies have demonstrated that ischemic preconditioning (PC) upregulates the expression and activity of COX-2 in the heart, and that this increase in COX-2 activity mediates the protective effects of the late phase of PC against both myocardial stunning and myocardial infarction. An obligatory role of COX-2 has been observed in the setting of late PC induced not only by ischemia but also by δ-opioid agonists and physical exercise, supporting the view that the recruitment of this protein is a central mechanism whereby the heart protects itself from ischemia. The beneficial actions of COX-2 appear to be mediated by the synthesis of PGE2 and/or PGI2. Since inhibition of iNOS in preconditioned myocardium blocks COX-2 activity whereas inhibition of COX-2 does not affect iNOS activity, COX-2 appears to be downstream of iNOS in the protective pathway of late PC. The results of these studies challenge the widely accepted paradigm that views COX-2 activity as detrimental. The discovery that COX-2 plays an indispensable role in the anti-stunning and anti-infarct effects of late PC demonstrates that the recruitment of this protein is a fundamental mechanism whereby the heart adapts to stress, thereby revealing a novel, hitherto unappreciated cardioprotective function of COX-2. From a practical standpoint, the recognition that COX-2 is an obligatory co-mediator (together with iNOS) of the protection afforded by late PC has implications for the clinical use of COX-2 selective inhibitors as well as nonselective COX inhibitors. For example, the possibility that inhibition of COX-2 activity may augment myocardial cell death by obliterating the innate defensive response of the heart against ischemia/reperfusion injury needs to be considered and is the object of much current debate. Furthermore, the concept that the COX-2 byproducts, PGE2 and/or PGI2, play a necessary role in late PC provides a basis for novel therapeutic strategies designed to enhance the biosynthesis of these cytoprotective prostanoids in the ischemic myocardium. From a conceptual standpoint, the COX-2 hypothesis of late PC expands our understanding of the function of this enzyme in the cardiovascular system and impels a critical reassessment of current thinking regarding the biologic significance of COX-2. © 2002 Elsevier Science B.V. All rights reserved.

DOI： 10.1016/S0008-6363(02)00414-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Although Src protein tyrosine kinases (PTKs) have been shown to be essential in late preconditioning (PC) against myocardial stunning, their role in triggering versus mediating late PC against myocardial infarction remains unclear. Four groups of conscious rabbits were subjected to a 30-min coronary occlusion on day 2, with or without PC ischemia on day 1. Administration of the Src PTK inhibitor lavendustin A (LD-A; 1 mg/kg iv) before the PC ischemia on day 1 (group III, n = 7) failed to block the delayed protective effect against myocardial infarction 24 h later. Late PC against infarction, however, was completely abrogated when LD-A was given 24 h after the PC ischemia, prior to the 30-min occlusion on day 2 (group IV, n = 8). We conclude that, in conscious rabbits, Src PTK activity is necessary for the mediation of late PC protection against myocardial infarction on day 2, but not for the initiation of this phenomenon on day 1. Taken together with previous studies in the setting of stunning, these findings reveal heretofore unrecognized differences in the roles of Src PTKs in late PC against stunning versus late PC against infarction.

DOI： 10.1152/ajpheart.00873.2001

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Background - Recent studies suggest that the late phase of ischemic preconditioning (PC) can be mimicked by pretreatment with NO donors. The ability of clinically relevant NO donors to induce PC against infarction, however, has not been evaluated. Furthermore, it is unknown whether tolerance to the hemodynamic actions of nitrates also extends to their PC effects. Methods and Results - Conscious rabbits underwent a 30-minute coronary occlusion and 3 days of reperfusion. A 60-minute intravenous (IV) infusion of nitroglycerin (NTG) ending 1 hour before occlusion reduced infarct size, indicating an early PC effect. When the time interval between NTG infusion and occlusion was extended to 24 or 72 hours, the infarct-sparing action of NTG became even more pronounced, indicating a robust late PC effect. Transdermal NTG patches elicited a late PC effect that was (1) equivalent to that induced by IV NTG, demonstrating the efficacy of transdermal NTG as an alternative form of NTG delivery for inducing late PC, and (2) similar in nitrate-tolerant and -nontolerant rabbits, demonstrating that tolerance does not extend to the PC effects of NTG. Conclusions - In conscious rabbits, administration of NTG via either the IV or the transdermal route elicits a robust protective effect against infarction that lasts for 72 hours. The magnitude of NTG-induced cardioprotection is equivalent to that observed during the late phase of ischemic PC and is not affected by the development of tolerance. These findings reveal a new action of nitrates and support novel applications of these drugs for protecting the ischemic myocardium in patients.

DOI： 10.1161/hc3201.092218

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We investigated whether activation of A1 or A3 adenosine receptors (ARs) induces late preconditioning (PC) against infarction in conscious rabbits using the selective AR agonists 2-chloro-N6-cyclopentyladenosine (CCPA) and N6-3-iodobenzyladenosine-5′-N-methylcarboxamide (IB-MECA). In vitro radioligand binding and cAMP assays demonstrated CCPA to be ≈200- to 400-fold selective for the rabbit A1AR and IB-MECA to be ≈20-fold selective for the rabbit A3AR. We observed that (1) pretreatment of rabbits 24 hours earlier with CCPA (100 μg/kg IV bolus) or IB-MECA (100 or 300 μg/kg) resulted in an ≈35% to 40% reduction in the size of the infarct induced by 30 minutes of coronary artery occlusion and 72 hours of reperfusion compared with vehicle-treated rabbits, whereas pretreatment with the selective A2AAR agonist CGS 21680 (100 μg/kg) had no effect; (2) the delayed cardioprotective effect of CCPA, but not that of IB-MECA, was completely blocked by coadministration of the highly selective A1AR antagonist N-0861; (3) inhibition of nitric oxide synthase (NOS) with Nω-nitro-L-arginine during the 30-minute occlusion abrogated the infarct-sparing action of CCPA but not that of IB-MECA; and (4) inhibition of ATP-sensitive potassium (KATP) channels with sodium 5-hydroxydecanoate during the 30-minute occlusion blocked the cardioprotective effects of both CCPA and IB-MECA. Taken together, these results indicate that activation of either A1ARs or A3ARs (but not A2AARs) elicits delayed protection against infarction in conscious rabbits and that both A1AR- and A3AR-induced cardioprotection involves opening of KATP channels. However, A1AR-induced late PC uses an NOS-dependent pathway whereas A3AR-induced late PC is mediated by an NOS-independent pathway.

DOI： 10.1161/01.RES.88.5.520

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DR DIETRICH STEINKOPFF VERLAG  

The goal of this study was to determine whether the protective effects of the A3AR agonist N6-(3-iodobenzyl)adenosine-5′-N-methylcarboxamide (IB-MECA) against myocardial stunning are mediated by the A1AR. Six groups of conscious rabbits underwent a sequence of six 4-minute coronary occlusion (O)/4-minute reperfusion (R) cycles for three consecutive days (days 1,2, and 3). In vehicle-treated rabbits (group I), the recovery of systolic wall thickening (WTh) in the ischemic/reperfused region was markedly depressed on day 1, indicating the presence of severe myocardial stunning. On days 2 and 3, however, the recovery of systolic WTh was markedly accelerated, indicating the presence of late ischemic preconditioning (PC). When rabbits were pretreated with the A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA, 100 μg/kg i.v.) or with IB-MECA (100 μg/kg i.v.) 10 min prior to the first sequence of O/R cycles on day 1 (group III and V, respectively), the recovery of systolic WTh was markedly accelerated compared to vehicle-treated animals (reflected as an ∼48% decrease in the total deficit of systolic WTh). The magnitude of the protection afforded by adenosine receptor agonists was equivalent to that provided by late ischemic PC. Pre-treating rabbits with the A1AR antagonist N-0861 completely blocked both the hemodynamic and the cardioprotective effects of CCPA (group IV). However, the same dose of N-0861 did not block the cardioprotective actions of IB-MECA (group VI). Importantly, N-0861 did not influence the degree of myocardial stunning in the absence of PC (group II) and it did not block the development of late ischemic PC. Taken together, these results provide conclusive evidence that the cardioprotective effects of IB-MECA are not mediated via the A1AR, supporting the concept that activation of A3ARs prior to an ischemic challenge provides protection against ischemia/reperfusion injury.

DOI： 10.1007/s003950170031

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Recent studies have demonstrated that the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA) and the adenosine A3 receptor agonist N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA) produce a delayed phase of protection against infarction similar to the late phase of ischemic preconditioning (PC). However, the mechanism for adenosine A1 or A3 receptor-induced late PC remains unknown. The goal of this study was to determine whether the delayed cardioprotective effects of adenosine A1 or A3 receptors are mediated by cyclooxygenase-2 (COX-2), which is an obligatory mediator of ischemic PC. We found that COX-2 protein expression (Western blotting) did not increase 24 h after the administration of either CCPA (100 μg/kg iv) or IB-MECA (300 μg/kg iv) compared with controls. To probe the role of constitutive COX-2 expression, conscious rabbits were subjected to 30-min coronary occlusion followed by 72-h reperfusion. Twenty-four hours before the occlusion, the rabbits were pretreated with CCPA (100 μg/kg iv) or IB-MECA (300 μg/kg iv). Both CCPA and IB-MECA resulted in a marked (∼47%) reduction in infarct size vs. controls [36.2 ± 4.0% of the risk region (n = 9), 31.2 ± 4.7% (n = 9), and 59.5 ± 3.8% (n = 9), respectively; P < 0.05], similar to that induced by the late phase of ischemic PC [31.8 ± 3.2% (n = 9)]. The selective COX-2 inhibitor N-(2-[cyclohexyloxy]4-nitrophenyl)methanesulfonamide (NS-398, 5 mg/kg), which abolished the protective effect of ischemic late PC, failed to block the protection of either CCPA or IB-MECA, indicating that COX-2 does not mediate the delayed protection of either CCPA or IB-MECA [CCPA + NS-398, 29.1 ± 3.4% (n = 7); IB-MECA + NS-398, 34.9 ± 2.9% (n = 8)]. NS-398 in itself did not affect infarct size [54.9 ± 3.7% (n = 9)]. Taken together, these results demonstrate that, in contrast to ischemia-induced late PC, the mechanisms of adenosine A1 or A3 receptor-induced late PC is independent of COX-2.

DOI： 10.1152/ajpheart.2001.281.2.h959

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It is unknown whether late preconditioning (PC) enhances the recovery of left ventricular (LV) function after a myocardial infarction. Thus 25 conscious rabbits were subjected to a 30-min coronary occlusion followed by 28 days of reperfusion after PC 24 h earlier with either ischemia or nitric oxide donor administration [S-nitroso-N-acetylpenicillamine (SNAP)]. The recovery of wall thickening (WTh) after reperfusion was significantly improved in the ischemic PC and SNAP PC groups compared with controls, both at rest and during dobutamine stress. Interestingly, neither ischemia- nor SNAP-induced late PC attenuated myocardial stunning from day 1 through day 14. Infarct size was smaller in the ischemic PC and SNAP PC groups compared with controls. In all groups, WTh at 28 days was positively and linearly related to the percentage of viable tissue in the region underlying the ultrasonic crystal (r = 0.90), indicating that the improvement in LV function after both ischemia-induced and NO donor-induced late PC can be fully explained by the reduction in infarct size; a separate effect of late PC on LV remodeling or LV contractility need not be invoked. In conclusion, in conscious rabbits late PC, induced either by ischemia or pharmacologically, not only limits infarct size but also enhances the recovery of LV function after myocardial infarction. This finding has important clinical implications and provides triphenyltetrazolium chloride-independent evidence that late PC limits myocellular death after sustained ischemia.

DOI： 10.1152/ajpheart.2000.279.5.h2372

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Language：Japanese   Publisher：(一社)日本循環器病予防学会  

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Language：Japanese   Publisher：(株)総合医学社  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

多摩地域で糖尿病診療に関心をもつ内科医を対象に、「糖尿病と慢性腎臓病(CKD)」に関するアンケート調査を2007年、2015年、2019年に実施し、得られたデータを糖尿病の専門性の有無で比較した。質問項目はCKDの認知度、「CKD診療ガイド(ライン)」の認知度、CKDでは心血管疾患リスクも高くなることへの認知度、CKD診療への参画に対する考え方、腎臓専門医との併診についての考え方の計5項目であった。内科医は2007年92人、2015年117人、2019年58人で、「日本糖尿病学会員」または「会員ではないが糖尿病が専門・準専門」を専門医とし、「専門ではないが関心はある」または「あまり関心がない」を非専門医とした。その結果、「CKD診療ガイド(ライン)」の認知度、CKD診療への参画や腎臓専門医との併診への積極性における専門医と非専門医との有意差は、2019年に認めなくなった。他の項目はいずれの年も有意差を認めなかった。

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Language：Japanese   Publisher：(株)じほう  

＜Points＞▼ジギタリスは、心収縮力増強作用と心拍数減少作用をもち、心房細動では房室伝導を遅延させ心拍数(心室レート)を減少させる。▼ジギタリスの心拍数減少作用は、労作時の心拍数上昇を抑え切れない。▼心房細動に対する心拍数調節の第一選択薬はβ遮断薬であり、ジギタリスは効果不十分の場合に補助的に使用する。▼ジギタリス使用例で死亡率が高いのは、ジギタリス自体より、投与に至る背景疾患や血中濃度によるところが大きい。(著者抄録)

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Language：Japanese   Publisher：(株)じほう  

＜Points＞▼ジギタリスは、心収縮力増強作用と心拍数減少作用をもち、心房細動では房室伝導を遅延させ心拍数(心室レート)を減少させる。▼ジギタリスの心拍数減少作用は、労作時の心拍数上昇を抑え切れない。▼心房細動に対する心拍数調節の第一選択薬はβ遮断薬であり、ジギタリスは効果不十分の場合に補助的に使用する。▼ジギタリス使用例で死亡率が高いのは、ジギタリス自体より、投与に至る背景疾患や血中濃度によるところが大きい。(著者抄録)

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞Point ・生体弁は非弁膜症性心房細動.・リスク評価はCHADS2スコアを基本とする.・CHADS2スコア1点以上はDOACを推奨,ワルファリンを考慮.・PT-INRは年齢によらず1.6〜2.6を目標とし,できるだけ2に近付ける.

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J00679&link_issn=&doc_id=20191213150006&doc_link_id=20191213150005&url=http%3A%2F%2Fsearch.jamas.or.jp%2Flink%2Fbc%2F20191213150005&type=jamaslink&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F99999_1.gif

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Language：Japanese   Publisher：The Medical Association of Nippon Medical School  

<p>Hypertension is a well-known risk factor for cardiovascular diseases. In addition, since hypertension is associated with the development of electrical and structural remodeling of atrial myocardium, control of blood pressure (BP) is important to prevent new-onset atrial fibrillation (AF). In patients presenting with AF during anticoagulation therapy, hypertension is a risk factor for both thromboembolism and hemorrhagic complications, especially intracranial hemorrhage (ICH). Therefore, strict BP control is required to reduce, or at least not to increase, the risk of both events. In the Japanese Guidelines for the Management of Hypertension 2014 (JSH2014), a BP of less than 130/80 mmHg is currently recommended to reduce the risk of ICH, based on the results of the Bleeding with Antithrombotic Therapy (BAT) study. However, because the BAT study was observational and included patients without AF, a true appropriate target BP for patients with AF during anticoagulation therapy remains uncertain. Therefore, we have reviewed the influence of hypertension and BP control on adverse outcomes in the subanalyses of the J-RHYTHM Registry, the Fushimi AF Registry, and the phase III clinical trials of non-vitamin K antagonist oral anticoagulants (NOACs). In the J-RHYTHM Registry, hypertension was an independent risk factor for major hemorrhage (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.05~2.21). The BP at baseline was not associated with any event, whereas the highest quartile of systolic BP (≥136 mmHg) at the time closest to the event or at the end of the follow-up was significantly associated with the incidence of thromboembolism (odds ratio [OR] 2.88, 95% CI 1.75~4.74) and major hemorrhage (OR 1.61, 95% CI 1.02~2.53). In the Fushimi AF Registry, although hypertension was not a significant risk for any event, the incidence of stroke/systemic embolism (SE) and major bleeding was significantly higher in patients with uncontrolled hypertension (systolic BP ≥150 mmHg) than in those without hypertension (HR 1.74, 95% CI 1.08~2.53 for stroke/SE; HR 2.01, 95% CI 1.21~3.23 for major bleeding). In the phase III trials of NOACs, hypertension was significantly associated with major hemorrhage in the RE-LY trial and with stroke/SE in the ROCKET-AF and ARISTOTLE trials. Although no specific target BP could be determined from these studies, it is consistent that the incidence rates were higher in patients with uncontrolled hypertension than in those with controlled BP or without hypertension. A decrease in the risk of adverse events can be expected if BP is appropriately controlled in patients with AF during anticoagulation therapy.</p>

DOI： 10.1272/manms.15.12

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DOI： 10.11272/jssabst.44.0_S161_2

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心房細動の有病率は、人口の高齢化に伴い、我が国でも今後増加することが予想される。心房細動の主要な合併症は心原性脳梗塞であり、その予防には抗凝固療法が必要であるが、同時に出血合併症のリスクも増すため、両者を比較検討し、ネットクリニカルベネフィットが得られる治療を選択する必要がある。さらに、心房細動例は非心臓死を含めた死亡率が高いため、全死亡を含めたネットクリニカルアウトカムを念頭に置いたケアが必要である。(著者抄録)

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Language：Japanese   Publisher：(株)最新医学社  

心房細動の有病率は、人口の高齢化に伴い、我が国でも今後増加することが予想される。心房細動の主要な合併症は心原性脳梗塞であり、その予防には抗凝固療法が必要であるが、同時に出血合併症のリスクも増すため、両者を比較検討し、ネットクリニカルベネフィットが得られる治療を選択する必要がある。さらに、心房細動例は非心臓死を含めた死亡率が高いため、全死亡を含めたネットクリニカルアウトカムを念頭に置いたケアが必要である。(著者抄録)

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メトホルミン投与例におけるヨード造影剤使用後の腎機能変化を検討するため、ヨード造影剤を使用した217例(年齢69±13歳、男149女68)を検査前48時間以内のメトホルミン服用有無別に2群に分けた(メトホルミン使用群19例、未使用群198例)。ヨード造影剤使用後の腎機能は両群とも悪化は認めず、メトホルミン使用群では有意に推算糸球体濾過量(estimated glomerular filtration rate:eGFR)が上昇した(59.5±16.7→64.2±15.5mL/min/1.73m2、p=0.003)。多変量解析の結果、メトホルミン使用がヨード造影剤使用後の腎機能に対して改善方向の独立因子であった(β=0.141、p=0.043)。両群ともヨード造影剤使用前の腎機能が良好で、ヨード造影剤使用量が少量かつ十分な輸液を実施したためと考えられた。本研究より、適切な管理を実施した低リスク例では、メトホルミン投与はヨード造影剤使用時に腎機能を悪化させない可能性が示唆された。(著者抄録)

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Other Link： http://search.jamas.or.jp/link/ui/2017287725

Language：Japanese   Publisher：(株)医学書院  

＜Point＞DOACとワルファリンは,目的は同じだが作用機序に大きな違いがある.トロンビン阻害薬と第Xa因子阻害薬は,臨床的には大きな差はないが,ダビガトランには中和薬がある.第Xa因子阻害薬間の有効性・安全性に大きな差はない.(著者抄録)

DOI： 10.11477/mf.1438200069

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心原性脳梗塞の予防には、早期に心房細動を見つけ出し、適切な抗凝固療法を実施することが重要である。国際的な第III相臨床試験では、直接作用型経口抗凝固薬(DOAC)の脳卒中抑制効果はワルファリンと同等以上で、頭蓋内出血は有意に低率であった。心原性塞栓症の予防薬、臨床試験とリアルワールドデータ、各国のガイドラインにおける抗血栓療法、心原性塞栓症予防における抗血小板薬の位置づけ、DOACのリアルワールドエビデンスについて概説した。

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I:日本糖尿病学会員、II:会員ではないが糖尿病が専門・準専門、III:専門ではないが関心がある、IVあまり関心がない、により、それぞれ専門医(I+II)と非専門医(III+IV)の2群に分けた。2005年が専門医37名、非専門医63名、2014年が専門医34名、非専門医89名であった。2005年に比べて2014年は両群ともメタボリックシンドローム(MS)の診療基準に基づいた診療を行っているという回答が増加したが、特定検診以外ではウエスト周囲長は殆ど測定しないとの回答が増加した。実際に指導する項目において、2014年の体重測定の指導率は、2005年と比べて専門医で4%上昇、非専門医で10%低下した。家庭血圧測定の指導率は、2014年に専門医で19%、非専門医で11.6%上昇した。食事指導において、塩分制限の実施方針では、両群ともに7g・10g以下の回答が減り、6g以下の回答が増えた。専門医でよリエネルギー制限が厳しいが、両群・両年とも標準体重1kgあたり30kcalの1800kcal/日の回答が多かった。コレステロール制限の実施方針では、両群とも制限が緩和され、行わないが増えた。

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<p></p>

DOI： 10.5105/jse.37.161

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：ELSEVIER IRELAND LTD  

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J-GLOBAL

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Language：Japanese   Publisher：(NPO)日本糖尿病情報学会  

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Language：Japanese   Publisher：(株)メディカルトリビューン  

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Language：Japanese   Publisher：(一社)日本循環器病予防学会  

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Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/hr.2015.41

Web of Science

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PubMed

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Language：Japanese   Publisher：(株)東京医学社  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：Japanese   Publisher：(一社)日本老年医学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本不整脈心電学会  

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Language：Japanese   Publisher：(一社)日本不整脈心電学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：日本臨床生理学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：Japanese   Publisher：日本成人病(生活習慣病)学会  

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