論文 - 海北 幸一
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Tokitsu T., Yamamoto E., Oike F., Hirata Y., Tsujita K., Yamamuro M., Kaikita K., Hokimoto S.
Journal of Hypertension 36 ( 3 ) 560 - 568 2018年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Hypertension
Background: Although pulse-wave velocity (PWV) is a recognized risk predictor for cardiovascular diseases, its association with cardiovascular outcomes in heart failure with preserved left ventricular ejection fraction (HFpEF) is unclear. Methods and results: The 502 patients with HFpEF finally enrolled in this study (mean follow-up duration: 1017 days) were divided into those with or without peripheral artery disease (PAD). The latter were further grouped according to brachial-Ankle PWV (baPWV) quintiles using an ankle-brachial pressure index device. Kaplan-Meier analysis revealed a significantly higher risk of all-cause mortality and total cardiovascular events (both P = 0.01) in HFpEF patients with than without PAD. Multivariate Cox hazard analysis, including predictors identified as significant by simple Cox hazard analysis, identified PAD as a significant and independent predictor of cardiovascular events (hazard ratio: 1.85; 95% confidence interval: 1.01-3.39; P = 0.04). In an analysis of HFpEF patients without PAD grouped according to baPWV quintiles, estimated glomerular filtration rate (r = 0.21, P < 0.01) and hemoglobin (r = 0.18, P = 0.01) levels correlated negatively with baPWV. In the Kaplan-Meier analysis, patients with a baPWV more than 1900 cm/s and those with the lowest baPWV (<1300 cm/s) had a significantly higher frequency of total cardiovascular events than patients with 1300 baPWV or less which is less than 1900, indicating a J-shaped association between baPWV and total cardiovascular events as well as similarities to HFpEF patients with PAD. By contrast, the lowest baPWV group had the highest risk of heart failure-related events, accompanied by the highest brain natriuretic peptide levels. Conclusion: Identifying complications of PAD and measuring baPWV values in HFpEF patients can improve risk stratification.
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Nishihara T., Oda S., Sueta D., Izumiya Y., Kaikita K., Tsujita K., Utsunomiya D., Nakaura T., Yamashita Y.
Circulation: Cardiovascular Imaging 11 ( 2 ) e007277 2018年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Circulation: Cardiovascular Imaging
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Yamabe H., Kaikita K., Matsumura T., Iwasa A., Koyama J., Uemura T., Morikami Y., Tsunoda R., Morihisa K., Fujimoto K., Kajiwara I., Matsui K., Tsujita K., Ogawa H.
Journal of Cardiology 71 ( 2 ) 129 - 134 2018年2月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of Cardiology
Background Experimental studies suggest that angiotensin II-receptor blockers can influence atrial remodeling and may prevent atrial fibrillation (AF). Therefore, we hypothesized that irbesartan may prevent the recurrence of AF following either catheter ablation or electrical cardioversion of AF. Methods Study on the Effect of Irbesartan on Atrial Fibrillation Recurrence in Kumamoto (SILK study) is a prospective, multicenter, randomized, and open-label comparative evaluation of the effects of irbesartan and amlodipine on AF recurrence in hypertensive patients with AF who are scheduled to undergo catheter ablation or electrical cardioversion of AF. The primary end point was either AF or atrial tachycardia (AT) recurrence. AF/AT recurrence was evaluated for 6 months using 24-h Holter electrocardiogram and portable electrocardiogram. The secondary endpoints included the change in blood pressure, the interval from the procedure to the first AF/AT recurrence, cardiovascular events, left atrial diameter (LAD), left ventricular ejection fraction (LVEF), and changes in the biomarkers [brain natriuretic polypeptide (BNP), high-sensitivity C-reactive protein (hs-CRP), urinary albumin/creatinine]. Results The study enrolled 98 patients (irbesartan; n = 47, amlodipine; n = 51). The recurrence of AF/AT was observed in 8 patients (17.0%) in the irbesartan group and in 10 patients (19.6%) in the amlodipine group. There was no significant difference in the AF/AT recurrence between the irbesartan and amlodipine groups. Blood pressure decreased similarly in both groups. There were no significant differences between the two groups as regards to the interval from the procedure to the first AF/AT recurrence, occurrence of cardiovascular events, changes in LAD and LVEF. BNP and urinary albumin/creatinine significantly decreased similarly in both groups, but no significant difference was found in hs-CRP between the two groups. Conclusions In hypertensive patients with AF, treatment with irbesartan did not have any advantage over amlodipine in the reduction of AF/AT recurrence after catheter ablation or electrical cardioversion.
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Onoue Y., Izumiya Y., Hanatani S., Ishida T., Arima Y., Yamamura S., Kimura Y., Araki S., Ishii M., Nakamura T., Oimatsu Y., Sakamoto K., Yamamoto E., Kojima S., Kaikita K., Tsujita K.
Circulation Journal 82 ( 11 ) 2905 - 2912 2018年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Circulation Journal
Background: Resistance exercise has beneficial effects for patients with peripheral arterial diseases. The hypothesis that muscle growth promotes angiogenesis by interacting with neighboring cells in ischemic lesions was assessed. Methods and Results: Skeletal muscle-specific inducible Akt1 transgenic (Akt1-TG) mice that induce growth of functional skeletal muscles as a model of resistance training were used. Proteomics analysis identified significant upregulation of heme oxigenase-1 (HO-1) in muscle tissue in Akt1-TG mice compared with control mice. Blood flow recovery after hindlimb ischemia was significantly increased in Akt1-TG mice compared with control mice. Enhanced blood flow and capillary density in Akt1-TG mice were completely abolished by the HO-1 inhibitor, Tin-mesoporphyrin. Immunohistochemistry showed that HO-1 expression was not increased in muscle cells, but it was increased in macrophages and endothelial cells. Consistent with these findings, blood flow recovery after hindlimb ischemia was similar between control mice and skeletal muscle-specific HO-1-knockout mice. Adenoviral-mediated overexpression of Akt1 did not increase HO-1 protein expression in C2C12 myotubes; however, the conditioned medium from Akt1-overexpressing C2C12 myotubes increased HO-1 expression in endothelial cells. Cytokine array demonstrated that a panel of cytokine secretion was upregulated in Akt1-overexpressing C2C12 cells, suggesting paracrine interaction between muscle cells and endothelial cells and macrophages. Conclusions: Akt1-mediated muscle growth improves blood flow recovery after hindlimb ischemia by enhancing HO-1 expression in neighboring cells.
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Shirahama R., Ono T., Nagamatsu S., Sueta D., Takashio S., Chitose T., Fujisue K., Sakamoto K., Yamamoto E., Izumiya Y., Kaikita K., Hokimoto S., Hori M., Harada-Shiba M., Kajiwara I., Ogawa H., Tsujita K.
Internal Medicine 57 ( 24 ) 3551 - 3557 2018年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Internal Medicine
The low-density lipoprotein-cholesterol (LDL-C) level of a 38-year-old man diagnosed with acute coronary syndrome was 257 mg/dL. The administration of a proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody in addition to rosuvastatin plus ezetimibe was initiated, reducing his LDL-C level to 37 mg/dL. A genetic analysis revealed both an LDL receptor (LDLR) mutation and a PCSK9 V4I mutation. Nine months after revascularization, intravascular ultrasound revealed plaque regression in the coronary arteries. LDLR/PCSK 9 mutation carriers are prone to coronary artery disease. Intensive LDL-C lowering by including PCSK9 antibody was associated with coronary plaque regression, suggesting the expectation of prognosis improvement.
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Sueta D., Kaikita K., Okamoto N., Yamabe S., Ishii M., Arima Y., Ito M., Oimatsu Y., Mitsuse T., Iwashita S., Nakamura E., Hokimoto S., Mizuta H., Ogawa H., Tsujita K.
Circulation Journal 82 ( 2 ) 524 - 531 2018年
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Circulation Journal
Background: The pharmacological advantage of combining physiotherapy with anticoagulants for the prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) is not fully known. Herein we investigated the potential benefit of this combination therapy in patients undergoing TKA. Methods and Results: The 38 patients were randomly assigned to a physiotherapy group (n=19) or a physiotherapy plus 30 mg/day edoxaban group (n=19). The occurrence of VTE was evaluated, as were serial changes in parameters measured by the Total Thrombus-formation Analysis System, a novel system for quantitatively analyzing thrombus formation using microchips with throm-bogenic surfaces (collagen plus tissue factor, atheroma [AR]-chip). Combination therapy significantly reduced the incidence of VTE after TKA compared with monotherapy (P=0.038). The area under the curve (AUC) of thrombus formation for the AR-chip (AR -AUC ) was significantly lower in the combination group (P=0.001) on Day 7 after TKA than before TKA, but no significant change was observed with monotherapy (P=0.809). In 13 VTE-positive patients, AR -AUC was significantly lower in the combination group (n=3) than in the monotherapy group (n=10) on Day 7 (P=0.045). Conclusions: The combination of physiotherapy and edoxaban significantly reduced the incidence of VTE after TKA compared with physiotherapy alone. However, it is possible that VTE occurrence after TKA is not only associated with thrombogenicity, but also rheological factors. 10 30 10 30
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Kaikita K., Yoshimura H., Ishii M., Kudoh T., Yamada Y., Yamamoto E., Izumiya Y., Kojima S., Shimomura H., Tsunoda R., Matsui K., Ogawa H., Tsujita K.
Circulation Journal 82 ( 6 ) 1517 - 1525 2018年
担当区分：筆頭著者, 責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Circulation Journal
Background: Patients with reduced-function CYP2C19 genotypes on dual antiplatelet therapy (DAPT) with aspirin and clopidogrel show higher clinical risk for acute myocardial infarction (AMI). We investigated the effect of CYP2C19 genotype-tailored adjunctive cilostazol therapy on treatment of AMI. Methods and Results: The study group of 138 patients with suspected AMI were screened for CYP2C19 genotype immediately after percutaneous coronary intervention (PCI) using a SPARTAN RX point-of-care device. Carriers of the CYP2C19 reducedfunction allele were randomized into DAPT (Carrier/DAPT) and DAPT plus 14-day cilostazol (Carrier/DAPT+Cilostazol) groups, while noncarriers were treated with DAPT (Noncarrier/DAPT). After exclusion of 10 patients, the remaining 128 patients were analyzed for P2Y12 reaction unit (PRU) using VerifyNow® P2Y12 system, and levels of biomarkers immediately after, and 1, 14, and 28 days after PCI. DAPT+Cilostazol reduced PRU levels in carriers (n=46) to those found in the Noncarrier/DAPT group (n=40), and significantly lower than those of the Carrier/DAPT group (n=42) at 14 days post-PCI. Discontinuation of cilostazol for 14 days was associated with a significant rise in PRU levels to those of the Carrier/DAPT group at 28 days post-PCI. Plasma B-type natriuretic peptide levels at 14 days post-PCI were lower in Carrier/DAPT+Cilostazol than in the other 2 groups, and the levels increased to those of the other groups at 28 days post-PCI after withdrawal of cilostazol. Conclusions: Adjunctive cilostazol therapy tailored to CYP2C19 genotype seemed useful in AMI patients with the CYP2C19 reduced-function allele.
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Disease on clinical outcomes after percutaneous coronary intervention for chronic total occlusions: A Japanese multicentre registry 査読あり
Naganuma T＊, Tsujita K, Mitomo S, Ishiguro H, Basavarajaiah S, Sato K, Kobayashi T, Obata J, Nagamatsu S, Yamanaga K, Komura N, Sakamoto K, Miyazaki T, Yamamoto E, Izumiya Y, Kojima S, Kaikita K, Hokimoto S, Ogawa H
Am J Cardiol 121 1519 - 1523 2018年
記述言語：英語 掲載種別：研究論文（学術雑誌）
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Direct Oral Anticoagulants Form Thrombus Different from Warfarin in a Microchip Flow Chamber System 査読あり
Ishii M., Kaikita K., Ito M., Sueta D., Arima Y., Takashio S., Izumiya Y., Yamamoto E., Yamamuro M., Kojima S., Hokimoto S., Yamabe H., Ogawa H., Tsujita K.
Scientific Reports 7 ( 1 ) 7399 2017年12月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Scientific Reports
Direct oral anticoagulants (DOACs) have low risk of intracranial hemorrhage compared to warfarin. We sought to clarify the different mechanisms responsible for suppression of bleeding events using the Total Thrombus-formation Analysis System (T-TAS), a flow-microchip chamber with thrombogenic surfaces. Blood samples were obtained at Off- and On-anticoagulant (trough) from 120 consecutive patients with atrial fibrillation (warfarin; n = 29, dabigatran; n = 19, rivaroxaban; n = 47, apixaban; n = 25), which were used for T-TAS to compute the area under the curve (AUC) (AR -AUC ) in the AR chip, and to measure plasma concentrations of DOACs at On-anticoagulant. In addition, the two-dimensional area covered by thrombi (%) in the capillary was analyzed every 3 minutes after sample applications. The AR -AUC correlated weakly and negatively with plasma concentrations of DOACs, and the levels at On-anticoagulant were lower in all groups than at Off-anticoagulant. AR -AUC levels at Off- and On-anticoagulant were identical among the groups. The thrombi areas in early phase were significantly larger in rivaroxaban and apixaban than warfarin and dabigatran groups. The findings suggested that visual analysis of the AR-chip can identify the differential inhibitory patterns of warfarin and DOACs on thrombus formation under flow condition. 10 30 10 30 10 30
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Ishii M., Kaikita K., Sato K., Sueta D., Fujisue K., Arima Y., Oimatsu Y., Mitsuse T., Onoue Y., Araki S., Yamamuro M., Nakamura T., Izumiya Y., Yamamoto E., Kojima S., Kim-Mitsuyama S., Ogawa H., Tsujita K.
JACC: Basic to Translational Science 2 ( 6 ) 655 - 668 2017年12月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：JACC: Basic to Translational Science
LCZ696 (sacubitril/valsartan) can lower the risk of cardiovascular events in chronic heart failure. However, it is unclear whether LCZ696 can improve prognosis in patients with acute myocardial infarction (MI). The present study shows that LCZ696 can prevent cardiac rupture after MI, probably due to the suppression of pro-inflammatory cytokines, matrix metalloproteinase-9 activity and aldosterone production, and enhancement of natriuretic peptides in mice. These findings suggest the mechanistic insight of cardioprotective effects of LCZ696 against acute MI, resulting in the belief that LCZ696 might be useful clinically to improve survival after acute MI.
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Tabata N., Yamamoto E., Hokimoto S., Yamashita T., Sueta D., Takashio S., Arima Y., Izumiya Y., Kojima S., Kaikita K., Matsui K., Fujimoto K., Sakamoto K., Shimomura H., Tsunoda R., Hirose T., Nakamura N., Sakaino N., Nakamura S., Yamamoto N., Matsumura T., Kajiwara I., Koide S., Sakamoto T., Nakao K., Oshima S., Tsujita K., Hanatani S., Fujisue K., Horio E., Morihisa K., Nishijima T., Noda K., Nagano M., Fukunaga T., Taguchi E., Miyamoto S., Katayama T., Matsubara J., Matsukawa M., Miyao Y., Ogura Y., Kudo T., Yamada Y., Usuku H., Yoshimura H., Fuchigami S., Ikemoto T., Ito T., Uemura T., Kurokawa H., Maruyama H., Sato K., Yamanaga K., Nakamura S., Chitose T., Ono T., Abe K., Doi H., Miyazaki T., Miura M., Okuyama E., Kikuta K., Kusaka H., Kuroki K., Fukushima R., Tayama S., Rokutanda T., Hanaoka Y.
Journal of the American Heart Association 6 ( 8 ) 2017年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of the American Heart Association
Background--The CHADS score has mainly been used to predict the likelihood of cerebrovascular accidents in patients with atrial fibrillation. However, increasing attention is being paid to this scoring system for risk stratification of patients with coronary artery disease. We investigated the value of the CHADS score in predicting cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. Methods and Results--This was a multicenter, observational cohort study. The subjects had been admitted to one of the participating institutions with coronary artery disease requiring percutaneous coronary intervention. We calculated the CHADS scores for 7082 patients (mean age, 69.7 years; males, 71.9%) without clinical evidence of atrial fibrillation. Subjects were subdivided into low- (0-1), intermediate- (2-3), and high-score (4-6) groups and followed for 1 year. The end point was a composite of cardiovascular/cerebrovascular death, nonfatal myocardial infarction, and ischemic stroke at 1-year follow-up. Rates of triple-vessel/left main trunk disease correlated positively with CHADS score categories. CHADS scores among single, double, and triple-vessel/left main trunk groups were 2 (1-2), 2 (1-3), and 2 (2-3), respectively (P < 0.001). A total of 194 patients (2.8%) had a cardiovascular/cerebrovascular event, and Kaplan-Meier analysis demonstrated a significantly higher probability of cardiovascular/cerebrovascular events in proportion to a higher CHADS score (log-rank test, P < 0.001). Multivariate Cox hazard analysis identified CHADS score (per 1 point) as an independent predictor of cardiovascular/cerebrovascular events (hazard ratio, 1.31; 95% CI, 1.17-1.47; P < 0.001). Conclusions--This large cohort study indicated that the CHADS score is useful for the prediction of cardiovascular/cerebrovascular events in coronary artery disease patients without atrial fibrillation. 2 2 2 2 2 2 2 2
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CYP2C19 variants and epoxyeicosatrienoic acids in patients with microvascular angina 査読あり
Akasaka T., Sueta D., Arima Y., Tabata N., Takashio S., Izumiya Y., Yamamoto E., Tsujita K., Kojima S., Kaikita K., Kajiwara A., Morita K., Oniki K., Saruwatari J., Nakagawa K., Hokimoto S.
IJC Heart and Vasculature 15 15 - 20 2017年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：IJC Heart and Vasculature
Background Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the impact of CYP2C19 polymorphisms and EETs on the patients with microvascular angina (MVA) caused by coronary microvascular dysfunction. Methods and results We examined CYP2C19 genotypes in patients with MVA (n = 81). MVA was defined as absence of coronary artery stenosis and epicardial spasms, and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. In MVA, the patients with CYP2C19 PM were 34.6% and high sense C-reactive protein (hs-CRP) levels in CYP2C19 PM were significantly higher than that of non-PM group (0.165 ± 0.116 vs. 0.097 ± 0.113 mg/dL, P = 0.026). Moreover, DHET levels in CYP2C19 PM were significantly lower than that of non-PM (10.4 ± 4.58 vs. 15.6 ± 11.1 ng/mL, P = 0.003 (11,12-DHET); 12.1 ± 3.79 vs. 17.3 ± 6.49 ng/mL, P = 0.019 (14,15-DHET)). Conclusions The decline of EET owing to CYP2C19 variants may affects coronary microvascular dysfunction via chronic inflammation.
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Yamamura S., Izumiya Y., Ishida T., Onoue Y., Kimura Y., Hanatani S., Araki S., Fujisue K., Sueta D., Kanazawa H., Takashio S., Usuku H., Sugamura K., Sakamoto K., Yamamoto E., Yamamuro M., Yasuda H., Kojima S., Kaikita K., Hokimoto S., Ogawa H., Tsujita K.
Heart and Vessels 32 ( 6 ) 708 - 713 2017年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Heart and Vessels
Wild-type transthyretin amyloidosis (ATTRwt) is often overlooked in elderly patients with left ventricular hypertrophy (LVH). Impaired atrial function, in addition to ventricular diastolic dysfunction, is one of the hallmarks of cardiac amyloidosis. Here, we assessed the hypothesis that atrial function evaluated by A-velocity in pulse Doppler echocardiography is useful to differentiate ATTRwt in elderly patients with LVH. We analyzed 133 consecutive patients who underwent tissue biopsy to rule out infiltrative cardiomyopathy in our institute. We excluded patients younger than 50 years, without LVH (LV thickness was less than 12 mm), with other types of cardiac amyloidosis and patients with chronic atrial fibrillation, and analyzed remaining 51 patients (ATTRwt: 16, non-ATTRwt: 35). ATTRwt patients were significantly older and had advanced heart failure compared with non-ATTRwt group. In echocardiography, E/A, E/e′, and relative wall thickness was significantly higher in ATTRwt group than non-ATTRwt group. A-velocity was significantly decreased in ATTRWT group compared with non-ATTRwt group (40.8 ± 20.8 vs. 78.7 ± 28.2 cm/s, p = 0.0001). Multivariate logistic analysis using eight forced inclusion models identified trans-mitral Doppler A-wave velocity was more significant factor of cardiac amyloidosis in ATTRwt. In receiver operating characteristic (ROC) analysis, the area under the curve (AUC) for A-wave velocity in discrimination between ATTRwt and non-ATTRwt were 0.86 (CI 0.76–0.96, p < 0.001). The cut-off value was 62.5 cm/s, and it yielded the best combination of sensitivity (69.7%) and specificity (87.5%) for prediction of amyloidosis. We concluded that reduced A-velocity predicts the presence of ATTRwt in elderly patients with LVH in sinus rhythm.
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Akasaka T., Sueta D., Tabata N., Takashio S., Yamamoto E., Izumiya Y., Tsujita K., Kojima S., Kaikita K., Matsui K., Hokimoto S.
Journal of the American Heart Association 6 ( 5 ) 2017年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of the American Heart Association
Background-Mean amplitude of glycemic excursion (MAGE) is commonly used to gauge the degree of glucose level fluctuations. MAGE plays a significant role in vascular endothelial dysfunction and cardiovascular events in patients with diabetes mellitus (DM), but its significance is not clear in non-DM patients. Thus, we examined the impact of MAGE and vascular endothelial dysfunction on clinical outcomes in non-DM patients with coronary artery disease. Methods and Results-We followed non-DM patients (n = 65) for 12 months who underwent percutaneous coronary intervention and assessed the relationship among MAGE, reactive hyperemia index (RHI) measured by reactive hyperemia peripheral arterial tonometry as endothelial function, and cardiovascular events. Cardiovascular events analyzed were cardiovascular death, myocardial infarction, unstable angina, and revascularizations. Compared with patients with MAGE < 65 mg/dL (normal glycemic excursions), the group with MAGE ≥ 65 mg/dL (high glycemic excursions) had significantly higher high-sensitivity C-reactive protein (0.10±0.11 mg/dL versus 0.18±0.13 mg/dL, P = 0.006) and lower RHI (0.64±0.21 versus 0.51±0.22, P = 0.035). The multivariable analysis identified high MAGE and low RHI ( ≤ 0.56) as risk factors associated with cardiovascular events (hazard ratio, 5.6; 95% RI, 1.72-18.4 [P = 0.004] versus hazard ratio, 4.5; 95% RI, 1.37-14.9 [P = 0.013]). When the prognosis was classified by combination with MAGE and RHI, the incidence of cardiovascular events was 46.7% (high MAGE+low RHI), 26.7% (high MAGE+high RHI), 20.0% (low MAGE+low RHI), and 6.6% (low MAGE+high RHI) in descending order (P = 0.014). Receiver operating characteristic curve analysis revealed that MAGE, RHI, and MAGE+RHI were each associated with cardiovascular events (area under the curve 0.780, 0.727, and 0.796, respectively). Conclusions-MAGE was associated with cardiovascular events in non-DM patients with coronary artery disease. Furthermore, the combination with MAGE and RHI was useful for further subdivision of the risk of cardiovascular events.
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Sueta D., Suyama K., Sueta A., Tabata N., Yamashita T., Tomiguchi M., Takeshita T., Yamamoto-Ibusuki M., Yamamoto E., Izumiya Y., Kaikita K., Yamamoto Y., Hokimoto S., Iwase H., Tsujita K.
Atherosclerosis 260 116 - 120 2017年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Atherosclerosis
Background and aims Lenvatinib (Lenvima ), an oral multi-kinase inhibitor, is effective in the treatment of differentiated thyroid carcinomas (DTCs). A severe adverse effect of lenvatinib is hypertension, thus limiting its use as an anti-cancer treatment. Although the pathogenesis of hypertension is generally assumed to involve microvascular bed reduction and an increase in peripheral vascular resistance due to a decrease in nitrogen oxide (NOx) production after vascular endothelial growth factor (VEGF) inhibition, the effects of hypertension on vascular endothelial function in actual patients remain unclear. Here, we examined how lenvatinib affects vascular endothelial function. Methods Ten consecutive DTC patients who did not take any cardiovascular agents were orally administered 24 mg of lenvatinib once daily. Using an EndoPAT2000 system, we used reactive hyperemia-peripheral arterial tonometry (RH-PAT) and evaluated vascular endothelial function on the basis of the RH-PAT index (RHI). We expressed the results as %RHI, which indicates the change compared with pretreatment levels. Additionally, we measured serum NOx and plasma VEGF concentrations pre- and post-treatment. Results All of the patients treated with lenvatinib exhibited significant hypertension; the %RHI levels were significantly decreased the day after treatment with lenvatinib. Furthermore, serum NOx and plasma VEGF concentrations were significantly decreased and increased, respectively, compared with pretreatment levels. These results indicate that hypertension induced by lenvatinib may be caused by a decrease in nitric oxide production, as a result of VEGF inhibition and impaired vascular endothelial function. Conclusions We provide the first demonstration that lenvatinib causes hypertension via vascular endothelial dysfunction in human subjects. ® ®
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Oimatsu Y., Kaikita K., Ishii M., Mitsuse T., Ito M., Arima Y., Sueta D., Takahashi A., Iwashita S., Yamamoto E., Kojima S., Hokimoto S., Tsujita K.
Journal of the American Heart Association 6 ( 4 ) 2017年4月
担当区分：責任著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Journal of the American Heart Association
BACKGROUND: Periprocedural bleeding events are common after percutaneous coronary intervention. We evaluated the association of periprocedural bleeding events with thrombogenicity, which was measured quantitatively by the Total Thrombus-formation Analysis System equipped with microchips and thrombogenic surfaces (collagen, platelet chip [PL]; collagen plus tissue factor, atheroma chip [AR]).
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Tabata N., Sueta D., Yamashita T., Utsunomiya D., Arima Y., Yamamoto E., Tsujita K., Kojima S., Kaikita K., Hokimoto S.
Hypertension Research 40 ( 4 ) 392 - 398 2017年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Hypertension Research
Little is known about the significance of asymptomatic intra-cranial lesions (ICL) identified by brain MRI in coronary artery disease (CAD) patients. Silent cerebral lesions are suggested to be associated with arterial stiffness in healthy subjects. We investigated whether subclinical ICL are associated with arterial stiffness and the prognosis in CAD patients without medical history of cerebrovascular diseases. We recruited CAD patients who required percutaneous coronary intervention (PCI), did not meet exclusion criteria, and agreed with MRI before PCI. Subjects were divided into two groups according to the presence of ICL of cerebral microbleeds or lacunar infarction. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). Clinical outcome was defined as a composite of cardiovascular death, non-fatal myocardial infarction, stroke, unstable angina and heart failure. In total, 149 patients underwent brain MRI. Patients with ICL (n=55) had significantly higher baPWV than those without ICL (1591-2204 vs. 1450-1956 cm per sec; P=0.009). A multivariate analysis showed that male sex (odds ratio (OR), 3.15; 95% confidence interval (CI), 1.38-7.20; P=0.006) and baPWV (OR, 1.001; 95% CI, 1.000-1.002; P=0.023) were predictors of ICL. In total, 12 patients experienced a cardiovascular event. The Kaplan-Meier analysis indicated a significantly higher incidence of cardiovascular events in patients with ICL (log-rank test: P=0.018). Multivariate Cox proportional hazards analyses indicated that ICL finding was a significant predictor of clinical outcome (hazard ratio, 3.41; 95% CI, 1.02-11.5; P=0.047). Patients with subclinical ICL had a higher baPWV and worse prognoses than those without ICL.
DOI： 10.1038/hr.2016.159
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Sueta D., Ito M., Uchiba M., Sakamoto K., Yamamoto E., Izumiya Y., Kojima S., Kaikita K., Shinriki S., Hokimoto S., Matsui H., Tsujita K.
Thrombosis Journal 15 ( 1 ) 8 2017年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Thrombosis Journal
Background: Because the venous thromboembolisms (VTEs) due to the coagulation factor V R506Q (FV Leiden) mutation is often seen in Caucasians, the VTE onset in Japan has not been reported. Case presentation: A 34-year-old man from north Africa experiencing sudden dyspnea went to a hospital for advice. The patient had pain in his right leg and a high plasma D-dimer level. A contrast-enhanced computed tomography scan revealed a contrast deficit in the bilateral pulmonary artery and in the right lower extremity. The patient was diagnosed with VTE, and anticoagulation therapy was initiated. Our targeted gene panel sequencing revealed that the occurrence of VTE was attributed to a presence of the FV Leiden mutation. Conclusions: This is the first report demonstrating VTE caused by the FV Leiden mutation in Japan.
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Sueta D., Hokimoto S., Sakamoto K., Akasaka T., Tabata N., Kaikita K., Honda O., Naruse M., Ogawa H.
International Journal of Cardiology 230 97 - 102 2017年3月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Cardiology
Background Malnutrition-Inflammation-Atherosclerosis (MIA) factors significantly and independently affect life prognosis of hemodialysis (HD) patients. We re-evaluated Japanese data, which have progressed ahead from a community-based observational study. The present study was designed to assess the contribution of these MIA factors to the mortality rate of Japanese HD patients in a community of 1.8 million people over a 36-month follow-up period. Methods and results A total of 5813 patients at 76 facilities were on maintenance HD in the Kumamoto Prefecture. Specifically, 4807 of these patients at 58 institutions were enrolled. Patients who exhibited lower serum albumin and higher serum C-reactive protein levels were defined as “malnourished” and “inflamed”, respectively, compared with the median values. Patients who underwent invasive procedures for atherosclerotic diseases were defined as “atherosclerotic”. The 36-month all-cause mortality rate in Japanese HD patients was 12.4%. This rate directly correlated with the number of MIA factors. The odds ratio of the all-cause mortality rate markedly and significantly increased as the number of factors increased. The presence of 3 MIA factors in HD patients was a significant predictor of mortality, as evidenced by a multivariate logistic regression analysis. Conclusions This study clearly demonstrated the close association between MIA syndrome and high mortality in Japanese HD patients. Early detection and the adjustment of MIA factors are mandatory.
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Hirakawa K., Yamamuro M., Uemura T., Takashio S., Kaikita K., Utsunomiya D., Nakayama M., Yamamoto E., Yamashita Y., Hokimoto S., Tsujita K.
International Journal of Cardiology 228 881 - 885 2017年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：International Journal of Cardiology
Backgrounds The relationship between microvascular dysfunction and plasma B-type natriuretic peptide (BNP) levels remains unclear in heart failure (HF) patients with cardiac fibrosis. Methods This study evaluated 55 consecutive non-ischemic HF patients in an effort to determine the relationship between endothelial independent coronary microvascular dysfunction and plasma BNP levels, as well as whether each measure is correlated with myocardial fibrosis. We evaluated plasma BNP levels in patients with stable HF. We used cardiac catheterization to measure trans-cardiac BNP release levels, measuring from the coronary sinus and the aortic root, and coronary flow reserve (CFR). Patients also underwent cardiac magnetic resonance imaging to evaluate for the presence of late gadolinium enhancement (LGE), as an indicator of cardiac fibrosis. Results CFR in cardiac catheterization was significantly and inversely correlated with plasma BNP levels (r = 0.336, p = 0.012) and trans-cardiac BNP release levels (r = 0.347, p = 0.041). Thirty-three patients were LGE-positive. CFR was significantly correlated with plasma BNP levels in the LGE-positive group (r = 0.349, p = 0.046), but this correlation was not significant in the LGE-negative group. (r = 0.338, p = 0.125). Multivariate logistic regression analysis revealed that a plasma BNP levels > 180 pg/ml at stable HF condition was significant and independent predictor of CFR < 2.5 in all patients (p = 0.035, odds ratio: 5.2, 95% confidence interval: 1.1–29.0), and in the LGE-positive group (p = 0.040, odds ratio: 5.4, 95% confidence interval: 1.1–27.2). Conclusions In non-ischemic HF patients especially those with cardiac fibrosis, endothelial independent microvascular dysfunction is closely correlated with plasma BNP levels, and ventricular wall tension.