Papers - KAIKITA Koichi
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Fujisue K., Nagamatsu S., Shimomura H., Yamashita T., Nakao K., Nakamura S., Ishihara M., Matsui K., Yamamoto N., Koide S., Matsumura T., Fujimoto K., Tsunoda R., Morikami Y., Matsuyama K., Oshima S., Sakamoto K., Izumiya Y., Kaikita K., Hokimoto S., Ogawa H., Tsujita K.
International Journal of Cardiology 268 23 - 26 2018.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Chronic kidney disease (CKD) deteriorates the prognosis of patients undergoing percutaneous coronary intervention (PCI). Because coronary artery disease (CAD) is the major cause of death in CKD patients, cardiovascular risk reduction has been clinically important in CKD. We hypothesized intensive lipid-lowering with statin/ezetimibe attenuated coronary atherosclerotic development even in patients with CKD. Methods: In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound (IVUS)-guided PCI were randomly assigned to receive atorvastatin/ezetimibe combination or atorvastatin alone (the dosage of atorvastatin was up-titrated to achieve the level of low-density lipoprotein cholesterol < 70 mg/dL). Serial volumetric IVUS findings obtained at baseline and 9–12 month follow-up to quantify the coronary plaque response in 202 patients were compared stratified by the presence or absence of CKD. Results: CKD was observed in 52 patients (26%) among 202 enrolled patients. Compared with the non-CKD group, the CKD group was significantly older (71.5 ± 8.6 years vs. 64.4 ± 9.6 years, P < 0.001) with similar prevalence of comorbid coronary risk factors and lipid profiles. Similar to the non-CKD group (−1.4 [−2.8 to −0.1]% vs. −0.2 [−1.7 to 1.0]%, P = 0.002), the atorvastatin/ezetimibe combination significantly reduced ∆PAV compared with atorvastatin alone even in the CKD group (−2.6 [−5.6 to −0.4]% vs. −0.9 [−2.4 to 0.2]%, P = 0.04). Conclusions: As with non-CKD, intensive lipid-lowering therapy with atorvastatin/ezetimibe demonstrated stronger coronary plaque regression effect even in patients with CKD compared with atorvastatin monotherapy. Trial registration: NCT01043380 (ClinicalTrials.gov).
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Hanatani S., Izumiya Y., Onoue Y., Tanaka T., Yamamoto M., Ishida T., Yamamura S., Kimura Y., Araki S., Arima Y., Nakamura T., Fujisue K., Takashio S., Sueta D., Sakamoto K., Yamamoto E., Kojima S., Kaikita K., Tsujita K.
International Journal of Cardiology 268 216 - 221 2018.10
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: Sarcopenia is frequently observed and associated with poor outcomes in patients with chronic kidney disease (CKD). A simple screening test for sarcopenia using age, grip strength, and calf circumference was recently developed. However, the clinical utility of this sarcopenia score in patients with CKD remains unclear. Methods and results: We calculated the sarcopenia score of 265 patients with CKD and followed the patients for cardiovascular events. The endpoint of this study was the composite of cardiovascular hospitalization and total mortality. We divided all participants into high (n = 166) and low (n = 99) sarcopenia score groups using a simple scoring system. Patients in the high sarcopenia score group showed significantly higher plasma B-type natriuretic peptide (BNP) levels than those in the low sarcopenia score group (median: 103.1, interquartile range: 46.3–310.0 vs. 46.7, 18.0–91.8 pg/mL; p < 0.0001). The Kaplan–Meier curve revealed that the risk of cardiovascular events was significantly greater in the high sarcopenia score group (log-rank test: p < 0.0001), even after potential confounding factors were corrected using propensity score matching. Multivariate Cox hazard analysis identified a high sarcopenia score (hazard ratio: 3.04, 95% confidence interval: 1.45–6.38, p = 0.003) as an independent predictor of the primary endpoints. Furthermore, the combination of a high sarcopenia score and high BNP level identified patients with a significantly higher probability of future events (p < 0.0001). Conclusions: This study demonstrates that this simple screening score for sarcopenia could be a useful tool for estimating the future adverse event risk in patients with CKD.
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Fujisue K., Shirakawa T., Nakamura S., Yamamoto N., Oshima S., Matsumura T., Tsunoda R., Hirai N., Tayama S., Nakamura N., Hirose T., Maruyama H., Fujimoto K., Kajiwara I., Sakamoto T., Nakao K., Sakaino N., Hokimoto S., Nagayoshi Y., Hokamaki J., Shimomura H., Sakamoto K., Yamamoto E., Izumiya Y., Kaikita K., Ogawa H., Tsujita K.
Journal of Cardiology 72 ( 4 ) 350 - 355 2018.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology
Background: Acute myocardial infarction (AMI) is mainly characterized by the rupture of lipid-rich vulnerable atherosclerotic plaque. The matrix metalloproteinases (MMPs) have been shown to play a critical role in inflammatory processes underlying plaque rupture. Some reports suggested statins inhibit the increased MMP levels after AMI. However, there are a few comparison studies between the different dosages of the same statin and circulating levels of MMPs. Purpose: This study will preliminarily investigate the potential effects of appropriate or low dose of rosuvastatin on circulating MMPs levels in AMI patients. Moreover, we will also obtain plasma from patients while undergoing diagnostic angiography to determine differences in various cardiac sites and peripheral vessels. Methods: This study is a multicenter, open-label, randomized, parallel-group study to be conducted to compare the appropriate or low dose of rosuvastatin in the effect on serum levels of inflammatory markers in AMI patients. The eligible patients undergoing percutaneous coronary intervention (PCI) will be randomly assigned to receive either appropriate or low-dose rosuvastatin daily using a web-based randomization software within 24 h after PCI. The low-dose group will be treated with rosuvastatin 2.5 mg once daily with a follow-up. The appropriate-dose group will begin treatment with rosuvastatin 5 mg once daily, and the dose of rosuvastatin will be titrated to 10 mg within 4 weeks. During administration of the study treatment, subjects will undergo laboratory testing including MMPs and be monitored for the occurrence of adverse events up to 24 weeks. The primary endpoint will be the change rate of MMPs at 24 weeks after administration. Conclusions: INVITATION will compare the appropriate or low dose of rosuvastatin in the effects on serum levels of inflammatory markers including MMPs in AMI patients. This study will provide significant information on rosuvastatin as an anti-inflammatory agent for AMI.
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Impact of current and past cancer history on the risk of cardiovascular events following percutaneous coronary intervention: a Kumamoto University Malignancy and Atherosclerosis (KUMA) study Reviewed
Tabata N, Sueta D＊, Yamamoto E, Takashio S, Arima Y, Araki S, Yamanaga K, Ishii M, Sakamoto K, Kanazawa H, Fujisue K, Hanatani S, Soejima H, Hokimoto S, Izumiya Y, Kojima S, Yamabe H, Kaikita K, Tsujita K
Eur Heart J - Qual Care Clin Outcomes 4 ( 4 ) 290 - 300 2018.10
Language：English Publishing type：Research paper (scientific journal)
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Nishihara T., Tokitsu T., Sueta D., Takae M., Oike F., Fujisue K., Usuku H., Takashio S., Hanatani S., Kanazawa H., Arima Y., Sakamoto K., Izumiya Y., Yamabe H., Kaikita K., Yamamoto E., Tsujita K.
American Journal of Hypertension 31 ( 10 ) 1098 - 1105 2018.9
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Hypertension
BACKGROUND Although serum potassium (sK) levels are closely associated with the prognosis of chronic heart failure patients, the clinical significance of sK levels in cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF) patients is not fully understood. METHODS This study was a retrospective, single-center, observational study. We enrolled 506 consecutive HFpEF patients admitted to Kumamoto University Hospital and divided them into four groups according to the quartiles of the sK levels at discharge (Q1: sK < 4.1 mEq/l, Q2: 4.1 ≤ sK < 4.4 mEq/l, Q3: 4.4 ≤ sK < 4.7 mEq/l, and Q4: sK ≥ 4.7 mEq/l). RESULTS No significant differences were observed in the use of all drugs (loop diuretics, mineralocorticoid receptor antagonists, renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, β-blockers, and statins) among the four groups. Hemoglobin, the estimated glomerular filtration rate, and pulse wave velocity levels were lower, and the serum sodium levels were higher in the Q4 group compared with those in the Q2 group. Kaplan-Meier analysis revealed significantly higher probabilities of both cardiovascular and HF-related events in the Q1, Q3, and Q4 groups than those in the Q2 group. Multivariate Cox proportional hazard analysis revealed that the Q1, Q3, and Q4 groups had significantly and independently higher probabilities of cardiovascular events compared with those in the Q2 group, indicating a J-shaped association between sK levels and cardiovascular events. CONCLUSIONS sK levels at discharge could provide important prognostic information in regard to HFpEF. Further evaluation in a larger number of patients might be needed. Clinical Trials Registration UMIN-CTR (http://www.umin.ac.jp/ctr/). Identifier UMIN000029600. Public Access Information Opt-out materials are available at the website: http://www.kumadai-junnai.com/home/wp-content/uploads/houkatsu.pdf.
DOI： 10.1093/ajh/hpy101
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Sueta D., Utsunomiya D., Izumiya Y., Nakaura T., Oda S., Kaikita K., Yamashita Y., Tsujita K.
Journal of Cardiology Cases 18 ( 3 ) 88 - 91 2018.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Cardiology Cases
Because the prognosis of pulmonary thromboembolism (PTE) will be often poor, early diagnosis and assessing severity at the first visit is important. A 76-year-old man with suspected venous thromboembolism and a contrast deficit in the pulmonary artery (PA) was revealed by contrast-enhanced computed tomography (CT) imaging by dual-layer spectral-detector CT (IQon Spectral CT , Philips Healthcare, Best, The Netherlands). The lung perfusion image showed decreased perfusion in the culprit lesion. The dual-energy analysis of the virtual monoenergetic imaging showed clear visualization of deep vein thrombosis (DVT). In a 64-year-old man, an IQon Spectral CT revealed a small contrast deficit in the PA. However, no perfusion abnormality was detected in the lung perfusion analysis. The IQon Spectral CT enables the detection of lung perfusion abnormalities in addition to PTE. The IQon Spectral CT imaging may be useful for the “one-stop shop” evaluation of PTE and DVT. <Learning objective: The prognosis of pulmonary thromboembolism (PTE) will be often poor, so early diagnosis and assessing severity at the first visit is important. The dual-layer spectral-detector computed tomography imaging for PTE, whereby the iodine map provided information regarding lung perfusion, whereas virtual monoenergetic images enabled clear visualization of deep vein thrombosis.> ® ® ® ®
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Yasuda S., Kaikita K., Ogawa H., Akao M., Ako J., Matoba T., Nakamura M., Miyauchi K., Hagiwara N., Kimura K., Hirayama A., Matsui K.
International Journal of Cardiology 265 108 - 112 2018.8
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Background: In atrial fibrillation (AF) patients with coronary artery disease (CAD), anticoagulants are commonly used in combination with antiplatelet drugs. However, dual therapy can increase the risk of bleeding, and the potential therapeutic benefits must be weighed against this. Therefore, it is recommended that dual therapy is only used for a limited time, and that monotherapy with anticoagulants should start from 1 year after percutaneous coronary intervention (PCI). However, there is a lack of evidence on the use of monotherapy, in particular with direct oral anticoagulants, in this group of patients. Methods: The AFIRE Study is a multicenter, prospective, randomized, open-label, parallel group study conducted in patients aged ≥20 years with non-valvular AF (NVAF) and CAD. Patients who have undergone PCI or coronary artery bypass graft at least 1 year prior to enrollment, or those without significant coronary lesions requiring PCI (≥50% stenosis), will be included. Approximately 2200 participants will be randomized to receive either rivaroxaban monotherapy or rivaroxaban plus an antiplatelet drug (aspirin, clopidogrel, or prasugrel). The primary efficacy endpoints are the composite of cardiovascular events (stroke, non-central nervous system embolism, myocardial infarction, and unstable angina pectoris requiring revascularizations) and all-cause mortality. The primary safety endpoint is major bleeding as defined by the International Society on Thrombosis and Haemostasis criteria. Conclusions: This study will be the first to assess the efficacy and safety of rivaroxaban monotherapy in NVAF patients with stable CAD.
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Shimokawa H., Yamashita T., Uchiyama S., Kitazono T., Shimizu W., Ikeda T., Kamouchi M., Kaikita K., Fukuda K., Origasa H., Sakuma I., Saku K., Okumura Y., Nakamura Y., Morimoto H., Matsumoto N., Tsuchida A., Ako J., Sugishita N., Shimizu S., Atarashi H., Inoue H.
International Journal of Cardiology 258 126 - 132 2018.5
Language：English Publishing type：Research paper (scientific journal) Publisher：International Journal of Cardiology
Aims: The EXPAND study examined the real-world efficacy and safety of rivaroxaban for the prevention of stroke and systemic embolism (SE) in Japanese patients with non-valvular atrial fibrillation (NVAF). Methods and results: This multicenter, prospective, non-interventional, observational, cohort study was conducted at 684 medical centers in Japan. A total of 7141 NVAF patients ≥20 years of age (mean, 71.6 ± 9.4 years) who were being or about to be treated with rivaroxaban (10 mg/day, 43.5%; 15 mg/day, 56.5%) were followed for an average of 897.1 (±206.8) days with a high follow-up rate (99.65%). The mean CHADS score at baseline was 2.1 (1.3) (0–1, 37%; 2, 29%; ≥3, 34%). The total incidence rate of symptomatic stroke and SE (primary efficacy endpoint) was 1.0%/year, and 0.5%, 0.9%, and 1.7%/year for those with CHADS scores of 0–1, 2, and ≥3, respectively. Cumulative incidence rates for major bleeding (primary safety endpoint) and non-major bleeding (secondary safety endpoint) were 1.2%/year and 4.9%/year, respectively. Differences were noted between new and current users only for major bleeding event rate (1.7% vs. 1.1%/year, P = 0.0024). Comparisons with previous studies suggested that rivaroxaban is effective and safe for low-risk patients (0–1 CHADS ), as shown for warfarin in the XANTUS international prospective post-marketing study. Conclusions: The EXPAND study demonstrated that low dosages of rivaroxaban for Japanese NVAF patients in real-world clinical practice, including those with CHADS scores 0–1, resulted in low rates of stroke and SE, and major and non-major bleeding. 2 2 2 2
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Nakayama M., Yamamuro M., Takashio S., Uemura T., Nakayama N., Hirakawa K., Oda S., Utsunomiya D., Kaikita K., Hokimoto S., Yamashita Y., Morita Y., Kimura K., Tamura K., Tsujita K.
Heart and Vessels 33 ( 4 ) 393 - 402 2018.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Heart and Vessels
Myocardial fibrosis and coronary endothelial dysfunction are important determinants of outcome in patients with heart failure. However, the relationship of these factors in patients with dilated cardiomyopathy (DCM) is not fully understood. This study aimed to investigate the relationship between endothelium-dependent coronary vasomotor abnormality and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) in patients with DCM. We examined 38 consecutive patients with DCM. All patients underwent CMR and the acetylcholine (ACh) provocation test using cardiac catheterization. During the ACh provocation test, we sampled blood simultaneously from the coronary sinus and aortic root to compare lactate concentrations, and quantified coronary blood flow volume using an intracoronary Doppler-tipped guidewire. LGE was detected in 17 (44.7%) patients. The lactate extraction ratio (LER) in the ACh provocation test was significantly decreased in the LGE-positive group (before vs after ACh, 18.6 ± 13.6 vs − 13.3 ± 24.8%; p < 0.001) and in the LGE-negative group (before vs after ACh, 14.2 ± 19.5 vs 3.3 ± 16.2%; p = 0.02). The rate of patients with an LER < 0% (indicating myocardial lactate production due to myocardial ischemia) was significantly higher in the LGE-positive group than in the LGE-negative group [12 (70.6%) vs 7 (33.3%); p = 0.02]. Multivariable logistic regression analysis showed that a post-ACh LER < 0% was a significant predictor of LGE positivity (odds ratio 7.75; 95% confidence interval 1.37–43.68; p = 0.02). In conclusion, ACh-provoked coronary vasomotor abnormality is associated with myocardial fibrosis in patients with DCM. These results suggest that coronary endothelial dysfunction is involved in myocardial fibrosis and worsening heart failure concomitant with DCM.
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Arima Y., Hokimoto S., Tabata N., Nakagawa O., Oshima A., Matsumoto Y., Sato T., Mukunoki T., Otani J., Ishii M., Uchikawa M., Yamamoto E., Izumiya Y., Kaikita K., Ogawa H., Nishiyama K., Tsujita K.
Journal of the American Heart Association 7 ( 6 ) 2018.3
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of the American Heart Association
BACKGROUND: Collateral arteries provide an alternative blood supply and protect tissues from ischemic damage in patients with peripheral artery disease. However, the mechanism of collateral artery development is difficult to validate. METHODS AND RESULTS: Collateral arteries were visualized using micro-x-ray computed tomography. Developmental characteristics were assessed using confocal microscopy. We conducted a single-center, retrospective, observational study and assessed the dilatation of collateral arteries on ischemic sides. We quantified the vascular volume in both ischemic and nonischemic legs. A prominent increase in vascular volume was observed in the ischemic leg using a murine hind-limb ischemia model. We also performed qualitative assessment and confirmed that the inferior gluteal artery functioned as a major collateral source. Serial analysis of murine hind-limb vessel development revealed that the inferior gluteal artery was a remnant of the ischial artery, which emerged as a representative vessel on the dorsal side during hind-limb organogenesis. We retrospectively analyzed consecutive patients who were admitted for the diagnosis or treatment of peripheral artery disease. The diameter of the inferior gluteal artery on the ischemic side showed significant dilatation compared with that on the nonischemic side. CONCLUSIONS: Our findings indicate that an embryonic remnant artery can become a collateral source under ischemic conditions. Flow enhancement in the inferior gluteal artery might become a novel therapeutic approach for patients with peripheral artery disease.
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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 2018.3
Language：English Publishing type：Research paper (scientific journal) Publisher：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 2018.2
Language：English Publishing type：Research paper (scientific journal) Publisher：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 2018.2
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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
Language：English Publishing type：Research paper (scientific journal) Publisher：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
Language：English Publishing type：Research paper (scientific journal) Publisher：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
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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
Authorship：Lead author, Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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 Reviewed
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
Language：English Publishing type：Research paper (scientific journal)
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Direct Oral Anticoagulants Form Thrombus Different from Warfarin in a Microchip Flow Chamber System Reviewed
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 2017.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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 2017.12
Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：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.